DL Kastner

E Zeggini

EF Remmers

MJ Ombrello

P Woo

W Thomson

Pediatric Rheumatology

English

null null

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MEETING ABSTRACT Open AccessPW01-038 – Genomewide association study ofStill’s diseaseMJ Ombrello1*, EF Remmers2, E Zeggini3, W Thomson4, DL Kastner2, P Woo5,International Childhood Arthritis Genetics Consortium (INCHARGE)From 7th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)Lausanne, Switerland. 22-26 May 2013IntroductionStill’s disease or systemic juvenile idiopathic arthritis (sJIA)is a severe inflammatory disease of childhood character-ized by periods of daily spiking fever, evanescent skin rash,severe arthritis, serositis, lymphoid hyperplasia, and, in upto half of cases, macrophage activation syndrome.Although thought to have a genetic component, the causesof sJIA are unknown.ObjectivesTo identify genetic factors that contribute to sJIAsusceptibility.MethodsWe generated single nucleotide polymorphism (SNP) gen-otypes from the genomic DNA of 988 children with sJIAand 514 healthy control subjects. These data were com-bined with SNP genotypes in silico from 7370 additionalhealthy control subjects. After dividing the dataset into 9strata by country of origin, we excluded samples and mar-kers that did not meet our strict quality requirements. Weperformed haplotype phasing with ShapeIT, SNP imputa-tion with IMPUTE2, and association testing withSNPTEST independently in each stratum. The results ofassociation testing were subjected to fixed- and random-effects meta-analyses with GWAMA. A second round ofmore intensive “deep imputation” was performed in eachregion with pmeta<1E-7. Using the directly genotyped SNPdata, we used imputation to deduce classical HLA types ineach stratum. Significant associations were further evalu-ated with multivariate logistic regression using SNPTESTand SNP & Variation Suite 7.ResultsUsing the above method, we ultimately tested a panel ofover 1.6M SNPs for association with sJIA. Using meta-analysis of SNP association data from 9 strata, we identi-fied 2 sJIA-associated regions that exceeded the stringentthreshold for genome wide significance (pmeta<5E-8). Thestrongest association was located in the major histocom-patibility complex locus, with one SNP nearest to HLA-DRB1 (rs112638393: pmeta=1.6E-10, OR 1.5 [1.3, 1.7])and a second located nearest to BTNL2 (rs115945836:pmeta=2.4E-10, OR 2.8 [2.0, 3.9]). Conditioning on theeffect of rs112638393 accounted for the majority of theeffect around HLA-DRB1, while revealing a significant,independent association signal spanning BTNL2 andHLA-DRA. Additionally, meta-analysis of the imputedHLA type associations from 8 strata revealed a strongassociation between HLA-DRB1*1101 and sJIA (pme-ta=1.2E-8, OR 2.1 [1.6, 2.7]). The second strongest regio-nal association, which also exceeded genome widesignificance, was located on Chr 1 nearest to LOC284661(rs16838915: pmeta=5.4E-9, OR 2.0 [1.6, 2.5]). Logisticregression analysis demonstrated no residual associationsignal in this region after conditioning on rs16838915. Intotal, our study identified 11 loci that were suggestive ofassociation with sJIA (p<5E-5).ConclusionWe have per-formed a genome-wide association study of a large col-lection of sJIA patients. We have identified 2 sJIAsusceptibility loci, HLA-DRB1 and LOC284661, both ofwhich have large effect sizes. The association of HLA-DRB1*1101 with sJIA suggests that antigen presentationand the adaptive immune system are involved in sJIA, anidea that would be further supported by involvement ofeither HLA-DRA or BTNL2. The specific roles of each of1Translational Genetics and Genomics Unit, NIAMS, Bethesda, MD, USAFull list of author information is available at the end of the articleOmbrello et al. Pediatric Rheumatology 2013, 11(Suppl 1):A91http://www.ped-rheum.com/content/11/S1/A91© 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.these loci in the pathogenesis of sJIA remain to beelucidated.Disclosure of interestNone declared.Authors’ details1Translational Genetics and Genomics Unit, NIAMS, Bethesda, MD, USA.2Inflammatory Disease Section, NHGRI, Bethesda, MD, USA. 3AppliedStatistical Genetics Group, Wellcome Trust Sanger Institute, Hinxton, UK.4Arthritis Research UK Epidemiology Unit, University of Manchester,Manchester, UK. 5Center of Paediatric and Adolescent Rheumatology,University College London, London, UK.Published: 8 November 2013doi:10.1186/1546-0096-11-S1-A91Cite this article as: Ombrello et al.: PW01-038 – Genomewideassociation study of Still’s disease. Pediatric Rheumatology 201311(Suppl 1):A91.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. Pediatric Rheumatology 2013, 11(Suppl 1):A91http://www.ped-rheum.com/content/11/S1/A91Page 2 of 2

PW01-038 – Genomewide association study of Still’s disease

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PW01-038 – Genomewide association study of Still’s disease

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