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• W2059285265 abstract "alopecia areata Fas ligand (TNF superfamily, member 6) genome-wide association MHC class II DQ alpha 2 MHC class II DQ beta C-type lectin domain family 16, member A major histocompatibility complex OX40 ligand thyroid adenoma associated tumor necrosis factor TNF (ligand) superfamily, member 4 Alopecia areata (AA) is a common human hair loss disorder that affects both sexes and all age groups. Although the precise etiopathogenesis of AA remains unknown, immunological and genetic association studies have implicated both innate and acquired immunity. Previous genetic research has identified several susceptibility factors. These comprise genes that are assumed to be involved in inflammation and in the regulation of T cells or other forms of immune modulation (Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar; John et al., 2011John K.K. Brockschmidt F.F. Redler S. et al.Genetic variants in CTLA4 are strongly associated with alopecia areata.J Invest Dermatol. 2011; 131: 1169-1172Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Jagielska et al., 2012Jagielska D. Redler S. Brockschmidt F.F. et al.Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance.J Invest Dermatol. 2012; 132: 2192-2197Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), genes in the histocompatibility leukocyte antigen (HLA)–encoding region (Entz et al., 2006Entz P. Blaumeiser B. Betz R.C. et al.Investigation of the HLA-DRB1 locus in alopecia areata.Eur J Dermatol. 2006; 16: 363-367PubMed Google Scholar; Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar), and various cytokine genes (Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar; Jagielska et al., 2012Jagielska D. Redler S. Brockschmidt F.F. et al.Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance.J Invest Dermatol. 2012; 132: 2192-2197Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar; Redler et al., 2012Redler S. Albert F. Brockschmidt F.F. et al.Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.Br J Dermatol. 2012; 167: 1360-1365Crossref PubMed Scopus (30) Google Scholar). To characterize the immune-related nature of AA further, we used the Immunochip to analyze a large and clinically well-characterized sample of 767 AA patients and 1,475 controls of Central-European origin and then followed up the most strongly associated variants in an independent Central-European sample of 1,016 cases and 1,060 controls (Supplementary Materials and Methods online). The Immunochip is a unique custom-based Illumina BeadChip array (Illumina, San Diego, CA) that enables dense mapping of a large number of susceptibility loci and risk variants for immune-mediated disease (Trynka et al., 2011Trynka G. Hunt K.A. Bockett N.A. et al.Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011; 43: 1193-1201Crossref PubMed Scopus (551) Google Scholar). Download .pdf (.63 MB) Help with pdf files Supplementary Material Ethical approval was obtained from the appropriate ethics committees, and all participants provided written informed consent prior to blood sampling. Following stringent quality control of the discovery Immunochip data (Supplementary Materials and Methods online), the strongest associations were observed for variants of the major histocompatibility complex (MHC) class II DQ beta 1 (HLA-DQB1) and class II DQ alpha 2 (HLA-DQA2), with P-values ranging from 5.59 × 10-15 to 1.71 × 10-19. Our discovery step also provided support for a large number of additional regions of interest that did not pass the threshold of genome-wide significance but which did reach nominal significance (Supplementary Table S3 online). To follow up the results of the discovery step, we first performed a targeted analysis of the HLA-region. This involved imputation using SNP2HLA and a stepwise logistic regression analysis (Supplementary Material and Methods online). This approach generated genome-wide/region-wide significant results for three independent HLA-DQB1 variants (rs9275208: Puncorr.=1.71 × 10-19, Pcorr.=2.1 × 10-14; single-nucleotide polymorphism (SNP) DQB1:32742309:Cx: Puncorr.=5.02 × 10-8, Pcorr.=4.25 × 10-4; HLA:DQB1:0503: Puncorr.=5.36 × 10-8, Pcorr.=4.35 × 10-4). In addition, genome-wide/region-wide significant results were obtained for variants of three further HLA-loci (HLA-DQA2, HLA-C, and HLA-DRB1; Supplementary Table S1 online). However, these three association signals were probably dependent on the detected HLA-DQB1 association signals. In a subsequent step, the 35 most strongly associated susceptibility variants outside the HLA region were followed up in our independent case-control sample. These variants were selected by choosing a maximum of two SNPs from all regions with nominal significance in the discovery step (Supplementary Materials and Methods online). Three of these 35 genotyped variants (rs4916209, rs11904361, and rs10798176) were replicated with nominal significance (Table 1). To obtain robust evidence for association, we performed a meta-analysis of the data from the discovery and follow-up cohorts. In this analysis, all three replicated variants failed to surpass the threshold of genome-wide significance but reached nominal significance as follows (Table 1): (i) Tumor necrosis factor (TNF; ligand) superfamily, member 4 (TNFSF4) variant rs4916209: Pcomb.=6.85 × 10-07; (ii) Thyroid adenoma associated (THADA) variant rs11904361: Pcomb.=3.04 × 10-05; and (iii) Fas ligand (TNF superfamily, member 6; FASLG) variant rs10798176: Pcomb.=7.2 × 10-05 (Table 1). None of the remaining 32 genotyped variants were replicated (Supplementary Table S3 online).Table 1Meta-analysis of data from the Immunochip analysis and the follow-up analysis from the three replicated markersSNPPosition1In base pairs, NCBI build 37.5.Gene symbolChrAllele (A/B)P Immunochip, λ-adjusted2P-values from the Central-European patients genotyped using the Immunochip.Allelic OR (95% CI)3OR calculation based on the minor allele.P follow-up4P-values from the follow-up analysis.Allelic OR (95% CI)3OR calculation based on the minor allele.P meta-analysis λ-adjusted5P-values combined from the Immunochip data and the follow-up sample.Allelic OR (95% CI)3OR calculation based on the minor allele.rs10798176172675525FASLG1C/T0.00161.34 (1.16, 1.56)0.03541.18 (1.03, 1.34)7.2 × 10-51.27 (1.17, 1.37)rs4916209173133489TNFSF41A/G0.00011.39 (1.22, 1.60)0.00481.2 (1.06, 1.34)6.85 × 10-71.32 (1.23, 1.41)rs1190436143848664THADA2C/T0.00150.69 (0.58, 0.84)0.02610.76 (0.53, 0.99)3.04 × 10-50.72 (0.65, 0.79)Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism.1 In base pairs, NCBI build 37.5.2 P-values from the Central-European patients genotyped using the Immunochip.3 OR calculation based on the minor allele.4 P-values from the follow-up analysis.5 P-values combined from the Immunochip data and the follow-up sample. Open table in a new tab Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism. Finally, conditional analyses were performed by fitting the SNP with the primary association signal of the known AA susceptibility loci as a covariate into a logistic regression model (Supplementary Materials and Methods online). This approach identified a to our knowledge yet unreported susceptibility variant of C-type lectin domain family 16, member A (KIAA0350/CLEC16A—16-11135145-A-INSERTION; Supplementary Table S2 online). Collectively, we identified HLA-DQB1 as a genome-wide significant AA susceptibility locus and a to our knowledge previously unreported KIAA0350/CLEC16A variant. Our results suggest that follow-up studies are warranted for the three additional loci with nominal significance—i.e., TNFSF4, THADA, and FASLG. Previous research has established that the HLA region on chromosome 6p21.3 is a key locus in the origin of the majority of autoimmune-mediated disorders, including AA (Catalog of Published Genome-Wide Association Studies: http://www.genome.gov/gwastudies/; Entz et al., 2006Entz P. Blaumeiser B. Betz R.C. et al.Investigation of the HLA-DRB1 locus in alopecia areata.Eur J Dermatol. 2006; 16: 363-367PubMed Google Scholar; Barahmani et al., 2008Barahmani N. de Andrade M. Slusser J.P. et al.Human leukocyte antigen class II alleles are associated with risk of alopecia areata.J Invest Dermatol. 2008; 128: 240-243Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar; Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar). In the present study, fine-mapping was performed using a published imputation and analysis protocol, which is the most comprehensive HLA-analysis approach to AA published to date. In accordance with previous findings, we obtained both genome-wide significant results for HLA-DQB1 and support for the predominant role of the HLA class II region in the association of the MHC region with AA (Entz et al., 2006Entz P. Blaumeiser B. Betz R.C. et al.Investigation of the HLA-DRB1 locus in alopecia areata.Eur J Dermatol. 2006; 16: 363-367PubMed Google Scholar; Barahmani et al., 2008Barahmani N. de Andrade M. Slusser J.P. et al.Human leukocyte antigen class II alleles are associated with risk of alopecia areata.J Invest Dermatol. 2008; 128: 240-243Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar; Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar). Furthermore, we identified three independent variants of HLA-DQB1 (Supplementary Table S1 online), which widens the spectrum of HLA variants implicated in AA. As regards TNFSF4, THADA, and FASLG, all three loci have been associated with Crohn's disease (Franke et al., 2010Franke A. McGovern D.P. Barrett J.C. et al.Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (1975) Google Scholar), thus pointing to a previously unknown genetic overlap between these two autoimmune disorders. Previous authors have also reported THADA as a susceptibility locus for thyroid adenomas (Franke et al., 2010Franke A. McGovern D.P. Barrett J.C. et al.Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (1975) Google Scholar; Patsopoulos et al., 2011Patsopoulos N.A. Esposito F. Reischl J. et al.Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011; 70: 897-912Crossref PubMed Scopus (270) Google Scholar), which is consistent with the clinical observation of comorbid thyroid disease and AA (Goh et al., 2006Goh C. Finkel M. Christos P.J. et al.Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history.J Eur Acad Dermatol Venereol. 2006; 20: 1055-1060Crossref PubMed Scopus (198) Google Scholar). FASLG encodes a protein that has a role in the regulation of cell growth and apoptosis (Niederkorn, 2006Niederkorn J.Y. See no evil, hear no evil, do no evil: the lessons of immune privilege.Nat Immunol. 2006; 7: 354-359Crossref PubMed Scopus (353) Google Scholar). TNFSF4, which is also known as OX40 ligand (OX40L), belongs to the TNF family. TNFSF4 encodes the cytokine OX40L (Al-Shamkhani et al., 1997Al-Shamkhani A. Mallett S. Brown M.H. et al.Affinity and kinetics of the interaction between soluble trimeric OX40 ligand, a member of the tumor necrosis factor superfamily, and its receptor OX40 on activated T cells.J Biol Chem. 1997; 272: 5275-5282Crossref PubMed Scopus (46) Google Scholar) and acts as a ligand for OX40, leading to the assembly of a signaling complex (So et al., 2011So T. Choi H. Croft M. OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling.J Immunol. 2011; 186: 3547-3555Crossref PubMed Scopus (65) Google Scholar). The OX40–OX40L interaction has been implicated in a wide range of immune-modulating processes (Croft et al., 2009Croft M. So T. Duan W. et al.The significance of OX40 and OX40L to T-cell biology and immune disease.Immunol Rev. 2009; 229: 173-191Crossref PubMed Scopus (363) Google Scholar). Blockade of the OX40–OX40L complex suppresses the development of autoimmune and chronic inflammatory disorders in mice (Higgins et al., 1999Higgins L.M. McDonald S.A. Whittle N. et al.Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with an OX40 ligand-IgG fusion protein.J Immunol. 1999; 162: 486-493Crossref PubMed Google Scholar). Inhibition of the formation of this complex might therefore represent a potential treatment approach for AA patients. However, further studies are required to prove this hypothesis. The identified KIAA0350/CLEC16A variant (16-11135145-A-INSERTION) is probably the best tagging SNP for the causal variant of this known AA susceptibility locus. In summary, our results provide support for the hypothesis that AA has an autoimmune origin and that T-cell pathways have a crucial role in its development. Our results also suggest that inhibition of the OX40–OX40L interaction has potential as a therapeutic approach. Elucidation of AA pathophysiology and the development of further therapeutic options would represent ground-breaking achievements in research into this common autoimmune disorder. We thank all patients for their participation in the study. We thank Bernd Pötzsch (Institute of Experimental Hematology and Transfusion Medicine, University of Bonn) for help with collecting DNA samples from anonymous blood donors. SR was a recipient of a BONFOR Gerok fellowship from the Medical Faculty of the University of Bonn. RCB and MMN are members of the DFG-funded Excellence Cluster ImmunoSensation. MMN is the recipient of a grant from the Alfried Krupp von Bohlen und Halbach-Stiftung. RCB is the recipient of a Heisenberg Professorship from the German Research Foundation (DFG). Supplementary material is linked to the online version of the paper at at http://www.nature.com/jid" @default.
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• W2059285265 title "Immunochip-Based Analysis: High-Density Genotyping of Immune-Related Loci Sheds Further Light on the Autoimmune Genetic Architecture of Alopecia Areata" @default.
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