Genetic variants in IRF2, STAT6, and TSLP are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis

Genetic variants in IRF2, STAT6, and TSLP are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis | 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 Article Genetic variants in IRF2 , STAT6 , and TSLP are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis Jana Zeitvogel, Ilona Klug, Stephan Traidl, Lennart Rösner, Susanne Mommert, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4723863/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Eczema herpeticum (EH) is a disseminated severe herpes simplex virus infection that occurs in a subset of patients with atopic dermatitis (AD). EH is a complex multifactorial disease caused by immunological changes, environmental influences, and genetic aberrations. The latter is becoming increasingly apparent, and several single nucleotide polymorphisms (SNP) have been associated with triggering EH, including genes related to interferon signaling, the epidermal barrier, and Th2-mediated immunity. So far, genetic studies have not considered the severity of AD, which may have led to associations related to AD severity rather than EH. To investigate genetic risk factors for EH in a European cohort, we analyzed several SNPs of the genes STAT6, IFNG, IFNGR1, IRF2 , and TSLP in AD patients with (ADEH+) versus a carefully matched control group of AD patients consisting of 44 patients matched for age, sex, and severity of AD (SCORAD) without a history of eczema herpeticum (ADEH-) by pyrosequencing. We confirmed an association of rs2416259 ( TSLP ), rs167769 ( STAT6 ), and rs11132242 ( IRF2 ) with ADEH + in our European cohort. However, the risk alleles for rs167769 and rs11132242 were contrary to previous reports that did not take age, sex, and disease severity into account. We could not confirm an association for several loci (rs3024975 (STAT6); rs2069705, rs2069718, rs2069727, and rs2430561 (IFNG); rs3799488 and rs9376269 (IFNGR1) ; rs1342852 ( IRF2 )) previously described in other cohorts. Moreover, linkage disequilibrium (LD) analysis revealed gametic LD and epistatic effects between STAT6 , IFNGR , and IFNG genes. Better knowledge of genetic factors predisposing to eczema herpeticum may allow the early identification of patients at increased risk and disease prevention. Our study provides important clues to possible key factors in the antiviral immunity in herpes simplex virus infection and thus to potential therapeutic interventions. Biological sciences/Genetics Biological sciences/Immunology Health sciences/Diseases Health sciences/Risk factors Figures Figure 1 Figure 2 Figure 3 Introduction Atopic dermatitis is a chronic inflammatory skin disease that affects over 20% of children and 2.2–17.6% of adults in Europe 1 . A subgroup of AD patients shows an increased risk of developing eczema herpeticum (EH), a severe and generalized herpes simplex virus 1 (HSV-1) infection (reviewed in 2 ). The mechanisms leading to this increased susceptibility are not fully understood. Since the seroprevalence of HSV-1 is 30–60% in children and over 80% in adults, but only 7–10% of AD patients will have EH, a genetic predisposition is assumed, and several single nucleotide polymorphisms (SNP) have already been associated with EH 3 – 5 . These SNPs affect genes involved in the pathogenesis of AD and protection against viral infections. Among them are genes encoding components of the epidermal barrier ( FLG, CLDN1 ), Th2-mediated immunity and Th1/Th2 balance ( STAT6, TSLP, IL-7R, TSLPR, IFNG, IFNGR1, IRF-2 ), and various mechanisms of host-defense including antiviral responses ( IFNG, IFNGR1, IRF-2, TSLP, TRIM15, SIDT2, SP110, CLEC7A ) 2 , 6 – 12 . In addition, the biological function of a few genes ( RBBP8NL, FRMD3, TPSG1, GSTZ1) is currently unknown 11 . So far, genetic studies have not considered the severity of AD, which may have led to associations related to AD severity rather than the ability to elicit an antiviral response. Furthermore, most of the research has been done in American cohorts, and data on Europeans are lacking. Thus, this study aimed to investigate the distribution of previously described SNPs in a European cohort of AD patients with (ADEH+) versus a disease-severity-matched control group of AD patients without a history of EH (ADEH-). For gene association studies, we selected SNPs of the well-described key genes of AD STAT6, IFNG, IFNGR1, IRF2 , and TSLP . These genes have important functions for balancing the Th1/Th2 immune response and/or are directly involved in antiviral immune responses, making them crucial for developing EH 2 , 13 . This study underscores the significance of three single nucleotide polymorphisms in the genes TSLP (rs2416259), STAT6 (rs167769), and IRF2 (rs11132242) for AD patients and their susceptibility to EH. However, the risk alleles for rs167769 and rs11132242 contradict previous reports. No association with ADEH + was found for rs3024975 (STAT6); rs2069705, rs2069718, rs2069727 and rs2430561 (IFNG); rs3799488 and rs9376269 (IFNGR1) and rs1342852 (IRF2) in our European cohort. Although none of the investigated SNPs in the genes IFNG and IFNGR 1 could be associated with EH, our LD analyses showed gametic LD and epistatic effects are present between the four IFNG loci and the STAT6 SNP rs167769 as well as with both IFNGR1 SNPs, confirming the importance of these 3 genes in the context of EH. A better knowledge of the genetic factors predisposing to EH may allow early identification of patients at increased risk, disease prevention, and even personalized therapeutic approaches in the future. Results rs2416259 (TSLP), rs167769 (STAT6), and rs11132242 (IRF2) are associated with ADEH+ We selected a total of 11 SNPs from the literature for genotyping (rs167769 and rs3024975 (both STAT6); rs2069705, rs2069718, rs2069727, and rs2430561 (IFNG); rs3799488 and rs9376269 (IFNGR1) ; rs1342852 and rs11132242 ( IRF2 ); and rs2416259 (TSLP) 6 – 8 , 10 , 14 ) and determined them by pyrosequencing in a European cohort of 44 patients with ADEH + and a control group of 44 ADEH– patients matched for age, sex, and SCORAD (Table 1 , Table 2 and Fig. 1 ). Age and severity are important factors for association studies as EH is more likely to affect patients with higher severity of AD (i.e., higher SCORAD, EASI, or IGA scores), and although EH can affect all ages, the probability of having experienced EH increases with advanced age 2 , 15 , 16 . Details for each SNP, such as position, function, and minor allele frequencies (MAFs), are listed in Table S1 in the supplemental information of this article. Table 1 Gender distribution. ADEH- ADEH+ Number of subjects 44 44 Female 20 (45%) 20 (45%) Male 24 (55%) 24 (55%) Table 2 Descriptive statistics of patient characteristics. Age SCORAD ADEH- ADEH+ ADEH- ADEH+ Minimum 19,00 20,00 3,100 2,200 25% Percentile 31,25 30,00 30,93 30,00 Median 40,50 38,50 38,25 38,50 75% Percentile 54,50 54,50 56,00 54,00 Maximum 75,00 83,00 85,50 86,00 Range 56,00 63,00 82,40 83,80 Mean 42,95 42,93 44,05 41,63 Std. Deviation 13,93 14,96 19,00 19,02 Std. Error of Mean 2,100 2,255 2,865 3,531 To test for genetic associations, we used the online software accessible at https://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl . We used the Fisher exact test to determine whether the allele frequencies in the ADEH and ADEH + patients at the 11 loci differed significantly from those expected for a population in Hardy-Weinberg equilibrium (HWE) (Table 3 ). All investigated SNPs met the HWE in the control and case group, except TSLP SNP rs2416259, which showed a deviation from the HWE in the case group (ADEH+) but not in the control group. HWE is often used as a quality control for genotyping, and loci deviating from HWE in controls are discarded. Since only the case group (ADEH+) deviated from HWE, it can be assumed that this is a symptom of disease association as proposed in previous studies (reviewed in 17 ) and not due to inbreeding, population stratification, or selection 18 . Table 3 Genetic association studies between IFNG, IFNGR1, IRF2, STAT6, and TSLP SNPs and ADEH- and ADEH + in European subjects. Statistical analysis was performed using the online software accessible at https://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl . Confidence interval (C.I.), dominant allele (DA), minor allele (MA), odds ratios (ORs), Hardy-Weinberg-Equilibrium (HWE). AllelE frequencies Basic allelic test Genotype frequencies. count (expected) HWE dominant model Additive model DA MA p-value OR (95% C.I.) DA homozygote heterozygote MA homozygote p-value (exact) p-value OR (95% C.I.) p-value OR IFNG rs2069705 AD EH A 55 (0.62) 50 (0.57) G 33 (0.38) 38 (0.43) 0.4423 1.27 (0.69–2.32) 16 (17.19) 14 (14.20) 23 (20.62) 22 (21.59) 5 (6.19) 8 (8.20) 0.54 1.0 0.6529 1.22 (0.51–2.96) 0.4276 1.32 rs2069718 AD EH A 38 (0.43) 47 (0.53) G 50 (0.57) 41 (0.47) 0.1745 0.66 (0.37–1.20) 6 (8.20) 10 (12.55) 26 (21.59) 27 (21.90) 12 (14.20) 7 (9.55) 0.23 0.22 0.2689 0.54 (0.18–1.63) 0.1276 0.59 rs2069727 AD EH T 50 (0.57) 56 (0.64) C 38 (0.43) 32 (0.36) 0.3555 0.75 (0.41–1.38) 11 (14.20) 17 (17.82) 28 (21.59) 22 (20.36) 5 (8.20) 5 (5.82) 0.07 0.75 0.1697 0.53 (0.21–1.32) 0.3057 0.74 rs 2430561 AD EH T 38 (0.43) 32 (0.36) A 50 (0.57) 56 (0.64) 0.3555 1.33 (0.73–2.44) 5 (8.20) 5 (5.82) 28 (21.59) 22 (20.36) 11 (14.20) 17 (17.82) 0.07 0.75 1.0000 1.00 (0.27–3.73) 0.3057 1.34 IFNGR1 rs3799488 AD EH T 78 (0.89) 73 (0.83) C 10 (0.11) 15 (0.17) 0.2803 1.60 (0.68–3.79) 34 (34.57) 31 (30.28) 10 (8.86) 11 (12.44) 0 (0.57) 2 (1.28) 1.0 0.58 0.4667 1.43 (0.55–3.71) 0.2853 2.57 rs9376269 AD EH C 68 (0.77) 63 (0.73) G 20 (0.23) 23 (0.27) 0.5391 1.24 (0.62–2.48) 28 (26.27) 24 (23.08) 12 (15.45) 15 (16.85) 4 (2.27) 4 (3.08) 0.19 0.45 0.4569 1.39 (0.59–3.27) 0.5795 1.15 IRF2 rs1342852 AD EH C 58 (0.66) 56 (0.64) T 30 (0.34) 32 (0.36) 0.7523 1.11 (0.59–2.05) 19 (19.11) 19 (17.82) 20 (19.77) 18 (20.36) 5 (5.11) 7 (5.82) 1.0 0.51 1.0000 1.00 (0.43–2.33) 0.7585 1.14 rs11132242 AD EH A 41 (0.47) 67 (0.76) G 47 (0.53) 21 (0.24) < 0.0001 0.27 (0.14–0.52) 9 (9.55) 26 (25.51) 23 (21.90) 15 (15.99) 12 (12.55) 3 (2.51) 1.0 0.68 0.0002 0.18 (0.07–0.46) 0.0001 0.28 STAT6 rs167769 AD EH C 62 (0.7) 48 (0.55) T 26 (0.3) 40 (0.45) 0.0293 1.99 (1.07–3.70) 21 (21.84) 13 (13.09) 20 (18.32) 22 (21.82) 3 (3.84) 9 (9.09) 0.72 1.00 0.0799 2.18 (0.91–5.23) 0.0278 2.14 rs3024975 AD EH G 78 (0.89) 83 (0.94) A 10 (0.11) 5 (0.06) 0.1771 0.47 (0.15–1.44) 35 (34.57) 39 (39.14) 8 (8.86) 5 (4.72) 1 (0.57) 0 (0.14) 0.44 1.00 0.2437 0.50 (0.15–1.63) 0.1883 0.51 TSLP rs2416259 AD EH A 70 (0.8) 68 (0.77) G 18 (0.2) 20 (0.23) 0.7141 1.14 (0.56–2.35) 29 (27.84) 31 (26.27) 12 (14.32) 6 (15.45) 3 (1.84) 7 (2.27) 0.35 < 0.0002 0.6471 0.81 (0.33–1.99) 0.7565 1.27 Testing for basic allelic differences revealed significant alterations only in the distribution of the alleles at the IRF2 locus rs11132242 (OR 0.27, p < 0.0001) and the STAT6 locus rs167769 (OR 1.99, p = 0.0293) (Table 3 and Fig. 2 ). Consistent with these findings, we observed a significant association between the minor allele of IRF2 SNP rs11132242 and ADEH + using both the dominant model (OR 0.178, p = 0.0002) and the additive model (Armitage trend test; OR = 0.28, p = 0.0001). The additive model also confirmed a significant association for rs167769 ( STAT6 ; OR = 2.14, p = 0.0278). In contrast to previous studies, we found no significant associations between the investigated IFNG or IFNGR1 SNPs and ADEH + compared to ADEH-. Intergenic linkage disequilibria between IFNG, IFNGR1, and STAT6 We tested for linkage disequilibrium (LD) using the online software SNPStats ( https://www.snpstats.net ) 19 . In line with the literature, the STAT6 loci rs167769 and rs3024975 showed an almost complete LD (D'=0.998) (Table S2 and Fig. 3 ). In addition, the analysis of the LDs of IFNG and IFNGR1 SNPs confirmed the results of a previous study by Leung et al. 7 . All investigated IFNG SNPs (rs2069705, rs2069718, rs2069727, rs2430561) were in almost complete LD to each other (D'=0.999); we made the same finding for IFNGR1 SNPs rs3799488 and rs9376269 (D'=0.999). Interestingly, there were LDs between loci of different genes: the four IFNG loci were in LD with the STAT6 SNP rs167769 as well as with both IFNGR1 SNPs. In addition, rs3799488 ( IFNGR1 ) and rs167769 ( STAT6 ) were in LD. Although there is no physically linked LD between these three genes, as IFNGR1 is located on chromosome 6 while STAT6 and IFNG are both located on chromosome 12, the data suggest a gametic LD and epistatic effects. Discussion Here, we focused on SNPs previously described to be associated with ADEH + and located in key AD genes, namely STAT6, IFNG, IFNGR1, IRF2, and TSLP. These genes are involved in key immunological events during AD, such as IL-4 and IFNG expression and signal transduction, Th1/Th2 balance, or isotype switching 20 . An impaired expression of any of these factors may affect susceptibility to viral infections 10 , 21 – 23 . rs2416259, a SNP located in an intron of TSLP , showed a deviation from the HWE in the case group (ADEH+), which is assumed to be a symptom of disease association (reviewed in 17 ). rs2416259 has been associated with EH and AD severity 6 . Although this SNP has not been described as deviating from HWE, previous studies have not analyzed HWE separately in the different patient groups. TSLP encodes for two different isoforms, a long-form (lf) and a short-form (sf)TSLP of 63 amino acids. While lfTSLP is increased in AD lesions and enhances Th2 responses by stimulating DCs to induce Th2 cells, sfTSLP levels are decreased (reviewed in 24 ). Upregulation of lfTSLP and downregulation of sfTSLP might facilitate HSV-1 infections as sfTSLP acts as an antimicrobial peptide and protects against HSV-1 infections (Zeitvogel et al. manuscript in preparation). Interferon regulatory factor 2 (IRF2) is a member of a family of transcription factors involved in the modulation of cellular responses to IFNs and viral infection. It is induced by IFNγ and acts as an antagonist of IRF1, thereby blocking IFN-mediated signaling 25 . Irf2 knockout mice show a defect in Th1 cell development and develop an inflammatory skin disease with histological evidence of epidermal thickening and keratinocyte proliferation similar to AD 26 . The intron variant rs111342852 was associated with a reduced IFNG expression 14 , which may explain an increased susceptibility to HSV-1 infections in carriers of this variant. We analyzed two SNPs of IRF2, rs11132242 and rs1342852. While the minor allele of rs11132242 was protective, rs1342852 showed no disease association in our cohort. These two SNPs, rs11132242 and rs1342852, were previously examined in an American cohort, one of which found a significantly increased risk of ADEH + associated with the minor alleles, whereas the second study could not confirm these results 11 , 14 . STAT6 is a key transcription factor of the type 2 dominated inflammatory micro milieu of AD 20 , 27 . It plays an important role in isotype switching to IgE synthesis and suppresses various antimicrobial peptides as well as IFNG expression. Both effects of activated STAT6 might increase the susceptibility to viral infections 10 , 21 – 23 . Here, we investigated the genetic association of rs167769, a 5’ UTR variant of STAT6, which could affect transcript levels, mRNA translation, and, thus, STAT6 protein levels. Contrary to a previous study in an American cohort that reported the minor allele (T) at rs167769 to be protective against EH 10 , in our European cohort, the minor allele was associated with an increased risk. We found no significant associations between the investigated IFNG or IFNGR1 SNPs and ADEH + compared to ADEH-. This finding contrasts the observation made in a European-American cohort where Leung et al. reported that carriers of the IFNG haplotype AGTA of the four SNPs rs2069705, rs2069718, rs2069727, rs2430561 have a higher risk of developing EH 7 . Moreover, they showed that two of these SNPs, rs2069727 (genotype CC) and rs 2430561 (genotype AA) , are functional, resulting in a reduced IFNG expression upon HSV-1 infection. Although no physically linked LD exists between the three genes IFNGR1, IFNG, and STAT6, as IFNGR1 is located on chromosome 6 while STAT6 and IFNG are both on chromosome 12, the data suggest a gametic LD and epistatic effects. Epistatic effects are very likely and align with previous reports showing that the interactions between STAT6, IFNG , and IFNGR1 regulate each other's phenotypic expression and influence the development and course of AD 28 – 30 . In conclusion, we confirmed an association of rs2416259 ( TSLP ), rs167769 ( STAT6 ), and rs11132242 ( IRF2 ) in our European cohort for ADEH+. However, our findings are inconsistent with previous reports as the risk alleles of rs167769 and rs11132242 are contradictory. We could not confirm an association in our European cohort for several loci previously described in American subjects. In addition to the different ethnicities, the study's size and the subjects' selection could also be reasons for the different results. The small number of cases is a limitation of our study. However, in contrast to several previous studies, we carefully paired our cohort to an age-, sex- and SCORAD-matched control group and thus corrected our results for AD severity. Several SNPs have been associated with AD severity, which can lead to false positive test associations if the study did not use carefully matched control groups. Larger studies are still needed to substantiate the associations and to clarify the functional impact of disease-associated SNPs on susceptibility to HSV-1 infection in AD patients. Nevertheless, the genes TSLP , STAT6 , and IRF2 were associated with EH across different cohorts and ethnicities, reinforcing these genes’ importance for EH. A better knowledge of the genetic factors predisposing to EH may allow the identification of patients at increased risk and, thus, specific patient education and even personalized early intervention. Material and Methods Cohorts 44 patients with ADEH + and a control group of 44 ADEH– patients matched for age, sex, and disease severity (SCORAD) (Table 1 , Table 2 , and Fig. 1 ) were recruited for this study from the Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. The Ethics Committee of the Hannover Medical School approved the study. It was in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983. All patients provided written informed consent. Pyrosequencing Samples were analyzed by pyrosequencing as described before 31 . Briefly, genomic DNA was isolated from peripheral blood using the Qiagen DNA mini kit (Qiagen, Hilden, Germany) according to the manufacturer ́s instructions. The region of interest was amplified using PyroMark Q24 PCR (Qiagen, Hilden, Germany) and a sequence-specific primer pair, one of which was biotinylated. The PCR product was denatured, and the biotinylated DNA strand was isolated using the PyroMark Q24 Vacuum Workstation (Qiagen) and streptavidin-coated Sepharose beads (Streptavidin Sepharose High Performance, GE Healthcare, Uppsala, Sweden) following the manufacturer´s instructions. The biotinylated single-stranded PCR amplicons were used as templates for pyrosequencing. Hybridization was performed with the specific sequencing primer, and the pyrosequencing was performed using PyroMark Gold reagents and the PyroMark Q24 machine (Qiagen) according to the manufacturer's instructions. All primers were designed using PyroMark Assay Design Software 2.0 (Qiagen) and synthesized by TIB Molbiol (Berlin, Germany) as a custom service. Primer sequences for each SNP and further details, such as position, function, and minor allele frequencies (MAFs), are listed in Table S1 in the supplemental information of this article. Statistics Genetic association studies were performed using the online software https://ihg.gsf.de/cgi-bin/hw/hwa1.pl (accessed on 22 September 2022). Basic allelic differences, the dominant model, and the additive model (Armitage trend test) were considered for data analysis. The Hardy-Weinberg equilibrium (HWE) was analyzed using the Fisher exact test. Linkage disequilibrium (LD) was analyzed using the web-based program SNPStats ( https://www.snpstats.net ) 19 . Data availability statement All data are presented in the figures and tables. The raw data are available from the corresponding author upon reasonable request. References Kowalska-Olędzka, E., Czarnecka, M. & Baran, A. Epidemiology of atopic dermatitis in Europe. J. Drug Assess. 8, 126–128 (2019). Traidl, S., Roesner, L., Zeitvogel, J. & Werfel, T. Eczema herpeticum in atopic dermatitis. Allergy 76, 3017–3027 (2021). Igde, M., Igde, F. A. & Yazici, Z. Herpes Simplex Type I Infection and Atopy Association in Turkish Children with Asthma and Allergic Rhinitis. Iran J Allergy Asthma Immunol 8, 149–54 (2009). James, C. et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull. World Health Organ. 98, 315–329 (2020). Wutzler, P. et al. Seroprevalence of herpes simplex virus type 1 and type 2 in selected German populations-relevance for the incidence of genital herpes. J. Med. Virol. 61, 201–207 (2000). Gao, P.-S. et al. Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J. Allergy Clin. Immunol. 125, 1403–1407.e4 (2010). Leung, D. Y. M. et al. Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-γ response. J. Allergy Clin. Immunol. 127, 965–973.e5 (2011). Gao, L. et al. Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum. J. Allergy Clin. Immunol. 136, 1591–1600 (2015). Howell, M. et al. Cathelicidin deficiency predisposes to eczema herpeticum. J. Allergy Clin. Immunol. 117, 836–841 (2006). Howell, M. D. et al. The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J. Allergy Clin. Immunol. 128, 1006–1014 (2011). Bin, L. et al. Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum. Allergy 76, 2510–2523 (2021). De Benedetto, A. et al. Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J. Allergy Clin. Immunol. 128, 242–246.e5 (2011). Damour, A., Garcia, M., Seneschal, J., Lévêque, N. & Bodet, C. Eczema Herpeticum: Clinical and Pathophysiological Aspects. Clin. Rev. Allergy Immunol. 59, 1–18 (2020). Gao, P.-S. et al. Genetic Variants in Interferon Regulatory Factor 2 (IRF2) Are Associated with Atopic Dermatitis and Eczema Herpeticum. J. Invest. Dermatol. 132, 650–657 (2012). Seegräber, M. et al. Recurrent eczema herpeticum - a retrospective European multicenter study evaluating the clinical characteristics of eczema herpeticum cases in atopic dermatitis patients. J. Eur. Acad. Dermatol. Venereol. JEADV 34, 1074–1079 (2020). Traidl, S. et al. High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 21, 1490–1498 (2023). Namipashaki, A. & Razaghi-Moghadam, Z. The Essentiality of Reporting Hardy-Weinberg Equilibrium Calculations in Population-Based Genetic Association Studies. CELL J. 17, 8 (2015). Balding, D. J. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781–791 (2006). Sole, X., Guino, E., Valls, J., Iniesta, R. & Moreno, V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 22, 1928–1929 (2006). Roesner, L. M., Zeitvogel, J. & Heratizadeh, A. Common and different roles of IL-4 and IL-13 in skin allergy and clinical implications. Curr. Opin. Allergy Clin. Immunol. 19, 319–327 (2019). Howell, M. D. The role of human beta defensins and cathelicidins in atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 7, 413–417 (2007). Howell, M. D. et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24, 341–348 (2006). Ohmori, Y. & Hamilton, T. A. IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages. J. Immunol. Baltim. Md 1950 159, 5474–5482 (1997). Bjerkan, L., Sonesson, A. & Schenck, K. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP). Pharmaceuticals 9, 41 (2016). Kröger, A., Köster, M., Schroeder, K., Hauser, H. & Mueller, P. P. Activities of IRF-1. J. Interferon Cytokine Res. Off. J. Int. Soc. Interferon Cytokine Res. 22, 5–14 (2002). Hida, S., Tadachi, M., Saito, T. & Taki, S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 106, 2011–2017 (2005). Lim, Y. et al. Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer. Nat. Commun. 12, 4217 (2021). Herberth, G. et al. Reduced IFN-γ- and enhanced IL-4-producing CD4 + cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 year of life. Pediatr. Allergy Immunol. 21, 5–13 (2010). Ivashkiv, L. B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 18, 545–558 (2018). Spilianakis, C. G. & Flavell, R. A. Epigenetic regulation of Ifng expression. Nat. Immunol. 8, 681–683 (2007). Mommert, S. et al. Genetic variations within the promotor region of the human histamine H4 receptor gene in psoriasis patients. Pharmacol. Res. 114, 121–127 (2016). Declarations Acknowledgments The study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2155 - project number 390874280. Biorender was used for the preparation of Figure 3. Author Contributions Statement J.Z. contributed to the study concept, methodology, design, analysis, and interpretation of data and wrote the main manuscript; I.K. performed the acquisition, collection, and investigation of data; S.T. and L.R. contributed to the collection of the clinical data and to editing the manuscript; S.M. contributed to methodology; K.D. contributed to review and editing the manuscript; T. W. obtained funding and supervised the study. All authors reviewed the manuscript. Additional Information The authors have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the results and/or discussion reported in this paper. 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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-4723863","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":330003194,"identity":"2abebe34-cf0c-4435-8570-5c2698331aa0","order_by":0,"name":"Jana Zeitvogel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIie3QMQrCMBSA4RcKnSKuKaXtFQIdXApepVk8R0ohk9JVb+FUulkIZErxAB0FJxcpCAVFW0cRUjeHfGTMz3sJgGX9I+fYdeie4DnIGhAfj4nLhI/EKvQylU5PHCRkTKWm05JIoDFxGFf6Rq4VBIUpoQrlw1tclq2b0ttpiHemMTTKuI84ZjlpynYmgO1r82JjQpiILuf2MSQHUwLqndAYg3ZbNE6Z8Jbhk3kaElCLfqNJvJ2wWN71/ImXtTzRvkqCgpvGfCA/3rcsy7K+egHVxkoD3wBCvQAAAABJRU5ErkJggg==","orcid":"","institution":"Hannover Medical School","correspondingAuthor":true,"prefix":"","firstName":"Jana","middleName":"","lastName":"Zeitvogel","suffix":""},{"id":330003195,"identity":"5b173ec2-dc50-42cb-b59e-5109d0ca5257","order_by":1,"name":"Ilona Klug","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Ilona","middleName":"","lastName":"Klug","suffix":""},{"id":330003196,"identity":"7f6cf158-51ba-406e-a7eb-483ce5646ed6","order_by":2,"name":"Stephan Traidl","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Traidl","suffix":""},{"id":330003197,"identity":"79645989-3925-45d7-a834-595fe91c683b","order_by":3,"name":"Lennart Rösner","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Lennart","middleName":"","lastName":"Rösner","suffix":""},{"id":330003198,"identity":"0614cc57-9445-41c4-a7e8-518fc322a514","order_by":4,"name":"Susanne Mommert","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"","lastName":"Mommert","suffix":""},{"id":330003199,"identity":"80a61863-a9ff-49e0-b060-cf03a98ba627","order_by":5,"name":"Katinka Döhner","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Katinka","middleName":"","lastName":"Döhner","suffix":""},{"id":330003201,"identity":"1d3bf0cf-698e-4f9f-bd21-c383550580ad","order_by":6,"name":"Thomas Werfel","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Werfel","suffix":""}],"badges":[],"createdAt":"2024-07-11 11:39:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4723863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4723863/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60850654,"identity":"e43608cc-fc10-424d-b88d-d053095b6543","added_by":"auto","created_at":"2024-07-22 20:54:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59083,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Age and (B) SCORAD distribution.\u003c/strong\u003e Age and SCORAD-matched ADEH+ and ADEH- subjects were used for this study.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4723863/v1/110d89c3d02148ade425d17a.png"},{"id":60850659,"identity":"84ab1e54-4da5-4b2f-bbc7-05451e3c69b2","added_by":"auto","created_at":"2024-07-22 20:54:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":102861,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ers11132242, rs167769, and rs2416259 show significant differences in the distribution of MA or genotypes.\u003c/strong\u003e (A) MA frequencies are depicted, and asterisks indicate significant differences calculated with the basic allelic test. (B) Frequencies of the homozygous genotype of the MA are represented. Asterisks indicate significant derivation of HWE. * p\u0026lt;0.05; ** p\u0026lt;0.005; *** p\u0026lt;0.0005.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4723863/v1/b3f97b8170aa8e6e2b5c2892.png"},{"id":60850656,"identity":"ea32d56f-96d1-4a68-9a57-7aeb46615c54","added_by":"auto","created_at":"2024-07-22 20:54:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":423900,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLD analysis reveals gametic and epistatic linkage between IFNGR1, STAT6, and IFNG genotypes. \u003c/strong\u003eChromosomal location, gene structure, and patterns of LD are shown. The color gradation from white to red reflects lower to higher LD. Statistical values are provided in the supplemental information for this article (Table S2).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4723863/v1/9f94773cd9b6c42d7cb21842.png"},{"id":67258274,"identity":"977ab7af-b721-4503-b88d-6c04939ee92f","added_by":"auto","created_at":"2024-10-23 05:24:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1304198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4723863/v1/10bf359c-2058-45ca-9a0b-ae80ba7044b9.pdf"},{"id":60850664,"identity":"1adb4281-03bb-4f07-8a22-1361e41ff47d","added_by":"auto","created_at":"2024-07-22 20:54:37","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":24983,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-4723863/v1/cc1ae24b2cef50d0dbe2a17f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eGenetic variants in \u003cem\u003eIRF2\u003c/em\u003e, \u003cem\u003eSTAT6\u003c/em\u003e, and \u003cem\u003eTSLP\u003c/em\u003e are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAtopic dermatitis is a chronic inflammatory skin disease that affects over 20% of children and 2.2\u0026ndash;17.6% of adults in Europe \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. A subgroup of AD patients shows an increased risk of developing eczema herpeticum (EH), a severe and generalized herpes simplex virus 1 (HSV-1) infection (reviewed in \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). The mechanisms leading to this increased susceptibility are not fully understood. Since the seroprevalence of HSV-1 is 30\u0026ndash;60% in children and over 80% in adults, but only 7\u0026ndash;10% of AD patients will have EH, a genetic predisposition is assumed, and several single nucleotide polymorphisms (SNP) have already been associated with EH \u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. These SNPs affect genes involved in the pathogenesis of AD and protection against viral infections. Among them are genes encoding components of the epidermal barrier (\u003cem\u003eFLG, CLDN1\u003c/em\u003e), Th2-mediated immunity and Th1/Th2 balance (\u003cem\u003eSTAT6, TSLP, IL-7R, TSLPR, IFNG, IFNGR1, IRF-2\u003c/em\u003e), and various mechanisms of host-defense including antiviral responses (\u003cem\u003eIFNG, IFNGR1, IRF-2, TSLP, TRIM15, SIDT2, SP110, CLEC7A\u003c/em\u003e) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In addition, the biological function of a few genes (\u003cem\u003eRBBP8NL, FRMD3, TPSG1, GSTZ1)\u003c/em\u003e is currently unknown \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSo far, genetic studies have not considered the severity of AD, which may have led to associations related to AD severity rather than the ability to elicit an antiviral response. Furthermore, most of the research has been done in American cohorts, and data on Europeans are lacking. Thus, this study aimed to investigate the distribution of previously described SNPs in a European cohort of AD patients with (ADEH+) versus a disease-severity-matched control group of AD patients without a history of EH (ADEH-). For gene association studies, we selected SNPs of the well-described key genes of AD \u003cem\u003eSTAT6, IFNG, IFNGR1, IRF2\u003c/em\u003e, and \u003cem\u003eTSLP\u003c/em\u003e. These genes have important functions for balancing the Th1/Th2 immune response and/or are directly involved in antiviral immune responses, making them crucial for developing EH \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study underscores the significance of three single nucleotide polymorphisms in the genes \u003cem\u003eTSLP\u003c/em\u003e (rs2416259), \u003cem\u003eSTAT6\u003c/em\u003e (rs167769), and \u003cem\u003eIRF2\u003c/em\u003e (rs11132242) for AD patients and their susceptibility to EH. However, the risk alleles for rs167769 and rs11132242 contradict previous reports. No association with ADEH\u0026thinsp;+\u0026thinsp;was found for rs3024975 (STAT6); rs2069705, rs2069718, rs2069727 and rs2430561 (IFNG); rs3799488 and rs9376269 (IFNGR1) and rs1342852 (IRF2) in our European cohort. Although none of the investigated SNPs in the genes \u003cem\u003eIFNG\u003c/em\u003e and \u003cem\u003eIFNGR\u003c/em\u003e1 could be associated with EH, our LD analyses showed gametic LD and epistatic effects are present between the four \u003cem\u003eIFNG\u003c/em\u003e loci and the \u003cem\u003eSTAT6\u003c/em\u003e SNP rs167769 as well as with both \u003cem\u003eIFNGR1\u003c/em\u003e SNPs, confirming the importance of these 3 genes in the context of EH. A better knowledge of the genetic factors predisposing to EH may allow early identification of patients at increased risk, disease prevention, and even personalized therapeutic approaches in the future.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ers2416259 (TSLP), rs167769 (STAT6), and rs11132242 (IRF2) are associated with ADEH+\u003c/h2\u003e \u003cp\u003eWe selected a total of 11 SNPs from the literature for genotyping (rs167769 and rs3024975 (both STAT6); rs2069705, rs2069718, rs2069727, and rs2430561 (IFNG); rs3799488 and rs9376269 \u003cem\u003e(IFNGR1)\u003c/em\u003e; rs1342852 and rs11132242 (\u003cem\u003eIRF2\u003c/em\u003e); and rs2416259 (TSLP) \u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e) and determined them by pyrosequencing in a European cohort of 44 patients with ADEH\u0026thinsp;+\u0026thinsp;and a control group of 44 ADEH\u0026ndash; patients matched for age, sex, and SCORAD (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Age and severity are important factors for association studies as EH is more likely to affect patients with higher severity of AD (i.e., higher SCORAD, EASI, or IGA scores), and although EH can affect all ages, the probability of having experienced EH increases with advanced age \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Details for each SNP, such as position, function, and minor allele frequencies (MAFs), are listed in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e in the supplemental information of this article.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGender distribution.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADEH-\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eADEH+\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of subjects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (45%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (55%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive statistics of patient characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eSCORAD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADEH-\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eADEH+\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eADEH-\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eADEH+\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMinimum\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3,100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2,200\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e25% Percentile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31,25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30,93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30,00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38,25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38,50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e75% Percentile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e54,00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaximum\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e75,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e85,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e86,00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRange\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e82,40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e83,80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42,95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42,93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e44,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e41,63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStd. Deviation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13,93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14,96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19,02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStd. Error of Mean\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2,255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2,865\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3,531\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo test for genetic associations, we used the online software accessible at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl\u003c/span\u003e\u003cspan address=\"https://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. We used the Fisher exact test to determine whether the allele frequencies in the ADEH and ADEH\u0026thinsp;+\u0026thinsp;patients at the 11 loci differed significantly from those expected for a population in Hardy-Weinberg equilibrium (HWE) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). All investigated SNPs met the HWE in the control and case group, except \u003cem\u003eTSLP\u003c/em\u003e SNP rs2416259, which showed a deviation from the HWE in the case group (ADEH+) but not in the control group. HWE is often used as a quality control for genotyping, and loci deviating from HWE in controls are discarded. Since only the case group (ADEH+) deviated from HWE, it can be assumed that this is a symptom of disease association as proposed in previous studies (reviewed in \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e) and not due to inbreeding, population stratification, or selection \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eGenetic association studies between IFNG, IFNGR1, IRF2, STAT6, and TSLP SNPs and ADEH- and ADEH\u0026thinsp;+\u0026thinsp;in European subjects.\u003c/b\u003e Statistical analysis was performed using the online software accessible at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl\u003c/span\u003e\u003cspan address=\"https://ihg.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Confidence interval (C.I.), dominant allele (DA), minor allele (MA), odds ratios (ORs), Hardy-Weinberg-Equilibrium (HWE).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"15\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" morerows=\"1\" nameend=\"c3\" namest=\"c1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eAllelE frequencies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eBasic allelic test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eGenotype frequencies. count (expected)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHWE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003edominant model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c15\" namest=\"c14\"\u003e \u003cp\u003eAdditive model\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003cp\u003e(95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDA homozygote\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eheterozygote\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMA homozygote\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003ep-value (exact)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003cp\u003e(95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cem\u003eIFNG\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers2069705\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e55 (0.62)\u003c/p\u003e \u003cp\u003e50 (0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003e33 (0.38)\u003c/p\u003e \u003cp\u003e38 (0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.4423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003cp\u003e(0.69\u0026ndash;2.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16 (17.19)\u003c/p\u003e \u003cp\u003e14 (14.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e23 (20.62)\u003c/p\u003e \u003cp\u003e22 (21.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5 (6.19)\u003c/p\u003e \u003cp\u003e8 (8.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.6529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003cp\u003e(0.51\u0026ndash;2.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.4276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers2069718\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e38 (0.43)\u003c/p\u003e \u003cp\u003e47 (0.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003e50 (0.57)\u003c/p\u003e \u003cp\u003e41 (0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003cp\u003e(0.37\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6 (8.20)\u003c/p\u003e \u003cp\u003e10 (12.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26 (21.59)\u003c/p\u003e \u003cp\u003e27 (21.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12 (14.20)\u003c/p\u003e \u003cp\u003e7 (9.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.2689\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003cp\u003e(0.18\u0026ndash;1.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.1276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e 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colname=\"c8\"\u003e \u003cp\u003e34 (34.57)\u003c/p\u003e \u003cp\u003e31 (30.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10 (8.86)\u003c/p\u003e \u003cp\u003e11 (12.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0 (0.57)\u003c/p\u003e \u003cp\u003e2 (1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.4667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003cp\u003e(0.55\u0026ndash;3.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.2853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e2.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e 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(23.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12 (15.45)\u003c/p\u003e \u003cp\u003e15 (16.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4 (2.27)\u003c/p\u003e \u003cp\u003e4 (3.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.4569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003cp\u003e(0.59\u0026ndash;3.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.5795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eIRF2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers1342852\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC\u003c/p\u003e \u003cp\u003e58 (0.66)\u003c/p\u003e \u003cp\u003e56 (0.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u003c/p\u003e \u003cp\u003e30 (0.34)\u003c/p\u003e \u003cp\u003e32 (0.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.7523\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003cp\u003e(0.59\u0026ndash;2.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e19 (19.11)\u003c/p\u003e \u003cp\u003e19 (17.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20 (19.77)\u003c/p\u003e \u003cp\u003e18 (20.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5 (5.11)\u003c/p\u003e \u003cp\u003e7 (5.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e1.0000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003cp\u003e(0.43\u0026ndash;2.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.7585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers11132242\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e41 (0.47)\u003c/p\u003e \u003cp\u003e67 (0.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003e47 (0.53)\u003c/p\u003e \u003cp\u003e21 (0.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003cp\u003e(0.14\u0026ndash;0.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9 (9.55)\u003c/p\u003e \u003cp\u003e26 (25.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e23 (21.90)\u003c/p\u003e \u003cp\u003e15 (15.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12 (12.55)\u003c/p\u003e \u003cp\u003e3 (2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003e0.0002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003cp\u003e(0.07\u0026ndash;0.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eSTAT6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers167769\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC\u003c/p\u003e \u003cp\u003e62 (0.7)\u003c/p\u003e \u003cp\u003e48 (0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u003c/p\u003e \u003cp\u003e26 (0.3)\u003c/p\u003e \u003cp\u003e40 (0.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.0293\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.99\u003c/p\u003e \u003cp\u003e(1.07\u0026ndash;3.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21 (21.84)\u003c/p\u003e \u003cp\u003e13 (13.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20 (18.32)\u003c/p\u003e \u003cp\u003e22 (21.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3 (3.84)\u003c/p\u003e \u003cp\u003e9 (9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.0799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.18\u003c/p\u003e \u003cp\u003e(0.91\u0026ndash;5.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e\u003cb\u003e0.0278\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e2.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers3024975\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003e78 (0.89)\u003c/p\u003e \u003cp\u003e83 (0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e10 (0.11)\u003c/p\u003e \u003cp\u003e5 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1771\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003cp\u003e(0.15\u0026ndash;1.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e35 (34.57)\u003c/p\u003e \u003cp\u003e39 (39.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8 (8.86)\u003c/p\u003e \u003cp\u003e5 (4.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1 (0.57)\u003c/p\u003e \u003cp\u003e0 (0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.2437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003cp\u003e(0.15\u0026ndash;1.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.1883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTSLP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers2416259\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eEH\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003e70 (0.8)\u003c/p\u003e \u003cp\u003e68 (0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003e18 (0.2)\u003c/p\u003e \u003cp\u003e20 (0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.7141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003cp\u003e(0.56\u0026ndash;2.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29 (27.84)\u003c/p\u003e \u003cp\u003e31 (26.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12 (14.32)\u003c/p\u003e \u003cp\u003e6 (15.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3 (1.84)\u003c/p\u003e \u003cp\u003e7 (2.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.6471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003cp\u003e(0.33\u0026ndash;1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e0.7565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTesting for basic allelic differences revealed significant alterations only in the distribution of the alleles at the \u003cem\u003eIRF2\u003c/em\u003e locus rs11132242 (OR 0.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and the \u003cem\u003eSTAT6\u003c/em\u003e locus rs167769 (OR 1.99, p\u0026thinsp;=\u0026thinsp;0.0293) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Consistent with these findings, we observed a significant association between the minor allele of \u003cem\u003eIRF2\u003c/em\u003e SNP rs11132242 and ADEH\u0026thinsp;+\u0026thinsp;using both the dominant model (OR 0.178, p\u0026thinsp;=\u0026thinsp;0.0002) and the additive model (Armitage trend test; OR\u0026thinsp;=\u0026thinsp;0.28, p\u0026thinsp;=\u0026thinsp;0.0001). The additive model also confirmed a significant association for rs167769 (\u003cem\u003eSTAT6\u003c/em\u003e; OR\u0026thinsp;=\u0026thinsp;2.14, p\u0026thinsp;=\u0026thinsp;0.0278).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn contrast to previous studies, we found no significant associations between the investigated \u003cem\u003eIFNG\u003c/em\u003e or \u003cem\u003eIFNGR1\u003c/em\u003e SNPs and ADEH\u0026thinsp;+\u0026thinsp;compared to ADEH-.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eIntergenic linkage disequilibria between IFNG, IFNGR1, and STAT6\u003c/h2\u003e \u003cp\u003eWe tested for linkage disequilibrium (LD) using the online software SNPStats (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.snpstats.net\u003c/span\u003e\u003cspan address=\"https://www.snpstats.net\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e19\u003c/sup\u003e. In line with the literature, the \u003cem\u003eSTAT6\u003c/em\u003e loci rs167769 and rs3024975 showed an almost complete LD (D'=0.998) (Table S2 and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, the analysis of the LDs of \u003cem\u003eIFNG\u003c/em\u003e and \u003cem\u003eIFNGR1\u003c/em\u003e SNPs confirmed the results of a previous study by Leung et al.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. All investigated \u003cem\u003eIFNG\u003c/em\u003e SNPs (rs2069705, rs2069718, rs2069727, rs2430561) were in almost complete LD to each other (D'=0.999); we made the same finding for \u003cem\u003eIFNGR1\u003c/em\u003e SNPs rs3799488 and rs9376269 (D'=0.999). Interestingly, there were LDs between loci of different genes: the four \u003cem\u003eIFNG\u003c/em\u003e loci were in LD with the \u003cem\u003eSTAT6\u003c/em\u003e SNP rs167769 as well as with both \u003cem\u003eIFNGR1\u003c/em\u003e SNPs. In addition, rs3799488 (\u003cem\u003eIFNGR1\u003c/em\u003e) and rs167769 (\u003cem\u003eSTAT6\u003c/em\u003e) were in LD. Although there is no physically linked LD between these three genes, as \u003cem\u003eIFNGR1\u003c/em\u003e is located on chromosome 6 while \u003cem\u003eSTAT6\u003c/em\u003e and \u003cem\u003eIFNG\u003c/em\u003e are both located on chromosome 12, the data suggest a gametic LD and epistatic effects.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere, we focused on SNPs previously described to be associated with ADEH\u0026thinsp;+\u0026thinsp;and located in key AD genes, namely STAT6, IFNG, IFNGR1, IRF2, and TSLP. These genes are involved in key immunological events during AD, such as IL-4 and IFNG expression and signal transduction, Th1/Th2 balance, or isotype switching \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. An impaired expression of any of these factors may affect susceptibility to viral infections \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ers2416259, a SNP located in an intron of \u003cem\u003eTSLP\u003c/em\u003e, showed a deviation from the HWE in the case group (ADEH+), which is assumed to be a symptom of disease association (reviewed in \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e). rs2416259 has been associated with EH and AD severity \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Although this SNP has not been described as deviating from HWE, previous studies have not analyzed HWE separately in the different patient groups. \u003cem\u003eTSLP\u003c/em\u003e encodes for two different isoforms, a long-form (lf) and a short-form (sf)TSLP of 63 amino acids. While lfTSLP is increased in AD lesions and enhances Th2 responses by stimulating DCs to induce Th2 cells, sfTSLP levels are decreased (reviewed in \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e). Upregulation of lfTSLP and downregulation of sfTSLP might facilitate HSV-1 infections as sfTSLP acts as an antimicrobial peptide and protects against HSV-1 infections (Zeitvogel et al. manuscript in preparation).\u003c/p\u003e \u003cp\u003eInterferon regulatory factor 2 (IRF2) is a member of a family of transcription factors involved in the modulation of cellular responses to IFNs and viral infection. It is induced by IFNγ and acts as an antagonist of IRF1, thereby blocking IFN-mediated signaling \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eIrf2\u003c/em\u003e knockout mice show a defect in Th1 cell development and develop an inflammatory skin disease with histological evidence of epidermal thickening and keratinocyte proliferation similar to AD \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. The intron variant rs111342852 was associated with a reduced \u003cem\u003eIFNG\u003c/em\u003e expression \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, which may explain an increased susceptibility to HSV-1 infections in carriers of this variant. We analyzed two SNPs of IRF2, rs11132242 and rs1342852. While the minor allele of rs11132242 was protective, rs1342852 showed no disease association in our cohort. These two SNPs, rs11132242 and rs1342852, were previously examined in an American cohort, one of which found a significantly increased risk of ADEH\u0026thinsp;+\u0026thinsp;associated with the minor alleles, whereas the second study could not confirm these results \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSTAT6 is a key transcription factor of the type 2 dominated inflammatory micro milieu of AD \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. It plays an important role in isotype switching to IgE synthesis and suppresses various antimicrobial peptides as well as \u003cem\u003eIFNG\u003c/em\u003e expression. Both effects of activated STAT6 might increase the susceptibility to viral infections \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Here, we investigated the genetic association of rs167769, a 5\u0026rsquo; UTR variant of STAT6, which could affect transcript levels, mRNA translation, and, thus, STAT6 protein levels. Contrary to a previous study in an American cohort that reported the minor allele (T) at rs167769 to be protective against EH \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, in our European cohort, the minor allele was associated with an increased risk.\u003c/p\u003e \u003cp\u003eWe found no significant associations between the investigated \u003cem\u003eIFNG\u003c/em\u003e or \u003cem\u003eIFNGR1\u003c/em\u003e SNPs and ADEH\u0026thinsp;+\u0026thinsp;compared to ADEH-. This finding contrasts the observation made in a European-American cohort where Leung et al. reported that carriers of the \u003cem\u003eIFNG\u003c/em\u003e haplotype AGTA of the four SNPs rs2069705, rs2069718, rs2069727, rs2430561 have a higher risk of developing EH \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Moreover, they showed that two of these SNPs, rs2069727 (genotype CC) and \u003cem\u003ers\u003c/em\u003e2430561 (genotype \u003cem\u003eAA)\u003c/em\u003e, are functional, resulting in a reduced \u003cem\u003eIFNG\u003c/em\u003e expression upon HSV-1 infection.\u003c/p\u003e \u003cp\u003eAlthough no physically linked LD exists between the three genes IFNGR1, IFNG, and STAT6, as \u003cem\u003eIFNGR1\u003c/em\u003e is located on chromosome 6 while \u003cem\u003eSTAT6\u003c/em\u003e and \u003cem\u003eIFNG\u003c/em\u003e are both on chromosome 12, the data suggest a gametic LD and epistatic effects. Epistatic effects are very likely and align with previous reports showing that the interactions between \u003cem\u003eSTAT6, IFNG\u003c/em\u003e, and \u003cem\u003eIFNGR1\u003c/em\u003e regulate each other's phenotypic expression and influence the development and course of AD \u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, we confirmed an association of rs2416259 (\u003cem\u003eTSLP\u003c/em\u003e), rs167769 (\u003cem\u003eSTAT6\u003c/em\u003e), and rs11132242 (\u003cem\u003eIRF2\u003c/em\u003e) in our European cohort for ADEH+. However, our findings are inconsistent with previous reports as the risk alleles of rs167769 and rs11132242 are contradictory. We could not confirm an association in our European cohort for several loci previously described in American subjects. In addition to the different ethnicities, the study's size and the subjects' selection could also be reasons for the different results. The small number of cases is a limitation of our study. However, in contrast to several previous studies, we carefully paired our cohort to an age-, sex- and SCORAD-matched control group and thus corrected our results for AD severity. Several SNPs have been associated with AD severity, which can lead to false positive test associations if the study did not use carefully matched control groups. Larger studies are still needed to substantiate the associations and to clarify the functional impact of disease-associated SNPs on susceptibility to HSV-1 infection in AD patients. Nevertheless, the genes \u003cem\u003eTSLP\u003c/em\u003e, \u003cem\u003eSTAT6\u003c/em\u003e, and \u003cem\u003eIRF2\u003c/em\u003e were associated with EH across different cohorts and ethnicities, reinforcing these genes\u0026rsquo; importance for EH. A better knowledge of the genetic factors predisposing to EH may allow the identification of patients at increased risk and, thus, specific patient education and even personalized early intervention.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCohorts\u003c/h2\u003e \u003cp\u003e44 patients with ADEH\u0026thinsp;+\u0026thinsp;and a control group of 44 ADEH\u0026ndash; patients matched for age, sex, and disease severity (SCORAD) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) were recruited for this study from the Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. The Ethics Committee of the Hannover Medical School approved the study. It was in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983. All patients provided written informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePyrosequencing\u003c/h2\u003e \u003cp\u003eSamples were analyzed by pyrosequencing as described before \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Briefly, genomic DNA was isolated from peripheral blood using the Qiagen DNA mini kit (Qiagen, Hilden, Germany) according to the manufacturer ́s instructions. The region of interest was amplified using PyroMark Q24 PCR (Qiagen, Hilden, Germany) and a sequence-specific primer pair, one of which was biotinylated. The PCR product was denatured, and the biotinylated DNA strand was isolated using the PyroMark Q24 Vacuum Workstation (Qiagen) and streptavidin-coated Sepharose beads (Streptavidin Sepharose High Performance, GE Healthcare, Uppsala, Sweden) following the manufacturer\u0026acute;s instructions. The biotinylated single-stranded PCR amplicons were used as templates for pyrosequencing. Hybridization was performed with the specific sequencing primer, and the pyrosequencing was performed using PyroMark Gold reagents and the PyroMark Q24 machine (Qiagen) according to the manufacturer's instructions.\u003c/p\u003e \u003cp\u003eAll primers were designed using PyroMark Assay Design Software 2.0 (Qiagen) and synthesized by TIB Molbiol (Berlin, Germany) as a custom service. Primer sequences for each SNP and further details, such as position, function, and minor allele frequencies (MAFs), are listed in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e in the supplemental information of this article.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eGenetic association studies were performed using the online software \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ihg.gsf.de/cgi-bin/hw/hwa1.pl\u003c/span\u003e\u003cspan address=\"https://ihg.gsf.de/cgi-bin/hw/hwa1.pl\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 22 September 2022). Basic allelic differences, the dominant model, and the additive model (Armitage trend test) were considered for data analysis. The Hardy-Weinberg equilibrium (HWE) was analyzed using the Fisher exact test. Linkage disequilibrium (LD) was analyzed using the web-based program SNPStats (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.snpstats.net\u003c/span\u003e\u003cspan address=\"https://www.snpstats.net\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eData availability statement\u003c/h3\u003e\n\u003cp\u003eAll data are presented in the figures and tables. The raw data are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKowalska-Olędzka, E., Czarnecka, M. \u0026amp; Baran, A. Epidemiology of atopic dermatitis in Europe. J. Drug Assess. 8, 126\u0026ndash;128 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraidl, S., Roesner, L., Zeitvogel, J. \u0026amp; Werfel, T. Eczema herpeticum in atopic dermatitis. Allergy 76, 3017\u0026ndash;3027 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIgde, M., Igde, F. A. \u0026amp; Yazici, Z. Herpes Simplex Type I Infection and Atopy Association in Turkish Children with Asthma and Allergic Rhinitis. Iran J Allergy Asthma Immunol 8, 149\u0026ndash;54 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJames, C. \u003cem\u003eet al.\u003c/em\u003e Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull. World Health Organ. 98, 315\u0026ndash;329 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWutzler, P. \u003cem\u003eet al.\u003c/em\u003e Seroprevalence of herpes simplex virus type 1 and type 2 in selected German populations-relevance for the incidence of genital herpes. J. Med. Virol. 61, 201\u0026ndash;207 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao, P.-S. \u003cem\u003eet al.\u003c/em\u003e Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J. Allergy Clin. Immunol. 125, 1403\u0026ndash;1407.e4 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeung, D. Y. M. \u003cem\u003eet al.\u003c/em\u003e Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-γ response. J. Allergy Clin. Immunol. 127, 965\u0026ndash;973.e5 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao, L. \u003cem\u003eet al.\u003c/em\u003e Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum. J. Allergy Clin. Immunol. 136, 1591\u0026ndash;1600 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowell, M. \u003cem\u003eet al.\u003c/em\u003e Cathelicidin deficiency predisposes to eczema herpeticum. J. Allergy Clin. Immunol. 117, 836\u0026ndash;841 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowell, M. D. \u003cem\u003eet al.\u003c/em\u003e The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J. Allergy Clin. Immunol. 128, 1006\u0026ndash;1014 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBin, L. \u003cem\u003eet al.\u003c/em\u003e Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum. Allergy 76, 2510\u0026ndash;2523 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Benedetto, A. \u003cem\u003eet al.\u003c/em\u003e Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J. Allergy Clin. Immunol. 128, 242\u0026ndash;246.e5 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamour, A., Garcia, M., Seneschal, J., L\u0026eacute;v\u0026ecirc;que, N. \u0026amp; Bodet, C. Eczema Herpeticum: Clinical and Pathophysiological Aspects. Clin. Rev. Allergy Immunol. 59, 1\u0026ndash;18 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao, P.-S. \u003cem\u003eet al.\u003c/em\u003e Genetic Variants in Interferon Regulatory Factor 2 (IRF2) Are Associated with Atopic Dermatitis and Eczema Herpeticum. J. Invest. Dermatol. 132, 650\u0026ndash;657 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeegr\u0026auml;ber, M. \u003cem\u003eet al.\u003c/em\u003e Recurrent eczema herpeticum - a retrospective European multicenter study evaluating the clinical characteristics of eczema herpeticum cases in atopic dermatitis patients. J. Eur. Acad. Dermatol. Venereol. JEADV 34, 1074\u0026ndash;1079 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraidl, S. \u003cem\u003eet al.\u003c/em\u003e High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 21, 1490\u0026ndash;1498 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNamipashaki, A. \u0026amp; Razaghi-Moghadam, Z. The Essentiality of Reporting Hardy-Weinberg Equilibrium Calculations in Population-Based Genetic Association Studies. CELL J. 17, 8 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalding, D. J. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781\u0026ndash;791 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSole, X., Guino, E., Valls, J., Iniesta, R. \u0026amp; Moreno, V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 22, 1928\u0026ndash;1929 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoesner, L. M., Zeitvogel, J. \u0026amp; Heratizadeh, A. Common and different roles of IL-4 and IL-13 in skin allergy and clinical implications. Curr. Opin. Allergy Clin. Immunol. 19, 319\u0026ndash;327 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowell, M. D. The role of human beta defensins and cathelicidins in atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 7, 413\u0026ndash;417 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowell, M. D. \u003cem\u003eet al.\u003c/em\u003e Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24, 341\u0026ndash;348 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhmori, Y. \u0026amp; Hamilton, T. A. IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages. J. Immunol. Baltim. Md 1950 159, 5474\u0026ndash;5482 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBjerkan, L., Sonesson, A. \u0026amp; Schenck, K. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP). Pharmaceuticals 9, 41 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKr\u0026ouml;ger, A., K\u0026ouml;ster, M., Schroeder, K., Hauser, H. \u0026amp; Mueller, P. P. Activities of IRF-1. J. Interferon Cytokine Res. Off. J. Int. Soc. Interferon Cytokine Res. 22, 5\u0026ndash;14 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHida, S., Tadachi, M., Saito, T. \u0026amp; Taki, S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 106, 2011\u0026ndash;2017 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim, Y. \u003cem\u003eet al.\u003c/em\u003e Multiplexed functional genomic analysis of 5\u0026rsquo; untranslated region mutations across the spectrum of prostate cancer. Nat. Commun. 12, 4217 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerberth, G. \u003cem\u003eet al.\u003c/em\u003e Reduced IFN-γ- and enhanced IL-4-producing CD4\u0026thinsp;+\u0026thinsp;cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 year of life. Pediatr. Allergy Immunol. 21, 5\u0026ndash;13 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIvashkiv, L. B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 18, 545\u0026ndash;558 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpilianakis, C. G. \u0026amp; Flavell, R. A. Epigenetic regulation of Ifng expression. Nat. Immunol. 8, 681\u0026ndash;683 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMommert, S. \u003cem\u003eet al.\u003c/em\u003e Genetic variations within the promotor region of the human histamine H4 receptor gene in psoriasis patients. Pharmacol. Res. 114, 121\u0026ndash;127 (2016).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany\u0026apos;s Excellence Strategy - EXC 2155 - project number 390874280.\u003c/p\u003e\n\u003cp\u003eBiorender was used for the preparation of Figure 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.Z. contributed to the study concept, methodology, design, analysis, and interpretation of data and wrote the main manuscript; I.K. performed the acquisition, collection, and investigation of data; S.T. and L.R. contributed to the collection of the clinical data and to editing the manuscript; S.M. contributed to methodology; K.D. contributed to review and editing the manuscript; T. W. obtained funding and supervised the study. All authors reviewed the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4723863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4723863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEczema herpeticum (EH) is a disseminated severe herpes simplex virus infection that occurs in a subset of patients with atopic dermatitis (AD). EH is a complex multifactorial disease caused by immunological changes, environmental influences, and genetic aberrations. The latter is becoming increasingly apparent, and several single nucleotide polymorphisms (SNP) have been associated with triggering EH, including genes related to interferon signaling, the epidermal barrier, and Th2-mediated immunity. So far, genetic studies have not considered the severity of AD, which may have led to associations related to AD severity rather than EH. To investigate genetic risk factors for EH in a European cohort, we analyzed several SNPs of the genes \u003cem\u003eSTAT6, IFNG, IFNGR1, IRF2\u003c/em\u003e, and \u003cem\u003eTSLP\u003c/em\u003e in AD patients with (ADEH+) versus a carefully matched control group of AD patients consisting of 44 patients matched for age, sex, and severity of AD (SCORAD) without a history of eczema herpeticum (ADEH-) by pyrosequencing. We confirmed an association of rs2416259 (\u003cem\u003eTSLP\u003c/em\u003e), rs167769 (\u003cem\u003eSTAT6\u003c/em\u003e), and rs11132242 (\u003cem\u003eIRF2\u003c/em\u003e) with ADEH\u0026thinsp;+\u0026thinsp;in our European cohort. However, the risk alleles for rs167769 and rs11132242 were contrary to previous reports that did not take age, sex, and disease severity into account. We could not confirm an association for several loci (rs3024975 (STAT6); rs2069705, rs2069718, rs2069727, and rs2430561 (IFNG); rs3799488 and rs9376269 \u003cem\u003e(IFNGR1)\u003c/em\u003e; rs1342852 (\u003cem\u003eIRF2\u003c/em\u003e)) previously described in other cohorts. Moreover, linkage disequilibrium (LD) analysis revealed gametic LD and epistatic effects between \u003cem\u003eSTAT6\u003c/em\u003e, \u003cem\u003eIFNGR\u003c/em\u003e, and \u003cem\u003eIFNG\u003c/em\u003e genes. Better knowledge of genetic factors predisposing to eczema herpeticum may allow the early identification of patients at increased risk and disease prevention. Our study provides important clues to possible key factors in the antiviral immunity in herpes simplex virus infection and thus to potential therapeutic interventions.\u003c/p\u003e","manuscriptTitle":"Genetic variants in IRF2, STAT6, and TSLP are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-22 20:54:32","doi":"10.21203/rs.3.rs-4723863/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"71a950a3-e63d-416b-bc5a-ebe00bb34f3d","owner":[],"postedDate":"July 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34974931,"name":"Biological sciences/Genetics"},{"id":34974932,"name":"Biological sciences/Immunology"},{"id":34974933,"name":"Health sciences/Diseases"},{"id":34974934,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-10-23T05:23:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-22 20:54:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4723863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4723863","identity":"rs-4723863","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}