Hla-dqb1*02, Hla-drb1*03 Alleles and Hla-dqb1*02-hla-drb1*03 Haplotype Confer a Significant Risk of Celiac Disease in the Mauritanian Population

Hla-dqb1*02, Hla-drb1*03 Alleles and Hla-dqb1*02-hla-drb1*03 Haplotype Confer a Significant Risk of Celiac Disease in the Mauritanian 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 Hla-dqb1 02, Hla-drb1 03 Alleles and Hla-dqb1 02-hla-drb1 03 Haplotype Confer a Significant Risk of Celiac Disease in the Mauritanian Population Saleck Mahfoudh Ebebecar, Malak Salame, Mohamed Hameyin, Tijani Hamed, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9058697/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background and aim: Celiac disease (CD) is an autoimmune disorder primarily caused by an abnormal immune response to dietary gluten in human leucocytes class II antigens carriers This preliminary study aimed to assess the specific risk conferred by DQB1 and DRB1 alleles to celiac disease development in the Mauritanian population. Materials and Methods: frequencies of HLA-DQB1and HLA-DRB1alleles and haplotypes were evaluated in 50 celiac disease (CD) patients. The association of HLA-DQB1 and HLA-DRB1with the disease was tested using a control group of 50 non-CD healthy individuals. Genotyping was performed by PCR-SSP and next-generation sequencing (NGS). Results: Genotyping of the studied population revealed that the most frequent alleles of DQB1/DRB1 gens among CD patients were DQB1*02(70%) and DQB1*03(9%) , DRB1*03 (52%) was the largest group followed by DRB1*07 (12%). The major allelic combination was DRB1*03–DQB1*02, with a frequency of 47%. Analysis of allele frequency in patients and controls revealed a significant association between CD and the two key HLA alleles here respectively DQB1*02(χ² = 44.46; p = 2.59 × 10⁻¹¹) and DRB1*03 (χ² = 8.32; p = 3.9 × 10⁻³). Significant association was also found with DQB1*02 -DRB1*03 (χ² = 31.47; p = 2.0 × 10⁻⁸). However, no considerable risk of the disease was conferred by any of the other haplotypes tested here. Conclusion: These preliminary results, consistent with previous literature on CD genetic susceptibility, support the predominant role of DQB1*02 and DRB1*03 alleles and haplotypes in celiac onset in our population. The availability of NGS typing for celiac disease may be an additive tool to exclude symptoms ambiguity during CD diagnosis in our medical facilities. HLA Celiac disease Gluten Mauritania Introduction Human leukocyte antigens (HLA) have been closely related to the natural history of numerous diseases particularly through its implication in the body's immune response [ 1 – 2 ]. Gluten is a group of proteins found in wheat, barely or rye and important for the shape and plasticity of various foods [ 3 ]. Most of people can eat food with gluten without any side effect, however, in some people, gluten can trigger a range of health issues of which celiac disease (CD) is the most known [ 4 ]. This condition may cause damage to gut (small intestine) with a set of symptoms such as diarrhea, abdominal pain and bloating [ 3 ]. CD is classified as a chronic autoimmune disorder provoked by an immune response to gluten ingestion in genetically predisposed individuals [ 5 ]. Indeed, confirmation of the disease symptoms is worldwide implemented, according to NASPGHAN (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition), by a titer 10 times the upper limit of IgA tissue transglutaminase antibody (IgA-TTG) followed by genetic testing for HLA class II molecules [ 6 ]. For instance, approximately 95% of Caucasians with CD express HLA-DQ2 ( HLA-DQA1* 05; HLA-DQB1* 02) haplotype, the remaining 5% of patients possess either the HLA-DQ8 haplotype ( HLA-DQA1* 03; HLA-DQB1* 03/) or another variant of HLA-DQ2 [ 7 , 8 ]. Although less explored in North African and sub-Saharan CD patients, the allele and haplotype of HLA antigens showed similar genetic pattern with different frequencies [ 9 ]. Celiac disease was also strongly associated with the HLA class II DR markers with evidences of for a genetic heterogeneity of this region reported in different populations [ 10 ]. We have previously assessed the global and ethnic distribution of the main HLA class I and class II antigens in the Mauritanian population [ 11 ]. Here, we investigated the potential risk conferred by DQB1 and -DRB1 alleles and haplotypes to CD onset in our population. Materials and methods Target Population: HLA-DQB1 and HLA-DRB1 allele frequencies were explored in 50 celiac disease patients recruited at the National Institute of Hepato-Virology (INHV) and the pediatric department of CHIVA Clinic respectively by a gastroenterologist and a pediatrician based on CD symptoms, rising serum levels of anti-tissue transglutaminase (anti-tTG IgA) and/or intestinal biopsy findings. Association between DQB1 and DRB1alleles and haplotypes with CD was assessed by contrast with a group of 50 healthy non CD individuals. DNA Extraction Genomic DNA extraction was performed from whole blood samples collected in EDTA tubes from each individual in the target population, following the protocol provided by the Qiagen kit (QIAamp DNA Mini Kit, Cat. No. 51104). Extracted DNA was evaluated quantitatively using a Qubit fluorometer and qualitatively by agarose gel electrophoresis. HLA-DQB1/DRB1Genotyping Fifty patients with CD and fifty healthy controls were HLA typed for DQB1/DRB1 loci determination by PCR–SSP (Polymerase Chain Reaction – Sequence Specific Primers) Lambda kits and HLA Fusion™ software, version 3.0.0 for allele identification. In 24 CD patients, we used the high-resolution next-generation sequencing (NGS), using Nanopore MinIon sequencer with Nanotype kits. Amplification, library preparation and sequencing were performed according to the sequencing kit procedure. Computational analysis was carried by Omixon software compatible with nanopore technology. To confirm analogy of both HLA typing here, 2 CD patients and controls were HLA typed using PCR-SSP and nanopore sequencing Statistical Analysis The prevalence and association of HLA -DQB1/DRB1 alleles and haplotypes with celiac disease were analyzed by SPSSS ver25.0 (SPSS Inc,Chicago,IL,USA). Allelic frequencies (Fr %) were calculated as : Fr(%) = (n allele/N total ) X 100 with, n is the count of the given allele and N the total number of alleles analyzed in the group. Results Prevalence of HLA-DQB1and HLA-DRB1 alleles and haplotypes in celiac disease patients In this cohort, the most frequent alleles among CD patients were DQB1*02 (70%), DQB1*03 (9%) at DQB1 locus, DRB1*03 (52%) and DRB1*07(12%) at the DRB1 locus respectively (table1). Calculation of HLA-DQB1-DRB1 locus combinations showed that the majority of haplotype carriers were DQB1*02-DRB1*03 (47%), followed by DQB1*02 -DRB1*07 (10%), DQB1*02 -DRB1*01 (8%) and DRB1*03–DQB1*03 (3 %) (table 1). Association of HLA-DQB1 and HLA-DRB1 alleles and haplotypes with celiac disease Reviewing their role as risk or protective factor for CD, the distribution of HLA-DQB1 alleles among patients and controls showed a significant association between DQB1*02 (χ² = 44.46, p = 2.59 × 10⁻¹¹; OR = 8.27), DQB1*03 (χ² = 19.38; p = 1.07 × 10⁻⁵; OR = 0.18), DQB1*04 (OR ≈ 0.12; p < 0.05) alleles and the disease. In contrast, no association was observed for DQB1*05 (OR ≈ 0,45; p =0,098) and DQB1*06 (OR ≈ 0,52%; p =0,200) (table 2). The analysis revealed also a significant association between DRB1*03 and celiac disease (χ² = 8,32; p = 3,9 × 10⁻³; OR = 3.48) and DRB1*01 (OR ≈ 4.85 p= 3,0 × 10⁻²). However, no significant association was observed for DRB1*07 (χ² = 0,89 p= 3,45 × 10⁻¹ OR=1,57) and DRB1*04 (χ² = 0, 00 p=1,0, OR=1,00) (table 3). Assessment of CD risk by HLA-DQB1 -HLA-DRB1allele combinations (Table 4) showed that the most prominent haplotype DQB1*02 -DRB1*03 (47%) was significantly associated with celiac disease (X 2 = 31.47 P-value =2.0 × 10⁻⁸, OR = 7.17). In contrast, none of the other present haplotypes was found affecting the disease development. Discussion HLA class II antigens have been specifically correlated with triggering several auto-immune diseases although the frequency of these disorders cannot be explained by genetics alone [12]. In this pilot study, we have used the highly accurate and affordable NGS Nanopore technology [13] to assess, in our population, the prevalence and conferred risk of two prominent HLA class II genes associated with celiac disease onset. Indeed, among the fifty CD patients tested, a good number (70%) carried DQB1*02 allele followed by DQB1*03 (9%). DRB1*03 was also found in 52% of patients while 12% carried DRB1*07. As a result, we have showed that 79% of CD patients were DQB1*02 or DQB1*03 and 64% carried either DRB1*03 or DRB1*07. Besides, a significant association with celiac disease was observed for the two main alleles respectively HLA-DQB1* 02 (p < 3×10⁻¹¹) and HLA-DRB1* 03 (p < 0.004). Furthermore, the most frequent haplotype DQB1*02-DRB1*03 (47%) was also significantly associated with the disease (p =2.0 × 10⁻⁸) in our cohort. Although preliminary, these results underlined the major role of DQB1*02 andDRB1*03 in genetic susceptibility to celiac disease in our population as reported by numerous reports worldwide [14]. For instance, of the sixty pediatric patients with CD typed at the University Clinical Centre of Kosovo (UCCK), the three most frequent alleles were HLA – DQB1*02 (58%), HLA-DRB1∗03 (38.3%), DRB1∗07 (17.5%) which also presented a much higher frequency among CD patients compared to control group (p< 0 0001, p< 0 0001 and p = 0 0023, respectively) [15]. In the Iranian population, a study performed in as similar size cohort revealed that among 40 CD individuals DQB1*02 was present in 33.75% of patients versus only 8.75% of controls with, overall, 65% of the patients affected by celiac disease hostingDQB1*02 or DQB1*03 alleles [16]. Likewise, 38 out of 49 (77.5%) Syrian children with CD were reported to carry either of these two main alleles [17]. Using PCR-based amplification of HLA and NGS sequencing, as in our protocol, on 143 Scandinavian CD patients and 135 non-celiac disease controls, showed that DQB1*02-DRB1*03 haplotypes conferred a strong risk of celiac disease (RR = 6.34; P-value < .0001) [18]. A study conducted on the modifying effect of HLA haplotypes located trans to DQB1*02-DRB1*03 in celiac patients of Southern Europe also found that homozygous DQB1*02-DRB1*03/DQB1*02-DRB1*03 and heterozygous DQB1*02-DRB1*03/DQB1*02-DRB1*07 were the only combinations that showed a significant and independent association to CD. That study confirmed a gene dosage effect of the DQB1*02-DRB1*03 haplotype [18,19]. In North Africa, although the disease frequency has been fast increasing, genetic etiology of the disease was rarely investigated. However, a study using HLA class II (HLA-DQA1/DQB1/DRB1) typing in Moroccan CD patients compared to a control group from has confirmed risk gradient for CD in the Moroccan population [9]. In the Tunisian population, the risk of developing celiac disease was also estimated to be 6.8 times greater for those having a double dose of DQB1*02[20]. Although our work was centered primarily on the potential risk of CD related to HLA DQB1*02 and HLA-DRB1*03 genes, it is well acknowledged that about 90-95% of CD patients are carrying DQ2.5 heterodimers encoded by DQB1*02 associated to DQA1*05 alleles in cis or in trans configuration, and DQ8 molecules with DQB1*03:02 generally combined to DQA1*03 variant [21, 22,23]. However, HLA-DQ2 and HLA-DQ8 heterodimers were reported to explain only about 40% of CD heritability [24,25]. The remaining 60% of genetic susceptibility to the disease were estimated to be shared between an unknown number of HLA and non-HLA genes [26,27]. The mechanism by which HLA alleles from various loci were involved in CD onset remained unclear. However, gluten proteins have been shown to contain various immunogenic peptides [28,29]. Bearing in mind the striking polymorphism of HLA system and its specific antigen presenting function, a correlation between the numerous gluten epitopes and various corresponding HLA antigens competent of triggering a T cell reaction in celiac disease is readily reasonable. This association has been supported, for instance, by the difference in the level of gluten peptide binding to HLA-DQ2 homozygous and heterozygous APC [30,31]. In this quantitative model, the relationship between HLA-DQB1 and DRB1 allele expression level and the available number gluten peptides may therefore be a critical limiting factor in the disease development [32]. According to this hypothesis, the non-association between CD and HLA-DQ2.2 [33,34], in contrast to the significant risk by HLA-DQ2.5, would be the result of a limited number HLA specific T cell response due to low amount of specific immunogenic gluten peptides [35,36]. This HLA-gene dose effect induced by antigenic gluten epitopes could also be involved in other auto immune diseases such as type I diabetes, rheumatoid arthritis, or systemic lupus erythematosus [37,38]. Conclusion This study confirmed the contribution of both HLA-DQB1*02 and HLA-DRB1*03 alleles and haplotypes in CD development in our population following a quantitative HLA-gene dose effect model. As CD is often unrecognized by practitioners, largely due to its variable clinical presentation, genetic testing could be an additive tool for its diagnosis to exclude ambiguity in our medical centers. Declarations Ethical considerations The study adhered to the Declaration of Hel­sinki and received approval from the University of Nouakchott’s Ethics Com­mittee (ethics clearance letter No002/2020/CE/UNA), on behalf of the Health Ministry. All Participants provided informed consent at the time of inclusion. Data availability The sequence data for the 24 patients typed by NGS using Nanopore technology (MinION) in our study are available as accessible links in a supplementary file Competing interests The authors declare no competing interests. Consent for publication Not Applicable Funding This research did not receive any external funding. The sequencing cost was covered by internal funds provided by the teaching department. Authors’ contributions Saleck Mahfoudh Ebebecar, carried out the experiments and manuscript writing. Tettou Soumbara, Tijani Hamed and Abdallahi Sidi Mohmed: assisted with data curation. Malak Salame, Fatimetou Vetten, Mohamed lemine Hmeity and Mohamed Hameyin, collected patient data and assisted with genotyping and statistical analysis. Houria Abdelghaffar and Ahmed Houmeida, validated the experiments, as well as the design and writing of the manuscript. Acknowledgments The authors thank all the medical staff at l’Institut National d’Hépato-virologiefor their invaluable assistance. References Laezza, M., Pisapia, L., Toro, B., Mercadante, V., Rispo, A., Gianfrani, C., & del Pozzo, G. (2024). Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients. Journal of Translational Autoimmunity , 8 . https://doi.org/10.1016/j.jtauto.2024.100240. Lundin KE, Wijmenga C. 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Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Malak","middleName":"","lastName":"Salame","suffix":""},{"id":627944849,"identity":"073deb3a-1092-4a94-a5d3-c9dfc36f9a8e","order_by":2,"name":"Mohamed Hameyin","email":"","orcid":"","institution":"National Institute of Hepato-Virology (INHV)","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Hameyin","suffix":""},{"id":627944850,"identity":"ad68c01e-f85d-4144-885a-5dc521be6ad9","order_by":3,"name":"Tijani Hamed","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Tijani","middleName":"","lastName":"Hamed","suffix":""},{"id":627944851,"identity":"f0976df5-2683-4da5-a772-c8522059db70","order_by":4,"name":"Fatimetou Vetten","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Fatimetou","middleName":"","lastName":"Vetten","suffix":""},{"id":627944852,"identity":"82c5853c-2c78-4b0c-96dc-7799ed2f9a7c","order_by":5,"name":"Tettou Soumbara","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Tettou","middleName":"","lastName":"Soumbara","suffix":""},{"id":627944853,"identity":"50f10d08-37a7-4107-9142-032dc5cbd24a","order_by":6,"name":"Mohamed lemine Hmeity","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"lemine","lastName":"Hmeity","suffix":""},{"id":627944854,"identity":"c5158f03-66da-45fd-a2bb-6f96d9905ddd","order_by":7,"name":"Abdallahi Sidi Mohmed","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Abdallahi","middleName":"Sidi","lastName":"Mohmed","suffix":""},{"id":627944855,"identity":"f3b9c9fc-a27b-4e5d-959e-59d0aad2ef48","order_by":8,"name":"Houria Abdelghaffar","email":"","orcid":"","institution":"Hassan II University","correspondingAuthor":false,"prefix":"","firstName":"Houria","middleName":"","lastName":"Abdelghaffar","suffix":""},{"id":627944856,"identity":"a918952b-1106-42ce-af70-7fdd1ef8f96d","order_by":9,"name":"Ahmed Houmeida","email":"","orcid":"","institution":"University of Nouakchott","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Houmeida","suffix":""}],"badges":[],"createdAt":"2026-03-07 13:23:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9058697/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9058697/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107707824,"identity":"b2587334-0d9e-4ae1-b0ff-29ac0c05d1b1","added_by":"auto","created_at":"2026-04-24 09:21:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":224977,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9058697/v1/4dbb590f-3e93-4682-82f7-16f9874d10c3.pdf"},{"id":107649124,"identity":"7b1b5c27-e4ad-4b3b-9223-17182aef6e35","added_by":"auto","created_at":"2026-04-23 14:47:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31396,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9058697/v1/7df96751701292339997aad9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eHla-dqb1*02, Hla-drb1*03 Alleles and Hla-dqb1*02-hla-drb1*03 Haplotype Confer a Significant Risk of Celiac Disease in the Mauritanian Population\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman leukocyte antigens (HLA) have been closely related to the natural history of numerous diseases particularly through its implication in the body's immune response [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Gluten is a group of proteins found in wheat, barely or rye and important for the shape and plasticity of various foods [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Most of people can eat food with gluten without any side effect, however, in some people, gluten can trigger a range of health issues of which celiac disease (CD) is the most known [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This condition may cause damage to gut (small intestine) with a set of symptoms such as diarrhea, abdominal pain and bloating [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CD is classified as a chronic autoimmune disorder provoked by an immune response to gluten ingestion in genetically predisposed individuals [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Indeed, confirmation of the disease symptoms is worldwide implemented, according to NASPGHAN (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition), by a titer 10 times the upper limit of IgA tissue transglutaminase antibody (IgA-TTG) followed by genetic testing for HLA class II molecules [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For instance, approximately 95% of Caucasians with CD express HLA-DQ2 (\u003cem\u003eHLA-DQA1*\u003c/em\u003e05; \u003cem\u003eHLA-DQB1*\u003c/em\u003e02) haplotype, the remaining 5% of patients possess either the HLA-DQ8 haplotype (\u003cem\u003eHLA-DQA1*\u003c/em\u003e03; \u003cem\u003eHLA-DQB1*\u003c/em\u003e03/) or another variant of HLA-DQ2 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although less explored in North African and sub-Saharan CD patients, the allele and haplotype of HLA antigens showed similar genetic pattern with different frequencies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCeliac disease was also strongly associated with the HLA class II DR markers with evidences of for a genetic heterogeneity of this region reported in different populations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe have previously assessed the global and ethnic distribution of the main HLA class I and class II antigens in the Mauritanian population [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Here, we investigated the potential risk conferred by DQB1 and -DRB1 alleles and haplotypes to CD onset in our population.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTarget Population:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHLA-DQB1 and HLA-DRB1 allele frequencies were explored in 50 celiac disease patients recruited at the National Institute of Hepato-Virology (INHV) and the pediatric department of CHIVA Clinic respectively by a gastroenterologist and a pediatrician based on CD symptoms, rising serum levels of anti-tissue transglutaminase (anti-tTG IgA) and/or intestinal biopsy findings. Association between DQB1 and DRB1alleles and haplotypes with CD was assessed by contrast with a group of 50 healthy non CD individuals. \u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDNA Extraction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA extraction was performed from whole blood samples collected in EDTA tubes from each individual in the target population, following the protocol provided by the Qiagen kit (QIAamp DNA Mini Kit, Cat. No. 51104). Extracted DNA was evaluated quantitatively using a Qubit fluorometer and qualitatively by agarose gel electrophoresis.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHLA-DQB1/DRB1Genotyping\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifty patients with CD and fifty healthy controls were HLA typed for DQB1/DRB1 loci determination by PCR\u0026ndash;SSP (Polymerase Chain Reaction \u0026ndash; Sequence Specific Primers) Lambda kits and HLA Fusion\u0026trade; software, version 3.0.0 for allele identification.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 24 CD patients, we used the high-resolution next-generation sequencing (NGS), using Nanopore MinIon sequencer with Nanotype kits. Amplification, library preparation and sequencing were performed according to the sequencing kit procedure. Computational analysis was carried by Omixon software compatible with nanopore technology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo confirm analogy of both HLA typing here, 2 CD patients and controls were HLA typed using PCR-SSP and nanopore sequencing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;Statistical Analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prevalence and association of HLA -DQB1/DRB1 alleles and haplotypes with celiac disease were analyzed by SPSSS ver25.0 (SPSS Inc,Chicago,IL,USA). Allelic frequencies (Fr %) were calculated\u0026nbsp;\u003cbr\u003eas : Fr(%) = (n allele/N total ) X 100 with, n is the count of the given allele and N the total number of alleles analyzed in the group.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003col\u003e\n \u003cli\u003e\u003cem\u003ePrevalence of HLA-DQB1and HLA-DRB1 alleles and haplotypes in celiac disease patients\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eIn this cohort, the most frequent alleles among CD patients were DQB1*02 (70%), DQB1*03 (9%) at DQB1 locus, DRB1*03 (52%) and DRB1*07(12%) at the DRB1 locus respectively (table1). \u0026nbsp;Calculation of HLA-DQB1-DRB1 locus combinations showed that the majority of haplotype carriers were DQB1*02-DRB1*03 (47%), followed by DQB1*02 -DRB1*07 (10%), DQB1*02 -DRB1*01 (8%) and DRB1*03\u0026ndash;DQB1*03 (3 %) (table 1).\u003c/p\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003e\u003cem\u003eAssociation of HLA-DQB1 and HLA-DRB1 alleles and haplotypes with celiac disease\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eReviewing their role as risk or protective factor for CD, the distribution of HLA-DQB1 alleles among patients and controls showed a significant association between DQB1*02 (\u0026chi;\u0026sup2; = 44.46, p =\u0026nbsp;2.59 \u0026times; 10⁻\u0026sup1;\u0026sup1;; OR = 8.27), DQB1*03 (\u0026chi;\u0026sup2; = 19.38; p =\u0026nbsp;1.07 \u0026times; 10⁻⁵; OR = 0.18), DQB1*04 (OR \u0026asymp; 0.12; p \u0026lt; 0.05) alleles and the disease. In contrast, no association was observed for DQB1*05 (OR \u0026asymp;\u0026nbsp;0,45; p =0,098) and DQB1*06 (OR \u0026asymp; 0,52%; p =0,200) (table 2). The analysis revealed also a significant association between DRB1*03 and celiac disease (\u0026chi;\u0026sup2; = 8,32; p =\u0026nbsp;3,9 \u0026times; 10⁻\u0026sup3;; OR = 3.48) and DRB1*01 (OR \u0026asymp; 4.85 p=\u0026nbsp;3,0 \u0026times; 10⁻\u0026sup2;). However, no significant association was observed for DRB1*07 (\u0026chi;\u0026sup2; =\u0026nbsp;0,89 p= 3,45 \u0026times; 10⁻\u0026sup1; OR=1,57) and\u0026nbsp;DRB1*04 (\u0026chi;\u0026sup2; =\u0026nbsp;0, 00 p=1,0, OR=1,00)\u0026nbsp;(table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAssessment of CD risk by\u0026nbsp;HLA-DQB1 -HLA-DRB1allele combinations (Table 4) showed that the most prominent haplotype DQB1*02 -DRB1*03 (47%) was significantly associated with celiac disease (X\u003csup\u003e2\u003c/sup\u003e = 31.47 P-value =2.0 \u0026times; 10⁻⁸, OR = 7.17). In contrast, none of the other present haplotypes was found affecting the disease development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHLA class II antigens have been specifically correlated with triggering several auto-immune diseases although the frequency of these disorders cannot be explained by genetics alone\u0026nbsp;\u003cstrong\u003e[12].\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this pilot study, we have used the highly accurate and affordable NGS Nanopore technology\u0026nbsp;\u003cstrong\u003e[13]\u0026nbsp;\u003c/strong\u003eto assess, in our population, the prevalence and conferred risk of two prominent HLA class II genes associated with celiac disease onset. Indeed,\u0026nbsp;among the fifty CD patients tested, a good number (70%) carried DQB1*02 allele followed by DQB1*03 (9%). DRB1*03 was also found in 52% of patients while 12% carried DRB1*07. As a result, we have showed that 79% of CD patients were DQB1*02 or DQB1*03 and 64% carried either DRB1*03 or DRB1*07. Besides, a significant association with celiac disease was observed for the two main alleles respectively HLA-DQB1*\u003cem\u003e02\u003c/em\u003e(p \u0026lt; 3\u0026times;10⁻\u0026sup1;\u0026sup1;)\u003cem\u003e\u0026nbsp;\u003c/em\u003eand \u003cem\u003eHLA-DRB1*\u0026nbsp;\u003c/em\u003e03 (p \u0026lt; 0.004). Furthermore, the most frequent haplotype DQB1*02-DRB1*03 (47%) was also significantly associated with the disease (p =2.0 \u0026times; 10⁻⁸) in our cohort.\u003c/p\u003e\n\u003cp\u003eAlthough preliminary, these results underlined the major role of DQB1*02 andDRB1*03 in genetic susceptibility to celiac disease in our population as reported by numerous reports worldwide\u0026nbsp;\u003cstrong\u003e[14].\u0026nbsp;\u003c/strong\u003eFor instance, of the sixty pediatric patients with CD typed at the University Clinical Centre of Kosovo (UCCK), the three most frequent alleles were HLA \u0026ndash; DQB1*02 (58%), HLA-DRB1\u0026lowast;03 (38.3%), DRB1\u0026lowast;07 (17.5%) which also presented a much higher frequency among CD patients compared to control group (p\u0026lt; 0 0001, p\u0026lt; 0 0001 and p = 0 0023, respectively)\u0026nbsp;\u003cstrong\u003e[15].\u0026nbsp;\u003c/strong\u003eIn the Iranian population, a study performed in as similar size cohort revealed that among 40 CD individuals DQB1*02 was present in 33.75% of patients versus only 8.75% of controls with, overall, 65% of the patients affected by celiac disease hostingDQB1*02 or DQB1*03 alleles [16]. Likewise, 38 out of 49 (77.5%) Syrian children with CD were\u0026nbsp;reported to carry either of these two main alleles [17]. Using PCR-based amplification of HLA and NGS sequencing, as in our protocol, on 143 Scandinavian CD patients and 135 non-celiac disease controls, showed that DQB1*02-DRB1*03 haplotypes conferred a strong risk of celiac disease (RR = 6.34; P-value \u0026lt; .0001) [18]. \u0026nbsp;A study conducted on the modifying effect of HLA haplotypes located trans to DQB1*02-DRB1*03 in celiac patients of Southern Europe also found that homozygous DQB1*02-DRB1*03/DQB1*02-DRB1*03 and heterozygous DQB1*02-DRB1*03/DQB1*02-DRB1*07 were the only combinations that showed a significant and independent association to CD.\u0026nbsp;That study confirmed a gene dosage effect of the DQB1*02-DRB1*03 haplotype\u0026nbsp;[18,19].\u003c/p\u003e\n\u003cp\u003eIn North Africa, although the disease frequency has been fast increasing, genetic etiology of the disease was rarely investigated. However, a study using HLA class II (HLA-DQA1/DQB1/DRB1) typing in Moroccan CD patients compared to a control group from has confirmed risk gradient for CD in the Moroccan population [9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the Tunisian population, the risk of developing celiac disease was also estimated to be 6.8 times greater for those having a double dose of DQB1*02[20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough\u0026nbsp;our work was centered primarily on the potential risk of CD related to\u0026nbsp;HLA DQB1*02 and HLA-DRB1*03 genes, it is well acknowledged that about 90-95% of CD patients are carrying DQ2.5 heterodimers encoded by DQB1*02 associated to DQA1*05 alleles in cis or in trans configuration, and DQ8 molecules with DQB1*03:02 generally combined to DQA1*03 variant [21, 22,23]. However, HLA-DQ2 and HLA-DQ8 heterodimers were reported to explain only about 40% of CD heritability\u0026nbsp;[24,25]. The remaining 60% of genetic susceptibility to the disease were estimated to be shared between an unknown number of HLA and non-HLA genes [26,27].\u003c/p\u003e\n\u003cp\u003eThe mechanism by which HLA alleles from various loci were involved in CD onset remained unclear. However, gluten proteins have been shown to contain various immunogenic peptides [28,29]. Bearing in mind the striking polymorphism of HLA system and its specific antigen presenting function, a correlation between the numerous gluten epitopes and various corresponding HLA antigens competent of triggering a T cell reaction in celiac disease is readily reasonable. This association has been supported, for instance, by the difference in the level of gluten peptide binding to HLA-DQ2 homozygous and heterozygous APC [30,31]. In this quantitative model, the relationship between HLA-DQB1 and DRB1 allele expression level and the available number gluten peptides may therefore be a critical limiting factor in the disease development [32]. According to this hypothesis, the non-association between CD and HLA-DQ2.2 [33,34], in contrast to the significant risk by HLA-DQ2.5, would be the result of a limited number HLA specific T cell response due to low amount of specific immunogenic gluten peptides [35,36]. This HLA-gene dose effect induced by antigenic gluten epitopes could also be involved in other auto immune diseases such as type I diabetes, rheumatoid arthritis, or systemic lupus erythematosus [37,38].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study confirmed the contribution of both HLA-DQB1*02 and HLA-DRB1*03 alleles and haplotypes in CD development in our population following a quantitative HLA-gene dose effect model. As CD is often unrecognized by practitioners, largely due to its variable clinical presentation, genetic testing could be an additive tool for its diagnosis to exclude ambiguity in our medical centers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical considerations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the Declaration of Hel\u0026shy;sinki and received approval from the University of Nouakchott\u0026rsquo;s Ethics Com\u0026shy;mittee (ethics clearance letter No002/2020/CE/UNA), on behalf of the Health Ministry. All Participants provided informed consent at the time of inclusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sequence data for the 24 patients typed by NGS using Nanopore technology (MinION) in our study are available as accessible links in a supplementary file\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any external funding. The sequencing cost was covered by internal funds provided by the teaching department.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSaleck Mahfoudh Ebebecar, carried out the experiments and manuscript writing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTettou Soumbara,\u0026nbsp;Tijani Hamed\u0026nbsp;and\u0026nbsp;Abdallahi Sidi Mohmed: assisted with data curation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMalak Salame,\u0026nbsp;Fatimetou Vetten, Mohamed lemine Hmeity\u0026nbsp;and\u0026nbsp;Mohamed Hameyin, collected patient data and assisted with genotyping and statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHouria Abdelghaffar and Ahmed Houmeida, validated the experiments, as well as the design and writing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the medical staff at l\u0026rsquo;Institut National d\u0026rsquo;H\u0026eacute;pato-virologiefor their invaluable assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLaezza, M., Pisapia, L., Toro, B., Mercadante, V., Rispo, A., Gianfrani, C., \u0026amp; del Pozzo, G. (2024). Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients. \u003cem\u003eJournal of Translational Autoimmunity\u003c/em\u003e, \u003cem\u003e8\u003c/em\u003e. https://doi.org/10.1016/j.jtauto.2024.100240.\u003c/li\u003e\n \u003cli\u003eLundin KE, Wijmenga C. Coeliac disease and autoimmune disease-genetic overlap and screening. NatRevGastroenterolHepatol 2015;12(9):507\u0026ndash;15. PMID: 26303674 DOI: 10.1038/nrgastro.2015.136\u003c/li\u003e\n \u003cli\u003eKeshtkari, A., Danaei, M., \u0026amp;Mollaali, M. (2024). Association of HLA-DQ4/5 genotype polymorphisms with celiac disease in a group of children in Southwest Iran: A case-control study. \u003cem\u003eHealth Science Reports\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e(7). https://doi.org/10.1002/hsr2.2242.\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eTh\u0026eacute;se : La maladie c\u0026oelig;liaque PR.\u0026nbsp;\u003c/em\u003e\u003cem\u003eBENDEDDOUCHE\u003c/em\u003e. BOUZIANE AKILA (2016-2017).\u003c/li\u003e\n \u003cli\u003eCastro-Antunes, M. M., Crovella, S., Brand\u0026atilde;o, L. A. C., Guimar\u0026atilde;es, R. L., Motta, M. E. F. A., \u0026amp; da Silva, G. A. P. (2011). 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Evaluation of HLA-DQ2 and HLA-DQ8 haplotypes in patients with endometriosis, A case-control study. \u003cem\u003eClinics\u003c/em\u003e, \u003cem\u003e79\u003c/em\u003e. https://doi.org/10.1016/j.clinsp.2023.100317\u003c/li\u003e\n \u003cli\u003eSchirru, E., Rossino, R., Diana, D., Jores, R. D., Baldera, D., Muntoni, S., Spiga, C., Ripoli, C., Ricciardi, M. R., Cucca, F., \u0026amp;Congia, M. (2024). HLA Genotyping in Children with Celiac Disease Allows to Establish the Risk of Developing Type 1 Diabetes. \u003cem\u003eClinical and Translational Gastroenterology\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(7), e00710. https://doi.org/10.14309/ctg.0000000000000710\u003c/li\u003e\n \u003cli\u003ePiancatelli, D., ben El Barhdadi, I., Oumhani, K., Sebastiani, P., Colanardi, A., \u0026amp;Essaid, A. (2017). HLA Typing and Celiac Disease in Moroccans. \u003cem\u003eMedical Sciences (Basel, Switzerland)\u003c/em\u003e, \u003cem\u003e5\u003c/em\u003e(1). https://doi.org/10.3390/medsci5010002.\u003c/li\u003e\n \u003cli\u003eWorld J Gastroenterol. Apr 14, 2025; 31(14): 104397 Published online Apr 14, 2025. doi: 10.3748/wjg.v31.i14.104397\u003c/li\u003e\n \u003cli\u003eHLA class I (-A, -B, -C) and class II (-DR, -DQ) polymorphism in the Mauritanian population PMID: 29298671 PMCID: PMC5751816 DOI: 10.1186/s12881-017-0514-4\u003c/li\u003e\n \u003cli\u003eDevriese, M., Rouquie, J., da Silva, S., Benassaya, N., Maillard, L., Dewez, M., Caillat-Zucman, S., Werner, G., \u0026amp; Taupin, J. L. (2024). Single locus HLA sequencing with the nanopore technology for HLA disease association diagnosis. \u003cem\u003eHLA\u003c/em\u003e, \u003cem\u003e103\u003c/em\u003e(3). https://doi.org/10.1111/tan.15424\u003c/li\u003e\n \u003cli\u003eHLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy PMID: 7558926DOI: 10.1016/0198-8859(94)00130-i\u003c/li\u003e\n \u003cli\u003eRamosaj-Morina, A., Kamenaric, M. B., Azemi, M., Spahiu, L., Grubic, Z., \u0026amp;Zunec, R. (2019). HLA haplotype association with celiac disease in albanian pediatric patients from kosovo. \u003cem\u003eGastroenterology Research and Practice\u003c/em\u003e, \u003cem\u003e2019\u003c/em\u003e. https://doi.org/10.1155/2019/7369014.\u003c/li\u003e\n \u003cli\u003eFallah, H., Akbari, M. T., Mirzajani, S., Ranjbaran, F., Mehdizadeh, B., Sayad, A., \u0026amp; Taheri, M. (2020). Association between HLA alleles and risk of celiac disease in Iranian patients. \u003cem\u003eHuman Antibodies\u003c/em\u003e, \u003cem\u003e28\u003c/em\u003e(2), 123\u0026ndash;129. https://doi.org/10.3233/HAB-190398\u003c/li\u003e\n \u003cli\u003eMurad, H., Jazairi, B., Khansaa, I., Olabi, D., \u0026amp; Khouri, L. (2018). HLA-DQ2 and -DQ8 genotype frequency in Syrian celiac disease children: HLA-DQ relative risks evaluation. \u003cem\u003eBMC Gastroenterology\u003c/em\u003e, \u003cem\u003e18\u003c/em\u003e(1). https://doi.org/10.1186/s12876-018-0802-2\u003c/li\u003e\n \u003cli\u003eS Alshiekh\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e, L P Zhao\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e, \u0026Aring; Lernmark\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003e, D E Geraghty\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e, \u0026Aring; T Naluai\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e, D Agardh\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003e HLA2017 Aug;90(2):95-101. doi: 10.1111/tan.13065. Epub 2017 Jun. 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Sollid, The roles ofMHCclass II genes andpost-372 translational modificationin celiac disease, Immunogenetics 373 69(2017),605\u0026ndash;616. PMID: 28695286 DOI: 10.1007/s00251-017-0985-7\u003c/li\u003e\n \u003cli\u003eSollid Ludvig M., Jabri Bana.\u003cem\u003eTriggers and drivers of autoimmunity: lessons from coeliac disease.\u003c/em\u003eNature Reviews Immunology. 2013;13(4):294\u0026ndash;302. PMID: 23493116 PMCID: PMC3818716 DOI: 10.1038/nri3407\u003c/li\u003e\n \u003cli\u003evan Heel David A., et al. \u003cem\u003eA genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.\u003c/em\u003e Nature Genetics. 2007;39(7):827\u0026ndash;829. PMID: 17558408 PMCID: PMC2274985 DOI: 10.1038/ng2058\u003c/li\u003e\n \u003cli\u003eDubois Pierre C.A., et al.\u003cem\u003eMultiple common variants for celiac disease influencing immune gene expression.\u003c/em\u003eNature Genetics. 2010;42(4):295\u0026ndash;302. 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[CrossRef] [PubMed].\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HLA, Celiac disease, Gluten, Mauritania","lastPublishedDoi":"10.21203/rs.3.rs-9058697/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9058697/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and aim:\u003c/strong\u003e Celiac disease (CD) is an autoimmune disorder primarily caused by an abnormal immune response to dietary gluten in human leucocytes class II antigens carriers\u003c/p\u003e\n\u003cp\u003eThis preliminary study aimed to assess the specific risk conferred by DQB1 and DRB1 alleles to celiac disease development in the Mauritanian population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods: \u003c/strong\u003efrequencies of HLA-DQB1and HLA-DRB1alleles and haplotypes were evaluated in 50 celiac disease (CD) patients. The association of HLA-DQB1 and HLA-DRB1with the disease was tested using a control group of 50 non-CD healthy individuals.\u003c/p\u003e\n\u003cp\u003eGenotyping was performed by PCR-SSP and next-generation sequencing (NGS).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults: \u003c/strong\u003e\u003c/em\u003eGenotyping of the studied population revealed that the most frequent alleles of DQB1/DRB1 gens among CD patients were DQB1*02(70%) and DQB1*03(9%) , DRB1*03 (52%) was the largest group followed by DRB1*07 (12%).\u003c/p\u003e\n\u003cp\u003eThe major allelic combination was DRB1*03–DQB1*02, with a frequency of 47%.\u003c/p\u003e\n\u003cp\u003eAnalysis of allele frequency in patients and controls revealed a significant association between CD and the two key HLA alleles here respectively DQB1*02(χ² = 44.46; p = 2.59 × 10⁻¹¹) and DRB1*03 (χ² = 8.32; p = 3.9 × 10⁻³). Significant association was also found with DQB1*02 \u0026nbsp;-DRB1*03 (χ² = 31.47; p = 2.0 × 10⁻⁸). However, no considerable risk of the disease was conferred by any of the other haplotypes tested here.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThese preliminary results, consistent with previous literature on CD genetic susceptibility, support the predominant role of DQB1*02 and DRB1*03 alleles and haplotypes in celiac onset in our population. The availability of NGS typing for celiac disease may be an additive tool to exclude symptoms ambiguity during CD diagnosis in our medical facilities.\u003c/p\u003e","manuscriptTitle":"Hla-dqb1*02, Hla-drb1*03 Alleles and Hla-dqb1*02-hla-drb1*03 Haplotype Confer a Significant Risk of Celiac Disease in the Mauritanian Population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 14:46:59","doi":"10.21203/rs.3.rs-9058697/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-27T12:22:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21992091936221770089552586253636921074","date":"2026-04-23T06:04:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T18:20:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93690494441800344818185367538197815634","date":"2026-04-22T16:55:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T08:31:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300877544080362847420849477565604413441","date":"2026-04-18T07:10:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38526436347863308468079971520070561118","date":"2026-04-15T14:36:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T11:55:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T07:37:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-24T07:29:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-21T23:28:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-03-21T23:23:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ad5260d-fdc5-45cb-9420-aed270542a74","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-23T14:46:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 14:46:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9058697","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9058697","identity":"rs-9058697","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}