Cosan, F

de Bakker, P

Gul, A

Kastner, DL

Kirino, Y

Ombrello, MJ

Remmers, EF

Pediatric Rheumatology

Harvard University - DASH 

 PW03-010 - MHC complexity in Behçet's disease  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Ombrello, MJ, Y Kirino, P de Bakker, F Cosan, DL Kastner, AGul, and EF Remmers. 2013. “PW03-010 - MHC complexity inBehçet's disease.” Pediatric Rheumatology Online Journal 11(Suppl 1): A236. doi:10.1186/1546-0096-11-S1-A236.http://dx.doi.org/10.1186/1546-0096-11-S1-A236.Published Version doi:10.1186/1546-0096-11-S1-A236Accessed February 19, 2015 3:43:07 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064458Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAMEETING ABSTRACT Open AccessPW03-010 - MHC complexity in Behçet’s diseaseMJ Ombrello1*, Y Kirino2, P de Bakker3,4, F Cosan5, DL Kastner6, A Gul5, EF Remmers6From 7th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)Lausanne, Switerland. 22-26 May 2013IntroductionFamily studies support a genetic contribution to Behçet’sdisease (BD), with a sibling recurrence-risk ratio of 11-52. The class I MHC molecule, HLA-B*51 (B*51), is thestrongest known genetic risk factor for BD, however thegene immediately centromeric to HLA-B, MICA, has alsobeen implicated in BD. Because of strong linkage disequi-librium (LD) between HLA-B and MICA, their respectivecontributions to BD susceptibility have been debated. Arecent report has proposed that B*51 is not a BD suscept-ibility allele, and several studies have identified B*51-independent association signals within the MHC.ObjectivesTo clarify the relationship between B*51 and BD, and totest for B*51-independent genetic variation within theMHC that influences BD susceptibility.MethodsUsing Illumina Human 370CNV SNP genotypes in aTurkish collection of 1244 BD patients and 1303 geogra-phically-matched healthy subjects, we examined SNPhaplotypes and LD patterns across the HLA-B/MICAregion with Haploview. We performed SNP imputationof the MHC using IMPUTE2 and the 1000 GenomesPhase 1 dataset. We inferred classical HLA types andtheir amino acids using SNP2HLA. Association testingand regression analyses were performed using SNPTESTand SNP & Variation Suite 7.ResultsWe identified a B*51(+) HLA-B/MICA haplotype thatwas strongly associated with BD (p=1.22E-46, OR 2.8).A B*51(-) version of the same haplotype occurred atequal frequencies in cases and controls, demonstratingthat B*51 is essential to the risk haplotype. Further, wefound that rs2848713, a variant on the MICA end of thehaplotype, conferred additional risk of BD in B*51(+)individuals. Through imputation, we generated a set of32,689 imputed SNPs. The 2 most strongly associatedSNPs were 4.8Kb centromeric of HLA-B (pmin=1.4E-50),but no SNP was more strongly associated with BD thanwas B*51 itself (p=1.3E-55). Conditioning on B*51revealed an association near HLA-A (pmin=5.4E-9), andupon adding a representative HLA-A SNP to the regres-sion model, we detected residual association centromericof HLA-B (p=1.5E-5). Analysis of imputed HLA typessupported these findings. In addition to the associationof BD with B*51 (p=2.2E-55), sequential regression ofimputed HLA types identified associations of HLA-A*03(p=1E-8), HLA-C*0701 (p=9.5E-4), and HLA-B*15(p=1.2E-4) with BD. Stepwise forward regression ofimputed HLA-B amino acids identified 6 HLA-B resi-dues that together fully accounted for the regional asso-ciation at HLA-B.ConclusionThis study affirms B*51 as the strongest risk factor ofBD. We have provided strong evidence opposing aB*51-independent role for MICA variants in BD sus-ceptibility. We have identified significant effects ofHLA-A*03 and HLA-C*0701, which protect against BD,and HLA-B*15, which confers risk of BD. We haveidentified a group of HLA-B amino acids, most of whichreside in the antigen binding groove, that togetheraccount for the entire association signal at the HLA-Blocus.Disclosure of interestNone declared.Authors’ details1Translational Genetics and Genomics Unit, NIAMS, Bethesda, USA.2Department of Internal Medicine and Clinical Immunology, Yokohama CityUniversity, Yokohama City, Japan. 3Division of Genetics, Brigham andWomen’s Hospital and Harvard Medical School, Boston, USA. 4Departmentsof Medical Genetics and of Epidemiology, University Medical Center Utrecht,1Translational Genetics and Genomics Unit, NIAMS, Bethesda, USAFull list of author information is available at the end of the articleOmbrello et al. Pediatric Rheumatology 2013, 11(Suppl 1):A236http://www.ped-rheum.com/content/11/S1/A236© 2013 Ombrello et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Utrecht, Netherlands. 5Istanbul Faculty of Medicine, Istanbul University,Istanbul, Turkey. 6Inflammatory Disease Section, NHGRI, Bethesda, USA.Published: 8 November 2013doi:10.1186/1546-0096-11-S1-A236Cite this article as: Ombrello et al.: PW03-010 - MHC complexity inBehçet’s disease. Pediatric Rheumatology 2013 11(Suppl 1):A236.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitOmbrello et al. 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PW03-010 - MHC complexity in Behçet's disease

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PW03-010 - MHC complexity in Behçet's disease

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