During the previous reporting period (Z01 AR041185-01) we established an international consortium for the purpose of identifying and obtaining DNA specimens from at least 1000 well-characterized cases of systemic onset JIA and 1000 ethnically-matched controls. This includes investigators from several of the major pediatric rheumatology centers in North America, including the Childrens Hospital of Philadelphia, Cincinnati Childrens Hospital Medical Center, the Hospital for Sick Children in Toronto, Stanford University, and the University of Utah;from several of the major pediatric rheumatology centers in Europe, including Great Ormand Street Hospital in London, Hopital Necker-Enfants Malades in Paris, the Gaslini Institute in Genova, and the Wilhelmena Hospital in Utrecht;and other centers in Turkey, Argentina, Brazil, and Australia. In early May, 2010, we hosted a meeting of international collaborators at the NIH, in which there were discussions regarding recruitment strategies, appropriate informed consent for genome-wide association studies (GWAS), sample shipment, genotyping, and data analysis. Because of the difficulties for some centers to recruit appropriate ethnically matched controls, where necessary in silico controls would be drawn from existing online databases, using bioinformatic tools to ensure appropriate matching by ancestry. All genotyping has been performed in the Inflammatory Disease Section, using Illumina Human Omni 1M-Quad, v1.0 bead chips and an Illumina iScan Beadarray scanner. To date, we have genotyped 1,221 study samples, 785 cases and 436 controls. Overall, 98% of these samples had greater than a 99% genotype call-rate. We are currently genotyping an additional 39 cases, bringing the total to 824. We have commitments of two additional sets of in silico SoJIA single nucleotide polymorphism (SNP) genotypes, which would bring the total number of cases to 959. We have obtained SNP genotypes for over 1500 healthy controls from the 1958 British Birth Cohort, and we will also include approximately 1500 controls from the U.S. of Northern European ancestry. Earlier in the reporting period we performed an interim analysis for submission as an abstract for the annual meeting of the American College of Rheumatology (ACR). For this study we performed SNP genotyping on 576 children fulfilling ILAR (International League of Associations for Rheumatology) criteria for SoJIA and 366 healthy subjects with Illumina Omni1M Quad beadchips and an iScan platform. Samples (cases/controls) were obtained from Cincinnati Children's Hospital Medical Center (205/210), University of Manchester (188/0), Genoa University (56/60), Hacettepe University (54/0), University of Utah (42/0), Stanford University (34/0), and Istanbul University (0/96). Additionally, Omni1M Quad genotypes from 60 unrelated HapMap CEU individuals were obtained from the Illumina iControl database for use in the genome-wide analysis. SNPs with call rates less than 95 %, minor allele frequencies less than 0.05, or Hardy-Weinberg Equilibrium P less than 10 to the negative fifth were excluded. Using MaCH imputation software, we assembled a chromosome 6 SNP set that included 1594 additional controls from the 1958 U.K. Birth Cohort. We used principal components (PC) analysis to exclude genetically dissimilar individuals and to correct association testing. PC analysis, association testing, and logistic regression analysis were performed using SVS7, and haplotypes were analyzed using Haploview. Two-digit HLA type data were available for most of the samples from Cincinnati, University of Manchester, and the U.K. Birth Cohort. Genome-wide association testing revealed 12 SNPs within the MHC Class II region whose associations exceeded the threshold for genome-wide significance (P less than 5 times 10 to the negative eighth). Analysis of the MaCH-imputed chromosome 6 SNP set identified 7 additional SNPs with P less than 5 times 10 to the negative eighth, and logistic regression identified rs615672 as responsible for the regional association. Further, we identified a 203 kB SoJIA-associated SNP haplotype (P = 5.33 times 10 to the negative twelfth;odds ratio = 2.184, 95% confidence interval = 1.74-2.74) which included HLA-DRB1, -DQA1, and -DQB1. This extended haplotype had a greater effect size and a stronger association than any individual SNP. This work will be presented as a podium presentation at the annual meeting of the ACR in November. During the upcoming reporting period, we plan to complete accrual of our discovery set of approximately 1000 SoJIA cases and approximately 4000 ethnically matched controls (including samples genotyped in the Inflammatory Disease Section and in silico data). GWAS data will be analyzed with appropriate corrections for population stratification. We will also try to identify an appropriate replication cohort.

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Ombrello, Michael J; Remmers, Elaine F; Tachmazidou, Ioanna et al. (2015) HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 112:15970-5