MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19  in the Israeli population

MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19 in the Israeli population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19 in the Israeli population Shay Ben Shachar, Noam Barda, Sigal Manor, Sapir Israeli, Noa Dagan, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-174593/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with Covid-19 severity. However, no clear association between HLA and Covid-19 incidence or severity has been reported. We conducted a large scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6,413 (8.8%) were found to have SARS-CoV-2 by PCR. a Total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups; A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization. We conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity. Immunology HLA SARS-CoV-2 association hospitalization Israel Ashkenazi Figures Figure 1 Figure 2 Figure 3 Research in Context A large number of small studies showing association between HLA and SARS-CoV-2 infection or Covid-19 outcome have been reported, including two very recent ones – “HLA-C* 04:01 is a Genetic Risk Allele for Severe Course of COVID-19”, and “The Search For An Association Of HLA Alleles And Covid-19 Related Mortality In The Russian Population”. All these studies propose associations, based on very small sample and a large number of tested HLA alleles. Given the importance of HLA for many infectious diseases, and the importance of the detection of risk factors for COVID, we built a very large sample of patients coupled with their HLA information to test the validity of the association claims. Indeed, in this very large sample and under proper statistical testing, no association was found with either infection or hospitalization. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic. Main text The Major Histocompatibility Complex (MHC) molecules are cell surface protein complexes encoded in the Human Leukocyte Antigens (HLA) locus. The HLA locus is highly polymorphic with thousands of different alleles and millions of haplotypes reported 1 2 . HLAs are associated with several infectious diseases. Previous disease association studies showed that some HLA haplotypes are highly correlated with multiple viral infections 3 , 4 , 5 and have been reported to confer differential susceptibility to infection and the severity of the resulting disease 6 . In particular, HLA class I alleles are key players in the immune defense against viruses as they initiate the activity of T cells against the invading intracellular pathogens 7 , 8 . Although presentation of viral antigens relies classically on MHC class I molecules, MHC class II genes have also been associated with the outcome of many viral infections 9 , 10 , 11 . Studies in a range of species 12 , 13 , 14 , 15 , including humans 16 , 17 , imply a heterozygous selection mechanism operating on the HLA loci as an explanation for the extensive variability of the MHC molecules 18 , 19 . However, recent results on human populations suggest that such an advantage may be limited 20 . In the context of Covid-19, specific HLAs have been associated with coronaviruses in the past, including SARS coronavirus infections 21 , 22 . Several efforts were made to identify HLA-related susceptibility to SARS-CoV-1 after the first SARS epidemic in East Asia 23 , 24 , 25 , 26 and the MERS-CoV outbreak in 2014 in Saudi Arabia 27 . Most of these case studies provided weak or conflicting results and required further validation due to the relatively small sample size. An association between the geographic distributions of Covid-19 and HLA alleles has been suggested 28 . Similarly, an association between severe disease outcome and specific HLAs was suggested by another small-scale whole-genome sequencing study 29 . In silico model raised the possibility that HLA supertypes may have a role in the severity of the disease 30 . Moreover, a reduced expression of human leukocyte antigen class DR (HLA-DR) was detected in peripheral blood mononuclear cells of Covid-19 patients 31 . Nevertheless, genome-wide association study (GWAS) among 1980 Italian and Spanish patients with severe Covid-19 detected a few loci associated with that state but no association with the HLA loci at chromosome 6 or heterozygote advantage was found 32 . However, another GWAS study analyzing 2244 critically-ill Covid-19 patients in the UK detected three variants in chromosome 6 but these variants were not replicated in other studies. Since population stratification in chromosome 6 (the major histocompatibility complex) is difficult to control, further studies will be required to determine whether these associations are real 33 . Two other large unpublished GWAS studies did not report a signal at the HLA locus on chromosome 6 34 , 35 . To the best of our knowledge there are no previous studies looking specifically at HLA subgroups among individuals with Covid-19. HLA allele and haplotype frequencies differ between populations belonging to different ethnic groups 36 , 37 . For example, among Jewish populations, similarities of HLA alleles may be seen within ethnicities, allowing an estimation of an individual's origin based on his HLA genotypes 38 . It has been estimated that decreased HLA variability may assist to detect signals relevant to a specific disease state. Indeed, specific HLAs were associated with different disorders in the Ashkenazi population, a large genetically isolated group 39 , 40 , 41 . Given the diversity of HLAs among populations, testing genetically isolated and genetically homogenous populations may provide an advantage in detecting the effects of specific genetic variants, in particular in Ashkenazi Jews. Our study aimed to utilize the presence of a large-scale cohort having HLA genotypes and a high rate of Covid-19 to test the possible role of specific HLA alleles in SARS-CoV-2 infection and its severity. Using a data set of this magnitude also allowed us to analyze associations between Covid-19 infection and HLA zygosity. Understanding how variation in HLA may affect both susceptibility and severity of Covid-19 infection could help to identify and stratify individuals at higher risk for the disease and may support future vaccination strategies. A case-control study with a test-negative design 42 was used to evaluate the infection outcome, while a retrospective cohort study was used to evaluate the hospitalization outcome. In the case-control design, patients tested positive or negative for SARS-CoV-2 were evaluated for their HLA alleles. In the cohort design, patients who were diagnosed with COVID-19 were followed-up to see who were hospitalized. The study was based on patient data taken from the data warehouse of Clalit Health Care (CHS), a large integrated payer-provider healthcare organization operating in Israel. CHS insures over 4.6 million Israelis (~50%), which are a representative sample of the entire population. HLA alleles were obtained from the Ezer Mizion Bone Marrow Donor Registry, which enlists the highest number of registered unrelated volunteer donors per capita in the world. The HLA resolution varies from serologic to DNA-based testing at low, intermediate, and allele resolution 43 . The initial analysis included HLA genotypes of 1,040,250 donors which represent all the populations composing the Ezer Mizion registry. High-resolution five-locus typing was imputed for all donors using GRIMM (GRaph IMputation and Matching for HLA Genotypes) 44 , which produces the most likely five-locus genotype consistent with the low-resolution typing and the self-defined ethnicity. For each subject in the dataset, we chose the unphased genotype with the highest probability. We also used the low resolution two-digit typing of each subject, as well as the homozygosity status of each allele. The study included all patients tested for SARS-CoV-2 by PCR that were members of CHS at the date of testing and had HLA data available. Cases were those patients tested positive, while controls were patients tested negative. Covariates for adjustment included age, sex, number of children in the household, population sector (ultra-orthodox vs. general, which has had an important impact on the epidemic in Israel), socioeconomic status, and ethnic origin (Ashkenazi vs. other). These covariates were extracted as of the test date. The number of children in the household was calculated based on CHS' demographic registry. The population sector was determined using the patient's primary-care clinic address. Socioeconomic status was determined based on a patient's home address. Patients were defined as Ashkenazi if they were Jewish and were born themselves or had at least one parent or 2 grandparents born in central or western Europe. A severe disease course was defined by hospitalization less than 2 weeks after the molecular diagnosis. The association between each HLA allele and the outcome, adjusted for the covariates listed above, was tested separately for each allele using logistic regression. Homozygosity was tested similarly, as a binary predictor, separately for each locus. Bonferroni correction was applied to the p-values and confidence intervals. The results were similar when the Benjamini-Hochberg false discovery rate was controlled 45 . Zygosity was computed based on two-digit HLA alleles at the appropriate locus. The study was performed with the approval of the Institutional Research Community (IRB) #0080-20-COM2). Overall, 72,912 individuals with HLA genotyping and at least one PCR test for Covid-19 were included in the study between March 1 st, 2020 and October 31th 2020. Of them, 8.8% (6,413) tested positive for SARS-CoV-2 by PCR. Demographic and socioeconomic data related to the population is available in Table 1. All HLA alleles were grouped by two-digit representations to minimize the number of tests, and only alleles with a frequency of at least 1 % were used. A total of 16 HLA-A, 20 HLA-B, 13 HLA-C, 5 HLA-DQB1, and 12 HLA-DRB1 (Table 2) met the criteria for analysis. No significant differences in HLA- allele frequency were detected between individuals with negative and positive SARS-CoV-2 PCR (Figure 1 Left panel). We further tested whether HLA genotypes may be associated with severe Covid-19 infection. Of the 6,413 infected individuals, 181 (2.6%) were hospitalized within 2 weeks. Again, no significant HLA genotypes were found to be associated with hospitalization among individuals positive for SARS-CoV-2 (Figure 1 Right panel). Given the association between HLA and ethnic origin and the fact that the Ashkenazi Jewish population is genetically isolated 35 , we tested for SARS-CoV-2 presence and severity within the Ashkenazi population. This analysis included 20,937 Ashkenazi donors, of which 1,495 were positive for SARS-CoV-2, and 45 were hospitalized. No significant association was observed between either SARS-CoV-2 positive frequency (Figure 2 Left panel) or Covid-19 severity (Figure 2 Right panel) and any HLA subgroup in the Ashkenazi population (Figure 2). To investigate whether HLA heterozygosity is associated with the outcome of SARS-CoV-2 infection we further tested whether an increased probability of SARS-CoV-2 infection or severe disease course are associated with a higher homozygous rate of each of the 5 HLA loci subgroup. No such association was detected either in the general population or in the Ashkenazi population (Figure 3). The Covid-19 pandemic is associated with heavy medical, economic, and social costs. A few factors were associated with decreased or increased risks of SARS-CoV-2 infection, including smoking 46 and gender (male) 47 . Genetic factors were also found to be associated with Covid-19 disease severity 48 , including a genomic segment of around 50 kilobases in size that is inherited from Neanderthals 49 . Similarly, a meta-analysis of GWAS studies of patients from Spain and Italy with severe Covid-19, which was defined as a hospitalization with respiratory failure, detected three significant loci with odd ratios of 1.32-1.77 per loci 32 . Given the important role of HLA in several viral infections, the above study analyzed the extended HLA region (chromosome 6, 25 through 34 Mb) but did not find significant SNP association signals at the HLA complex. Another GWAS study analyzing 2244 critically-ill Covid-19 patients in the UK detected potential association between variants in chromosome 6 and Covid-19 33 . Our study, performed on a large scale dataset, did not detect any specific HLA subgroups associated with increased or decreased risk for SARS-CoV-2 infection, or a severe disease course causing hospitalization. We also did not detect any associations of heterozygote advantage with Covid-19 when we analyzed the entire study population or when analyzing a sub-population. Despite clear successes in identifying novel disease susceptibility genes, GWAS approach have not been without controversy 50 . A major limitation of this approach is the need to adopt a high level of significance to account for the multiple tests burden due to the very large number of loci compared concurrently. As such, it can miss important associations. In contrast with GWAS studies, we incorporated HLA alleles with a prevalence of >1% in the Israeli population. This approach enabled a large-scale analysis not of a few HLA subtypes but of f 66 variants, and still no association was found in the HLA region Two main caveats should be considered. First, the imputation of HLA alleles may induce errors. However, the precision of the imputation was previously established 51 . Moreover, no association was found with the A alleles that were typed in the vast majority of subjects. Finally, the analysis was performed at the two-digit level, which is practically unaffected by imputation. Another possible limitation is the age distribution. Our study included only a small proportion of hospitalized cases 181/6,413 (2.6%). This may be related to the average young age of individuals for whom we have HLA data. However, this should not affect the results related to SARS-CoV-2 infection. While hospitalization alone may not be an indicator of disease severity, we expect a significant enrichment of severe cases in hospitalized patients. The lack of HLA association reported here and in previous smaller studies, and the absence of advantage for heterozygote may suggest that heterozygote advantage in HLA may be more limited in general than often considered. This is in agreement with more recent claims that other mechanisms beyond heterozygote advantage or pathogen-driven balancing selection may be the source of the large HLA polymorphism 2 , 20 . We did not detect an HLA association with the initial phases of infection and hospitalization. As in other diseases, the initial response to the disease in the first few days is mainly mediated by the innate immune response, limiting the involvement of HLA and T Cells. HLA may still be involved in the later phases of the disease progression, such as long term sequels, or complications following hospitalization. A long-term follow-up will be needed to test for those. Declarations Ethical Approval - This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Clalit medical services (IRB) #0080-20-COM2. Consent to Participate – No experiment was performed on humans, so there is no consent to report. Consent to Publish – all authors agreed to this publications. Authors Contributions - YL, SM and SB wrote the paper. NB performed the statistical analysis. SI performed the HLA imputation. SC corrected the manuscript and helped with the final version. NA, RB and BZ supplied the data analyzed here. Funding – there are not funding sources to report Competing Interests – there are not competing interests to report Availability of data and materials – The data is personal HLA typing and Covid-19 status and cannot be provided. All the aggregated data is explicated in the figures and tables. The frequency of each allele in each dataset can be obtained from the authors upon demand. Conflict of Interest - The authors declare that they have no conflict of interest. References 1 Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA Database. Nucleic Acids Res 2020; 48 : D948–55. 2 Alter I, Gragert L, Fingerson S, Maiers M, Louzoun Y. HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes. PLoS Comput Biol 2017; 13 : e1005693. 3 Lin GG, Scott JG. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 2012; 100 : 130–4. 4 Loffredo JT, Sidney J, Bean AT, et al. Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. J Immunol 2009; 182 : 7763–75. 5 Blackwell JM, Jamieson SE, Burgner D. HLA and infectious diseases. Clin Microbiol Rev 2009; 22 : 370–85. 6 Sanchez-Mazas A. A review of HLA allele and SNP associations with highly prevalent infectious diseases in human populations. Swiss Med Wkly 2020; 150 : w20214. 7 Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and immune regulation: How do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections? Front Immunol 2017; 8 : 1–26. 8 Parham P. The immune system, 4th edn. Garland Science, 2014. 9 Tamori A, Kawada N. HLA class II associated with outcomes of hepatitis B and C infections. World J Gastroenterol 2013; 19 : 5395–401. 10 Ranasinghe S, Cutler S, Davis I, et al. Association of HLA-DRB1-restricted CD4 + T cell responses with HIV immune control. Nat Med 2013; 19 : 930–3. 11 Sierra B, Alegre R, Pérez AB, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol 2007; 68 : 531–40. 12 Penn DJ, Damjanovich K, Potts WK. MHC heterozygosity confers a selective advantage against multiple-strain infections. Proc Natl Acad Sci U S A 2002; 99 : 11260–4. 13 Takeshima S, Matsumoto Y, Chen J, Yoshida T, Mukoyama H, Aida Y. Evidence for cattle major histocompatibility complex (BoLA) class II DQA1 gene heterozygote advantage against clinical mastitis caused by Streptococci and Escherichia species. Tissue Antigens 2008; 72 : 525–31. 14 Evans ML, Neff BD. Major histocompatibility complex heterozygote advantage and widespread bacterial infections in populations of Chinook salmon (Oncorhynchus tshawytscha). Mol Ecol 2009; 18 : 4716–29. 15 Niskanen AK, Kennedy LJ, Ruokonen M, et al. Balancing selection and heterozygote advantage in major histocompatibility complex loci of the bottlenecked Finnish wolf population. Mol Ecol 2014; 23 : 875–89. 16 Arora J, Pierini F, McLaren PJ, Carrington M, Fellay J, Lenz TL. HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation. Mol Biol Evol 2020; 37 : 639–50. 17 Hraber P, Kuiken C, Yusim K. Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection. Hepatology 2007; 46 : 1713–21. 18 Spurgin LG, Richardson DS. How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings. Proceedings Biol Sci 2010; 277 : 979–88. 19 Sommer S. The importance of immune gene variability (MHC) in evolutionary ecology and conservation. Front Zool 2005; 2 : 16. 20 Lobkovsky AE, Levi L, Wolf YI, et al. Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC. Proc Natl Acad Sci U S A 2019; 116 : 14098–104. 21 Oh HLJ, Gan SKE, Bertoletti A, Tan YJ. Understanding the T cell immune response in SARS coronavirus infection. Emerg Microbes Infect 2012; 1 : 0. 22 Sanchez-Mazas A. HLA studies in the context of coronavirus outbreaks. Swiss Med Wkly 2020; 150 : w20248. 23 Keicho N, Itoyama S, Kashiwase K, et al. Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population. Hum Immunol 2009; 70 : 527–31. 24 Lin M, Tseng HK, Trejaut JA, et al. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Genet 2003; 4 : 1–7. 25 Chen YMA, Liang SY, Shih YP, et al. Epidemiological and genetic correlates of severe acute respiratory syndrome coronavirus infection in the hospital with the highest nosocomial infection rate in Taiwan in 2003. J Clin Microbiol 2006; 44 : 359–65. 26 Xiong P, Zeng X, Song MS, et al. Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: A cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China. Int J Immunogenet 2008; 35 : 69–74. 27 Hajeer AH, Balkhy H, Johani S, Yousef MZ, Arabi Y. Association of human leukocyte antigen class II alleles with severe Middle East respiratory syndrome-coronavirus infection. Ann Thorac Med 2016; 11 : 211–3. 28 Pisanti S, Deelen J, Gallina AM, et al. Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19. J Transl Med 2020; 18 : 1–16. 29 Wang F, Huang S, Gao R, et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov 2020; 6 . DOI:10.1038/s41421-020-00231-4. 30 Tomita Y, Ikeda T, Sato R, Sakagami T. Association between HLA gene polymorphisms and mortality of COVID-19: An in silico analysis. Immunity, Inflamm Dis 2020. DOI:10.1002/iid3.358. 31 Arunachalam PS, Wimmers F, Mok CKP, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science (80- ) 2020; 369 : 1210–20. 32 Ellinghaus D, Degenhardt F, Bujanda L, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med 2020. DOI:10.1056/NEJMoa2020283. 33 Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in Covid-19. Nature 2020; published online Dec. DOI:10.1038/s41586-020-03065-y. 34 Roberts GHL, Park DS, Coignet M V, et al. AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci. medRxiv 2020; : 2020.10.06.20205864. 35 Shelton JF, Shastri AJ, Ye C, et al. Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity. medRxiv 2020; : 2020.09.04.20188318. 36 Oksenberg JR, Barcellos LF, Cree BAC, et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004; 74 : 160–7. 37 Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001; 68 : 686–99. 38 Klitz W, Gragert L, Maiers M, et al. Genetic differentiation of Jewish populations. Tissue Antigens 2010; 76 : 442–58. 39 Khankhanian P, Matsushita T, Madireddy L, et al. Genetic contribution to multiple sclerosis risk among Ashkenazi Jews. BMC Med Genet 2015; 16 : 1–10. 40 Liu X, Cheng R, Verbitsky M, et al. Genome-Wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population. BMC Med Genet 2011; 12 : 104. 41 Goes FS, McGrath J, Avramopoulos D, et al. Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet Part B, Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 2015; 168 : 649–59. 42 Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 2013; 31 : 2165–8. 43 Manor S, Halagan M, Shriki N, et al. High-resolution HLA A∼B∼DRB1 haplotype frequencies from the Ezer Mizion Bone Marrow Donor Registry in Israel. Hum Immunol 2016; 77 . DOI:10.1016/j.humimm.2016.09.004. 44 Maiers M, Halagan M, Gragert L, et al. GRIMM: GRaph IMputation and matching for HLA genotypes. Bioinformatics 2019; 35 : 3520–3. 45 Yoav Benjamini, Yosef Hochberg. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B 1995; 57 : 289–300. 46 Polosa R, Caci G. COVID-19: counter-intuitive data on smoking prevalence and therapeutic implications for nicotine. Intern Emerg Med 2020; 15 : 853–6. 47 Abate BB, Kassie AM, Kassaw MW, Aragie TG, Masresha SA. Sex difference in coronavirus disease (COVID-19): a systematic review and meta-analysis. BMJ Open 2020; 10 : e040129. 48 Nasir J WB and VK. COVID-19 HGI Results for Data Freeze 4. https://www.covid19hg.org/blog/2020-11-24-covid-19-hgi-results-for-data-freeze-4-october-2020/. 2020. https://www.covid19hg.org/blog/2020-11-24-covid-19-hgi-results-for-data-freeze-4-october-2020/. 49 Zeberg H, Pääbo S. The major genetic risk factor for severe COVID-19 is inherited from Neandertals. bioRxiv 2020; : 2020.07.03.186296. 50 Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet 2019; 20 : 467–84. 51 Maiers M, Halagan M, Gragert L, et al. GRIMM: GRaph IMputation and matching for HLA genotypes. Bioinformatics 2019; 35 : 3520–3. Tables Table 1: Demographic Characterization of study groups groups Overall Ashkenazi Total number 72,912 20,937 PCR positive (%) 6,413 (8.8) 1495 (7.1) Mean Age (SD) 40.26 (11.56) 41.10 (11.41) Females (%) 42,669 (58.5) 12,623 (60.3) Males (%) 30,243 (41.5) 8,314 (39.7) Mean # of children (SD) 2.08 (1.78) 2.05 (1.73) Ultraorthodox sector (%) 3,815 (5.2) 925 (4.4) Socioeconomic level-low (%) 6,881 (9.4) 1,347 ( 6.4) Socioeconomic level-med (%) 29,822 (40.9) 7,412 (35.4) Socioeconomic level-high (%) 36,209 (49.7) 12,178 (58.2) Hospitalized (%) 181 (2.8) 45 (2.8) Hospitalized mean Age (SD) 39.39 (11.85) 40.64 (11.62) Hospitalized females (%) 74 (40.9) 16 (35.6) Hospitalized males (%) 107 (59.1) 29 (64.4) Table 1: Characterization of the individuals with HLA genotyping and at least one PCR test for Covid-19 that were included in the study. Table 2: HLA- subgroups (2-digit) analyzed HLA-A HLA-B HLA-C HLA-DQB1 HLA-DRB1 A_1 B_7 C_1 DQ_2 DR_1 A_2 B_8 C_2 DQ_3 DR_3 A_3 B_13 C_3 DQ_4 DR_4 A_11 B_14 C_4 DQ_5 DR_7 A_23 B_15 C_5 DQ_6 DR_8 A_24 B_18 C_6 DR_10 A_25 B_27 C_7 DR_11 A_26 B_35 C_8 DR_12 A_29 B_38 C_12 DR_13 A_30 B_40 C_14 DR_14 A_31 B_41 C_15 DR_15 A_32 B_44 C_16 DR_16 A_33 B_49 C_17 A_66 B_50 A_68 B_51 A_69 B_52 B_53 B_55 B_57 B_58 Table 2: List of two-digit HLA alleles with a population frequency >1%, analyzed in the study Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 13 Feb, 2021 Reviews received at journal 13 Feb, 2021 First submitted to journal 20 Jan, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-174593","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":11880830,"identity":"6848df38-2835-4a17-a3c6-9cdfa289c02d","order_by":0,"name":"Shay Ben Shachar","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shay","middleName":"Ben","lastName":"Shachar","suffix":""},{"id":11880831,"identity":"dcb09c46-8534-4100-9d94-fdf41dfe0a7a","order_by":1,"name":"Noam Barda","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noam","middleName":"","lastName":"Barda","suffix":""},{"id":11880832,"identity":"237c27c3-cbfa-4b6e-ad35-9c7dd7abac8c","order_by":2,"name":"Sigal Manor","email":"","orcid":"","institution":"Ezer mitzion","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sigal","middleName":"","lastName":"Manor","suffix":""},{"id":11880833,"identity":"4748b959-4677-4b69-82c6-d703080a53a7","order_by":3,"name":"Sapir Israeli","email":"","orcid":"","institution":"Bar Ilan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sapir","middleName":"","lastName":"Israeli","suffix":""},{"id":11880834,"identity":"fb85d3f1-301c-4dfa-8748-d49aa07b86c7","order_by":4,"name":"Noa Dagan","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noa","middleName":"","lastName":"Dagan","suffix":""},{"id":11880835,"identity":"bd1b58b7-1bc2-494f-8ed5-6f83903fe66a","order_by":5,"name":"Shai Carmi","email":"","orcid":"","institution":"Hebrew University School of Medicine: The Hebrew University of Jerusalem School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shai","middleName":"","lastName":"Carmi","suffix":""},{"id":11880836,"identity":"8b3b28ad-e19d-4ff3-b961-bcd0d0bceec8","order_by":6,"name":"Ran Balicer","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ran","middleName":"","lastName":"Balicer","suffix":""},{"id":11880837,"identity":"0f07a624-8bc2-465d-8a8d-d020753131d6","order_by":7,"name":"Bracha Zisser","email":"","orcid":"","institution":"Ezer Mitzion","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bracha","middleName":"","lastName":"Zisser","suffix":""},{"id":11880838,"identity":"b1e0d948-7b57-40c3-b453-db192bae7555","order_by":8,"name":"Yoram Louzoun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACPigtB8RsDIwNEhBuQgFuLWxQ2piBgRlZiwFhLYkNEC0wcXxa2HuMP3xsO5y+tv38sQeMOywSG9gPP2B4gE8LzxkDw5lth3O3nUlmN2A8I5HYwJNmgN9hEjkGybwgLQeS2SQY24BaGHII+AWo5TBQS7rZ+cdQLfxvCGoxbAZqSTC7AbNFgpAtPMeKGWecSzfcduOxmUTiGQnjNolnBgfwaeFnb9784UOZtbzZ+cRnEh931Mn28yc/fPijArcWKGiGUAkMkJg6QFADA0MdEWpGwSgYBaNgxAIAd2xKFP3hjcoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1714-6148","institution":"Bar Ilan University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yoram","middleName":"","lastName":"Louzoun","suffix":""}],"badges":[],"createdAt":"2021-01-28 12:32:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-174593/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-174593/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6070722,"identity":"01f02517-dfdb-499b-a456-ed912864a032","added_by":"auto","created_at":"2021-02-17 22:23:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":273494,"visible":true,"origin":"","legend":"Odds Ratio (OR) as a function of HLA allele. In all figures, the dot represents the odds ratio, and the interval represents the 95% confidence intervals (Bonferroni correction). The left plot is for SARS-CoV-2 infection and the right plot is for hospitalization. We trim error bars at 3 for better visualization. The analysis presented here is for the full population. One can see that no HLA allele is significantly associated.","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-174593/v1/2d3a899c22a4794bd82b883a.jpg"},{"id":6070723,"identity":"9260162b-d577-4e1f-95d2-a96e5552a726","added_by":"auto","created_at":"2021-02-17 22:23:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":280102,"visible":true,"origin":"","legend":"Odds Ratio (OR) as a function of HLA allele in the Ashkenazi population. In all figures, the dot represents the odds ratio, and the interval represents the 95% confidence intervals (Bonferroni correction). The left plot is for SARS-CoV-2 infection and the right plot is for hospitalization. We trim error bars at 3 for better visualization. The analysis presented here is for the Ashkenazi population. One can see that no HLA allele is significantly associated","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-174593/v1/26dadf6801f7f31f9229e35d.jpg"},{"id":6071152,"identity":"8259893c-df1d-42de-8d46-b5f7eee993ef","added_by":"auto","created_at":"2021-02-17 22:26:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141541,"visible":true,"origin":"","legend":"Effect of homozygosity on either infection or hospitalization in the entire studied population or the Ashkenazi population. Again no significant association was found. Homozygosity at a given locus is defined as having the same low-resolution allele in this locus.","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-174593/v1/007bb34b889d1525a248b3b3.jpg"},{"id":13660977,"identity":"4300cf10-139a-4310-98b7-e8c9658c8edb","added_by":"auto","created_at":"2021-09-17 10:27:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":542762,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-174593/v1/554c45e4-afde-43a5-9ac2-2557021c7915.pdf"}],"financialInterests":"","formattedTitle":"MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19 in the Israeli population","fulltext":[{"header":"Research in Context","content":"\u003cp\u003eA large number of small studies showing association between HLA and SARS-CoV-2 infection or Covid-19 outcome have been reported, including two very recent ones \u0026ndash; \u0026ldquo;HLA-C* 04:01 is a Genetic Risk Allele for Severe Course of COVID-19\u0026rdquo;, and \u0026ldquo;The Search For An Association Of HLA Alleles And Covid-19 Related Mortality In The Russian Population\u0026rdquo;. All these studies propose associations, based on very small sample and a large number of tested HLA alleles.\u003c/p\u003e\n\u003cp\u003eGiven the importance of HLA for many infectious diseases, and the importance of the detection of risk factors for COVID, we built a very large sample of patients coupled with their HLA information to test the validity of the association claims.\u003c/p\u003e\n\u003cp\u003eIndeed, in this very large sample and under proper statistical testing, no association was found with either infection or hospitalization. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic.\u003c/p\u003e"},{"header":"Main text","content":"\u003cp\u003eThe Major Histocompatibility Complex (MHC) molecules are cell surface protein complexes encoded in the Human Leukocyte Antigens (HLA) locus. The HLA locus is highly polymorphic with thousands of different alleles and millions of haplotypes reported\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e. HLAs are associated with several infectious diseases. Previous disease association studies showed that some HLA haplotypes are highly correlated with multiple viral infections\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e and have been reported to confer differential susceptibility to infection and the severity of the resulting disease\u003csup\u003e6\u003c/sup\u003e. In particular, HLA class I alleles are key players in the immune defense against viruses as they initiate the activity of T cells against the invading intracellular pathogens \u003csup\u003e7\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e. Although presentation of viral antigens relies classically on MHC class I molecules, MHC class II genes have also been associated with the outcome of many viral infections\u003csup\u003e9\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e10\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e11\u003c/sup\u003e. Studies in a range of species\u003csup\u003e12\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e13\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e14\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e, including humans\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e, imply a heterozygous selection mechanism operating on the HLA loci as an explanation for the extensive variability of the MHC molecules\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e. However, recent results on human populations suggest that such an advantage may be limited\u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn the context of Covid-19, specific HLAs have been associated with coronaviruses in the past, including SARS coronavirus infections\u003csup\u003e21\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e. Several efforts were made to identify HLA-related susceptibility to SARS-CoV-1 after the first SARS epidemic in East Asia\u003csup\u003e23\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e24\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e26\u003c/sup\u003e and the MERS-CoV outbreak in 2014 in\u003ca href=\"https://en.wikipedia.org/wiki/Saudi_Arabia\"\u003e Saudi Arabia\u003c/a\u003e\u003csup\u003e27\u003c/sup\u003e. Most of these case studies provided weak or conflicting results and required further validation due to the relatively small sample size. An association between the geographic distributions of Covid-19 and HLA alleles has been suggested\u003csup\u003e28\u003c/sup\u003e. Similarly, an association between severe disease outcome and specific HLAs was suggested by another small-scale whole-genome sequencing study\u003csup\u003e29\u003c/sup\u003e. In silico model raised the possibility that HLA supertypes may have a role in the severity of the disease\u003csup\u003e30\u003c/sup\u003e. Moreover, a reduced expression of human leukocyte antigen class DR (HLA-DR) was detected in peripheral blood mononuclear cells of Covid-19 patients\u003csup\u003e31\u003c/sup\u003e. Nevertheless, genome-wide association study (GWAS) among 1980 Italian and Spanish patients with severe Covid-19 detected a few loci associated with that state but no association with the HLA loci at chromosome 6 or heterozygote advantage was found\u003csup\u003e32\u003c/sup\u003e. However, another GWAS study analyzing\u0026nbsp;2244 critically-ill Covid-19 patients in the UK detected three variants in chromosome 6 but these variants were not replicated in other studies. Since population stratification in chromosome 6 (the major histocompatibility complex) is difficult to control, further studies will be required to determine whether these associations are real\u003csup\u003e33\u003c/sup\u003e. Two other large unpublished GWAS studies did not report a signal at the HLA locus on chromosome 6\u003csup\u003e34\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e35\u003c/sup\u003e. To the best of our knowledge there are no previous studies looking specifically at HLA subgroups among individuals with Covid-19.\u003c/p\u003e\n\u003cp\u003eHLA allele and haplotype frequencies differ between populations belonging to different ethnic groups\u003csup\u003e36\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e37\u003c/sup\u003e. For example, among Jewish populations, similarities of HLA alleles may be seen within ethnicities, allowing an estimation of an individual's origin based on his HLA genotypes\u003csup\u003e38\u003c/sup\u003e. It has been estimated that decreased HLA variability may assist to detect signals relevant to a specific disease state. Indeed, specific HLAs were associated with different disorders in the Ashkenazi population, a large genetically isolated group\u003csup\u003e39\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e40\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e41\u003c/sup\u003e. Given the diversity of HLAs among populations, testing genetically isolated and genetically homogenous populations may provide an advantage in detecting the effects of specific genetic variants, in particular in Ashkenazi Jews.\u003c/p\u003e\n\u003cp\u003eOur study aimed to utilize the presence of a large-scale cohort having HLA genotypes and a high rate of Covid-19 to test the possible role of specific HLA alleles in SARS-CoV-2 infection and its severity. Using a data set of this magnitude also allowed us to analyze associations between Covid-19 infection and HLA zygosity. Understanding how variation in HLA may affect both susceptibility and severity of Covid-19 infection could help to identify and stratify individuals at higher risk for the disease and may support future vaccination strategies.\u003c/p\u003e\n\u003cp\u003eA case-control study with a test-negative design\u003csup\u003e42\u003c/sup\u003e was used to evaluate the infection outcome, while a retrospective cohort study was used to evaluate the hospitalization outcome. In the case-control design, patients tested positive or negative for SARS-CoV-2 were evaluated for their HLA alleles. In the cohort design, patients who were diagnosed with COVID-19 were followed-up to see who were hospitalized.\u003c/p\u003e\n\u003cp\u003eThe study was based on patient data taken from the data warehouse of Clalit Health Care (CHS), a large integrated payer-provider healthcare organization operating in Israel. CHS insures over 4.6 million Israelis (~50%), which are a representative sample of the entire population.\u003c/p\u003e\n\u003cp\u003eHLA alleles were obtained from the Ezer Mizion Bone Marrow Donor Registry, which enlists the highest number of registered unrelated volunteer donors per capita in the world. The HLA resolution varies from serologic to DNA-based testing at low, intermediate, and allele resolution\u003csup\u003e43\u003c/sup\u003e. The initial analysis included HLA genotypes of 1,040,250 donors which represent all the populations composing the Ezer Mizion registry. High-resolution five-locus typing was imputed for all donors using GRIMM (GRaph IMputation and Matching for HLA Genotypes)\u003csup\u003e44\u003c/sup\u003e, which produces the most likely five-locus genotype consistent with the low-resolution typing and the self-defined ethnicity. For each subject in the dataset, we chose the unphased genotype with the highest probability. We also used the low resolution two-digit typing of each subject, as well as the homozygosity status of each allele.\u003c/p\u003e\n\u003cp\u003eThe study included all patients tested for SARS-CoV-2 by PCR that were members of CHS at the date of testing and had HLA data available. Cases were those patients tested positive, while controls were patients tested negative. Covariates for adjustment included age, sex, number of children in the household, population sector (ultra-orthodox vs. general, which has had an important impact on the epidemic in Israel), socioeconomic status, and ethnic origin (Ashkenazi vs. other). These covariates were extracted as of the test date. The number of children in the household was calculated based on CHS' demographic registry. The population sector was determined using the patient's primary-care clinic address. Socioeconomic status was determined based on a patient's home address. Patients were defined as Ashkenazi if they were Jewish and were born themselves or had at least one parent or 2 grandparents born in central or western Europe. A severe disease course was defined by hospitalization less than 2 weeks after the molecular diagnosis.\u003c/p\u003e\n\u003cp\u003eThe association between each HLA allele and the outcome, adjusted for the covariates listed above, was tested separately for each allele using logistic regression. Homozygosity was tested similarly, as a binary predictor, separately for each locus. Bonferroni correction was applied to the p-values and confidence intervals. The results were similar when the Benjamini-Hochberg false discovery rate was controlled\u003csup\u003e45\u003c/sup\u003e. Zygosity was computed based on two-digit HLA alleles at the appropriate locus. The study was performed with the approval of the Institutional Research Community (IRB) #0080-20-COM2).\u003c/p\u003e\n\u003cp\u003eOverall, 72,912 individuals with HLA genotyping and at least one PCR test for Covid-19 were included in the study between March 1\u003csup\u003est,\u003c/sup\u003e 2020 and October 31th 2020. Of them, 8.8% (6,413) tested positive for SARS-CoV-2 by PCR. Demographic and socioeconomic data related to the population is available in Table 1.\u003c/p\u003e\n\u003cp\u003eAll HLA alleles were grouped by two-digit representations to minimize the number of tests, and only alleles with a frequency of at least 1 % were used. A total of 16 HLA-A, 20 HLA-B, 13 HLA-C, 5 HLA-DQB1, and 12 HLA-DRB1 (Table 2) met the criteria for analysis. No significant differences in HLA- allele frequency were detected between individuals with negative and positive SARS-CoV-2 PCR (Figure 1 Left panel).\u003c/p\u003e\n\u003cp\u003eWe further tested whether HLA genotypes may be associated with severe Covid-19 infection. Of the 6,413 infected individuals, 181 (2.6%) were hospitalized within 2 weeks. Again, no significant HLA genotypes were found to be associated with hospitalization among individuals positive for SARS-CoV-2 (Figure 1 Right panel).\u003c/p\u003e\n\u003cp\u003eGiven the association between HLA and ethnic origin and the fact that the Ashkenazi Jewish population is genetically isolated\u003csup\u003e35\u003c/sup\u003e, we tested for SARS-CoV-2 presence and severity within the Ashkenazi population. This analysis included 20,937 Ashkenazi donors, of which 1,495 were positive for SARS-CoV-2, and 45 were hospitalized. No significant association was observed between either SARS-CoV-2 positive frequency (Figure 2 Left panel) or Covid-19 severity (Figure 2 Right panel) and any HLA subgroup in the Ashkenazi population (Figure 2).\u003c/p\u003e\n\u003cp\u003eTo investigate whether HLA heterozygosity is associated with the outcome of SARS-CoV-2 infection we further tested whether an increased probability of SARS-CoV-2 infection or severe disease course are associated with a higher homozygous rate of each of the 5 HLA loci subgroup. No such association was detected either in the general population or in the Ashkenazi population (Figure 3).\u003c/p\u003e\n\u003cp\u003eThe Covid-19 pandemic is associated with heavy medical, economic, and social costs. A few factors were associated with decreased or increased risks of SARS-CoV-2 infection, including smoking\u003csup\u003e46\u003c/sup\u003e and gender (male)\u003csup\u003e47\u003c/sup\u003e. Genetic factors were also found to be associated with Covid-19 disease severity \u003csup\u003e48\u003c/sup\u003e, including a genomic segment of around 50 kilobases in size that is inherited from Neanderthals\u003csup\u003e49\u003c/sup\u003e. Similarly, a meta-analysis of GWAS studies of patients from Spain and Italy with severe Covid-19, which was defined as a hospitalization with respiratory failure, detected three significant loci with odd ratios of 1.32-1.77 per loci\u003csup\u003e32\u003c/sup\u003e. Given the important role of HLA in several viral infections, the above study analyzed the extended HLA region (chromosome 6, 25 through 34 Mb) but did not find significant SNP association signals at the HLA complex. Another GWAS study analyzing 2244 critically-ill Covid-19 patients in the UK detected potential association between variants in chromosome 6 and Covid-19\u003csup\u003e33\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur study, performed on a large scale dataset, did not detect any specific HLA subgroups associated with increased or decreased risk for SARS-CoV-2 infection, or a severe disease course causing hospitalization. We also did not detect any associations of heterozygote advantage with Covid-19 when we analyzed the entire study population or when analyzing a sub-population. Despite clear successes in identifying novel disease susceptibility genes, GWAS approach have not been without controversy\u003csup\u003e50\u003c/sup\u003e. A major limitation of this approach is the need to adopt a high level of significance to account for the multiple tests burden due to the very large number of loci compared concurrently. As such, it can miss important associations. In contrast with GWAS studies, we incorporated HLA alleles with a prevalence of \u0026gt;1% in the Israeli population. This approach enabled a large-scale analysis not of a few HLA subtypes but of f 66 variants, and still no association was found in the HLA region\u003c/p\u003e\n\u003cp\u003eTwo main caveats should be considered. First, the imputation of HLA alleles may induce errors. However, the precision of the imputation was previously established\u003csup\u003e51\u003c/sup\u003e. Moreover, no association was found with the A alleles that were typed in the vast majority of subjects. Finally, the analysis was performed at the two-digit level, which is practically unaffected by imputation. Another possible limitation is the age distribution. Our study included only a small proportion of hospitalized cases 181/6,413 (2.6%). This may be related to the average young age of individuals for whom we have HLA data. However, this should not affect the results related to SARS-CoV-2 infection. While hospitalization alone may not be an indicator of disease severity, we expect a significant enrichment of severe cases in hospitalized patients.\u003c/p\u003e\n\u003cp\u003eThe lack of HLA association reported here and in previous smaller studies, and the absence of advantage for heterozygote may suggest that heterozygote advantage in HLA may be more limited in general than often considered. This is in agreement with more recent claims that other mechanisms beyond heterozygote advantage or pathogen-driven balancing selection may be the source of the large HLA polymorphism\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eWe did not detect an HLA association with the initial phases of infection and hospitalization. As in other diseases, the initial response to the disease in the first few days is mainly mediated by the innate immune response, limiting the involvement of HLA and T Cells. HLA may still be involved in the later phases of the disease progression, such as long term sequels, or complications following hospitalization. A long-term follow-up will be needed to test for those.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e - This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Clalit medical services (IRB) #0080-20-COM2.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e \u0026ndash; No experiment was performed on humans, so there is no consent to report.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e \u0026ndash; all authors agreed to this publications.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eAuthors Contributions\u003c/strong\u003e - YL, SM and SB wrote the paper. NB performed the statistical analysis. SI performed the HLA imputation. SC corrected the manuscript and helped with the final version. NA, RB and BZ supplied the data analyzed here.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eFunding\u003c/strong\u003e \u0026ndash; there are not funding sources to report\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e \u0026ndash; there are not competing interests to report\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e \u0026ndash; The data is personal HLA typing and Covid-19 status and cannot be provided. All the aggregated data is explicated in the figures and tables. The frequency of each allele in each dataset can be obtained from the authors upon demand.\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u0026nbsp;- The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003cp\u003e1 Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA Database. \u003cem\u003eNucleic Acids Res\u003c/em\u003e 2020; \u003cstrong\u003e48\u003c/strong\u003e: D948\u0026ndash;55.\u003c/p\u003e\n\u003cp\u003e2 Alter I, Gragert L, Fingerson S, Maiers M, Louzoun Y. HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes. \u003cem\u003ePLoS Comput Biol\u003c/em\u003e 2017; \u003cstrong\u003e13\u003c/strong\u003e: e1005693.\u003c/p\u003e\n\u003cp\u003e3 Lin GG, Scott JG. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. \u003cem\u003eNat Rev Immunol\u003c/em\u003e 2012; \u003cstrong\u003e100\u003c/strong\u003e: 130\u0026ndash;4.\u003c/p\u003e\n\u003cp\u003e4 Loffredo JT, Sidney J, Bean AT, \u003cem\u003eet al.\u003c/em\u003e Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. \u003cem\u003eJ Immunol\u003c/em\u003e 2009; \u003cstrong\u003e182\u003c/strong\u003e: 7763\u0026ndash;75.\u003c/p\u003e\n\u003cp\u003e5 Blackwell JM, Jamieson SE, Burgner D. HLA and infectious diseases. \u003cem\u003eClin Microbiol Rev\u003c/em\u003e 2009; \u003cstrong\u003e22\u003c/strong\u003e: 370\u0026ndash;85.\u003c/p\u003e\n\u003cp\u003e6 Sanchez-Mazas A. A review of HLA allele and SNP associations with highly prevalent infectious diseases in human populations. \u003cem\u003eSwiss Med Wkly\u003c/em\u003e 2020; \u003cstrong\u003e150\u003c/strong\u003e: w20214.\u003c/p\u003e\n\u003cp\u003e7 Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and immune regulation: How do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections? \u003cem\u003eFront Immunol\u003c/em\u003e 2017; \u003cstrong\u003e8\u003c/strong\u003e: 1\u0026ndash;26.\u003c/p\u003e\n\u003cp\u003e8 Parham P. The immune system, 4th edn. Garland Science, 2014.\u003c/p\u003e\n\u003cp\u003e9 Tamori A, Kawada N. HLA class II associated with outcomes of hepatitis B and C infections. \u003cem\u003eWorld J Gastroenterol\u003c/em\u003e 2013; \u003cstrong\u003e19\u003c/strong\u003e: 5395\u0026ndash;401.\u003c/p\u003e\n\u003cp\u003e10 Ranasinghe S, Cutler S, Davis I, \u003cem\u003eet al.\u003c/em\u003e Association of HLA-DRB1-restricted CD4\u003csup\u003e+\u003c/sup\u003e T cell responses with HIV immune control. \u003cem\u003eNat Med\u003c/em\u003e 2013; \u003cstrong\u003e19\u003c/strong\u003e: 930\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003e11 Sierra B, Alegre R, P\u0026eacute;rez AB, \u003cem\u003eet al.\u003c/em\u003e HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. \u003cem\u003eHum Immunol\u003c/em\u003e 2007; \u003cstrong\u003e68\u003c/strong\u003e: 531\u0026ndash;40.\u003c/p\u003e\n\u003cp\u003e12 Penn DJ, Damjanovich K, Potts WK. MHC heterozygosity confers a selective advantage against multiple-strain infections. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e 2002; \u003cstrong\u003e99\u003c/strong\u003e: 11260\u0026ndash;4.\u003c/p\u003e\n\u003cp\u003e13 Takeshima S, Matsumoto Y, Chen J, Yoshida T, Mukoyama H, Aida Y. Evidence for cattle major histocompatibility complex (BoLA) class II DQA1 gene heterozygote advantage against clinical mastitis caused by Streptococci and Escherichia species. \u003cem\u003eTissue Antigens\u003c/em\u003e 2008; \u003cstrong\u003e72\u003c/strong\u003e: 525\u0026ndash;31.\u003c/p\u003e\n\u003cp\u003e14 Evans ML, Neff BD. Major histocompatibility complex heterozygote advantage and widespread bacterial infections in populations of Chinook salmon (Oncorhynchus tshawytscha). \u003cem\u003eMol Ecol\u003c/em\u003e 2009; \u003cstrong\u003e18\u003c/strong\u003e: 4716\u0026ndash;29.\u003c/p\u003e\n\u003cp\u003e15 Niskanen AK, Kennedy LJ, Ruokonen M, \u003cem\u003eet al.\u003c/em\u003e Balancing selection and heterozygote advantage in major histocompatibility complex loci of the bottlenecked Finnish wolf population. \u003cem\u003eMol Ecol\u003c/em\u003e 2014; \u003cstrong\u003e23\u003c/strong\u003e: 875\u0026ndash;89.\u003c/p\u003e\n\u003cp\u003e16 Arora J, Pierini F, McLaren PJ, Carrington M, Fellay J, Lenz TL. HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation. \u003cem\u003eMol Biol Evol\u003c/em\u003e 2020; \u003cstrong\u003e37\u003c/strong\u003e: 639\u0026ndash;50.\u003c/p\u003e\n\u003cp\u003e17 Hraber P, Kuiken C, Yusim K. Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection. \u003cem\u003eHepatology\u003c/em\u003e 2007; \u003cstrong\u003e46\u003c/strong\u003e: 1713\u0026ndash;21.\u003c/p\u003e\n\u003cp\u003e18 Spurgin LG, Richardson DS. How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings. \u003cem\u003eProceedings Biol Sci\u003c/em\u003e 2010; \u003cstrong\u003e277\u003c/strong\u003e: 979\u0026ndash;88.\u003c/p\u003e\n\u003cp\u003e19 Sommer S. The importance of immune gene variability (MHC) in evolutionary ecology and conservation. \u003cem\u003eFront Zool\u003c/em\u003e 2005; \u003cstrong\u003e2\u003c/strong\u003e: 16.\u003c/p\u003e\n\u003cp\u003e20 Lobkovsky AE, Levi L, Wolf YI, \u003cem\u003eet al.\u003c/em\u003e Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e 2019; \u003cstrong\u003e116\u003c/strong\u003e: 14098\u0026ndash;104.\u003c/p\u003e\n\u003cp\u003e21 Oh HLJ, Gan SKE, Bertoletti A, Tan YJ. Understanding the T cell immune response in SARS coronavirus infection. \u003cem\u003eEmerg Microbes Infect\u003c/em\u003e 2012; \u003cstrong\u003e1\u003c/strong\u003e: 0.\u003c/p\u003e\n\u003cp\u003e22 Sanchez-Mazas A. HLA studies in the context of coronavirus outbreaks. \u003cem\u003eSwiss Med Wkly\u003c/em\u003e 2020; \u003cstrong\u003e150\u003c/strong\u003e: w20248.\u003c/p\u003e\n\u003cp\u003e23 Keicho N, Itoyama S, Kashiwase K, \u003cem\u003eet al.\u003c/em\u003e Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population. \u003cem\u003eHum Immunol\u003c/em\u003e 2009; \u003cstrong\u003e70\u003c/strong\u003e: 527\u0026ndash;31.\u003c/p\u003e\n\u003cp\u003e24 Lin M, Tseng HK, Trejaut JA, \u003cem\u003eet al.\u003c/em\u003e Association of HLA class I with severe acute respiratory syndrome coronavirus infection. \u003cem\u003eBMC Med Genet\u003c/em\u003e 2003; \u003cstrong\u003e4\u003c/strong\u003e: 1\u0026ndash;7.\u003c/p\u003e\n\u003cp\u003e25 Chen YMA, Liang SY, Shih YP, \u003cem\u003eet al.\u003c/em\u003e Epidemiological and genetic correlates of severe acute respiratory syndrome coronavirus infection in the hospital with the highest nosocomial infection rate in Taiwan in 2003. \u003cem\u003eJ Clin Microbiol\u003c/em\u003e 2006; \u003cstrong\u003e44\u003c/strong\u003e: 359\u0026ndash;65.\u003c/p\u003e\n\u003cp\u003e26 Xiong P, Zeng X, Song MS, \u003cem\u003eet al.\u003c/em\u003e Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: A cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China. \u003cem\u003eInt J Immunogenet\u003c/em\u003e 2008; \u003cstrong\u003e35\u003c/strong\u003e: 69\u0026ndash;74.\u003c/p\u003e\n\u003cp\u003e27 Hajeer AH, Balkhy H, Johani S, Yousef MZ, Arabi Y. Association of human leukocyte antigen class II alleles with severe Middle East respiratory syndrome-coronavirus infection. \u003cem\u003eAnn Thorac Med\u003c/em\u003e 2016; \u003cstrong\u003e11\u003c/strong\u003e: 211\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003e28 Pisanti S, Deelen J, Gallina AM, \u003cem\u003eet al.\u003c/em\u003e Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19. \u003cem\u003eJ Transl Med\u003c/em\u003e 2020; \u003cstrong\u003e18\u003c/strong\u003e: 1\u0026ndash;16.\u003c/p\u003e\n\u003cp\u003e29 Wang F, Huang S, Gao R, \u003cem\u003eet al.\u003c/em\u003e Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. \u003cem\u003eCell Discov\u003c/em\u003e 2020; \u003cstrong\u003e6\u003c/strong\u003e. DOI:10.1038/s41421-020-00231-4.\u003c/p\u003e\n\u003cp\u003e30 Tomita Y, Ikeda T, Sato R, Sakagami T. Association between HLA gene polymorphisms and mortality of COVID-19: An in silico analysis. \u003cem\u003eImmunity, Inflamm Dis\u003c/em\u003e 2020. DOI:10.1002/iid3.358.\u003c/p\u003e\n\u003cp\u003e31 Arunachalam PS, Wimmers F, Mok CKP, \u003cem\u003eet al.\u003c/em\u003e Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. \u003cem\u003eScience (80- )\u003c/em\u003e 2020; \u003cstrong\u003e369\u003c/strong\u003e: 1210\u0026ndash;20.\u003c/p\u003e\n\u003cp\u003e32 Ellinghaus D, Degenhardt F, Bujanda L, \u003cem\u003eet al.\u003c/em\u003e Genomewide Association Study of Severe Covid-19 with Respiratory Failure. \u003cem\u003eN Engl J Med\u003c/em\u003e 2020. DOI:10.1056/NEJMoa2020283.\u003c/p\u003e\n\u003cp\u003e33 Pairo-Castineira E, Clohisey S, Klaric L, \u003cem\u003eet al.\u003c/em\u003e Genetic mechanisms of critical illness in Covid-19. \u003cem\u003eNature\u003c/em\u003e 2020; published online Dec. DOI:10.1038/s41586-020-03065-y.\u003c/p\u003e\n\u003cp\u003e34 Roberts GHL, Park DS, Coignet M V, \u003cem\u003eet al.\u003c/em\u003e AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci. \u003cem\u003emedRxiv\u003c/em\u003e 2020; : 2020.10.06.20205864.\u003c/p\u003e\n\u003cp\u003e35 Shelton JF, Shastri AJ, Ye C, \u003cem\u003eet al.\u003c/em\u003e Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity. \u003cem\u003emedRxiv\u003c/em\u003e 2020; : 2020.09.04.20188318.\u003c/p\u003e\n\u003cp\u003e36 Oksenberg JR, Barcellos LF, Cree BAC, \u003cem\u003eet al.\u003c/em\u003e Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. \u003cem\u003eAm J Hum Genet\u003c/em\u003e 2004; \u003cstrong\u003e74\u003c/strong\u003e: 160\u0026ndash;7.\u003c/p\u003e\n\u003cp\u003e37 Mignot E, Lin L, Rogers W, \u003cem\u003eet al.\u003c/em\u003e Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. \u003cem\u003eAm J Hum Genet\u003c/em\u003e 2001; \u003cstrong\u003e68\u003c/strong\u003e: 686\u0026ndash;99.\u003c/p\u003e\n\u003cp\u003e38 Klitz W, Gragert L, Maiers M, \u003cem\u003eet al.\u003c/em\u003e Genetic differentiation of Jewish populations. \u003cem\u003eTissue Antigens\u003c/em\u003e 2010; \u003cstrong\u003e76\u003c/strong\u003e: 442\u0026ndash;58.\u003c/p\u003e\n\u003cp\u003e39 Khankhanian P, Matsushita T, Madireddy L, \u003cem\u003eet al.\u003c/em\u003e Genetic contribution to multiple sclerosis risk among Ashkenazi Jews. \u003cem\u003eBMC Med Genet\u003c/em\u003e 2015; \u003cstrong\u003e16\u003c/strong\u003e: 1\u0026ndash;10.\u003c/p\u003e\n\u003cp\u003e40 Liu X, Cheng R, Verbitsky M, \u003cem\u003eet al.\u003c/em\u003e Genome-Wide association study identifies candidate genes for Parkinson\u0026rsquo;s disease in an Ashkenazi Jewish population. \u003cem\u003eBMC Med Genet\u003c/em\u003e 2011; \u003cstrong\u003e12\u003c/strong\u003e: 104.\u003c/p\u003e\n\u003cp\u003e41 Goes FS, McGrath J, Avramopoulos D, \u003cem\u003eet al.\u003c/em\u003e Genome-wide association study of schizophrenia in Ashkenazi Jews. \u003cem\u003eAm J Med Genet Part B, Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet\u003c/em\u003e 2015; \u003cstrong\u003e168\u003c/strong\u003e: 649\u0026ndash;59.\u003c/p\u003e\n\u003cp\u003e42 Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. \u003cem\u003eVaccine\u003c/em\u003e 2013; \u003cstrong\u003e31\u003c/strong\u003e: 2165\u0026ndash;8.\u003c/p\u003e\n\u003cp\u003e43 Manor S, Halagan M, Shriki N, \u003cem\u003eet al.\u003c/em\u003e High-resolution HLA A\u0026sim;B\u0026sim;DRB1 haplotype frequencies from the Ezer Mizion Bone Marrow Donor Registry in Israel. \u003cem\u003eHum Immunol\u003c/em\u003e 2016; \u003cstrong\u003e77\u003c/strong\u003e. DOI:10.1016/j.humimm.2016.09.004.\u003c/p\u003e\n\u003cp\u003e44 Maiers M, Halagan M, Gragert L, \u003cem\u003eet al.\u003c/em\u003e GRIMM: GRaph IMputation and matching for HLA genotypes. \u003cem\u003eBioinformatics\u003c/em\u003e 2019; \u003cstrong\u003e35\u003c/strong\u003e: 3520\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003e45 Yoav Benjamini, Yosef Hochberg. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. \u003cem\u003eJ R Stat Soc Ser B\u003c/em\u003e 1995; \u003cstrong\u003e57\u003c/strong\u003e: 289\u0026ndash;300.\u003c/p\u003e\n\u003cp\u003e46 Polosa R, Caci G. COVID-19: counter-intuitive data on smoking prevalence and therapeutic implications for nicotine. \u003cem\u003eIntern Emerg Med\u003c/em\u003e 2020; \u003cstrong\u003e15\u003c/strong\u003e: 853\u0026ndash;6.\u003c/p\u003e\n\u003cp\u003e47 Abate BB, Kassie AM, Kassaw MW, Aragie TG, Masresha SA. Sex difference in coronavirus disease (COVID-19): a systematic review and meta-analysis. \u003cem\u003eBMJ Open\u003c/em\u003e 2020; \u003cstrong\u003e10\u003c/strong\u003e: e040129.\u003c/p\u003e\n\u003cp\u003e48 Nasir J WB and VK. COVID-19 HGI Results for Data Freeze 4. https://www.covid19hg.org/blog/2020-11-24-covid-19-hgi-results-for-data-freeze-4-october-2020/. 2020. https://www.covid19hg.org/blog/2020-11-24-covid-19-hgi-results-for-data-freeze-4-october-2020/.\u003c/p\u003e\n\u003cp\u003e49 Zeberg H, P\u0026auml;\u0026auml;bo S. The major genetic risk factor for severe COVID-19 is inherited from Neandertals. \u003cem\u003ebioRxiv\u003c/em\u003e 2020; : 2020.07.03.186296.\u003c/p\u003e\n\u003cp\u003e50 Tam V, Patel N, Turcotte M, Boss\u0026eacute; Y, Par\u0026eacute; G, Meyre D. Benefits and limitations of genome-wide association studies. \u003cem\u003eNat Rev Genet\u003c/em\u003e 2019; \u003cstrong\u003e20\u003c/strong\u003e: 467\u0026ndash;84.\u003c/p\u003e\n\u003cp\u003e51 Maiers M, Halagan M, Gragert L, \u003cem\u003eet al.\u003c/em\u003e GRIMM: GRaph IMputation and matching for HLA genotypes. \u003cem\u003eBioinformatics\u003c/em\u003e 2019; \u003cstrong\u003e35\u003c/strong\u003e: 3520\u0026ndash;3.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-left:21.3pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; color: rgb(0, 0, 0); font-size: 11px;\"\u003eTable 1: Demographic \u0026nbsp;Characterization of study groups groups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"border: none;width:449.1pt;margin-left:27.25pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 14.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003e\u0026nbsp;Overall\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 14.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eAshkenazi\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eTotal number\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e72,912\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e20,937\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003ePCR positive \u0026nbsp;(%)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e6,413 (8.8)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e1495 (7.1)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eMean Age (SD)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e40.26 (11.56)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e41.10 (11.41)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eFemales (%) \u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e42,669 (58.5)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e12,623 (60.3)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eMales (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e30,243 (41.5)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e8,314 (39.7)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eMean # of children (SD)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e2.08 (1.78)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e2.05 (1.73)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eUltraorthodox\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003esector (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e3,815 (5.2)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e925 (4.4)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eSocioeconomic level-low \u0026nbsp; \u0026nbsp; (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e6,881 (9.4)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e1,347 ( 6.4)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eSocioeconomic level-med \u0026nbsp; \u0026nbsp; (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e29,822 (40.9)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e7,412 (35.4)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eSocioeconomic level-high (%)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e36,209 (49.7)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e12,178 (58.2)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eHospitalized \u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e181 (2.8)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e45 (2.8)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eHospitalized mean Age (SD)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e39.39 (11.85)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e40.64 (11.62)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eHospitalized females \u0026nbsp;(%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e74 (40.9)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e16 (35.6)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 188.1pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eHospitalized males (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e107 (59.1)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e29 (64.4)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-left:21.3pt;text-align:justify;line-height:200%;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cspan style=\"background: white;\"\u003eTable 1:\u0026nbsp;\u003c/span\u003eCharacterization of the\u0026nbsp;individuals with HLA genotyping and at least one PCR test for Covid-19 that were included in the study.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-left:21.3pt;text-align:justify;line-height:200%;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-left:21.3pt;line-height:200%;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eTable 2: HLA- subgroups (2-digit) analyzed\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border: none;width:395.0pt;margin-left:30.35pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHLA-A\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHLA-B\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHLA-C\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHLA-DQB1\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHLA-DRB1\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eA_1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDQ_2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDR_1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eA_2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_14\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New 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style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDR_8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: 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style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times 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style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_12\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 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14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_40\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eC_14\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt 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style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDR_16\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: 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11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New 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bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eA_68\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_51\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eA_69\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eB_52\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 93pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: 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style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 14.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-left:21.3pt;text-align:justify;line-height:200%;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eTable 2: List of\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; color: rgb(0, 0, 0); font-size: 11px;\"\u003etwo-digit HLA alleles with a population frequency \u0026gt;1%, analyzed in the study \u0026nbsp;\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"HLA, SARS-CoV-2, association, hospitalization, Israel, Ashkenazi","lastPublishedDoi":"10.21203/rs.3.rs-174593/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-174593/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with Covid-19 severity. However, no clear association between HLA and Covid-19 incidence or severity has been reported. We conducted a large scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6,413 (8.8%) were found to have SARS-CoV-2 by PCR. a Total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups; A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization.\u003c/p\u003e\u003cp\u003eWe conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity.\u003c/p\u003e","manuscriptTitle":"MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19 in the Israeli population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-17 22:23:51","doi":"10.21203/rs.3.rs-174593/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2021-02-14T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-02-14T00:00:00+00:00","index":0,"fulltext":""},{"type":"submitted","content":"Journal of Clinical Immunology","date":"2021-01-20T13:15:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8df812da-a70b-4eff-b875-32eaeef40bdf","owner":[],"postedDate":"February 17th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":2456297,"name":"Immunology"}],"tags":[],"updatedAt":"2021-05-19T05:57:36+00:00","versionOfRecord":[],"versionCreatedAt":"2021-02-17 22:23:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-174593","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-174593","identity":"rs-174593","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}