ANALYSIS OF SUSCEPTIBILITY LOCI FOR JUVENILE IDIOPATHIC ARTHRITIS IN THE EXTENDED MHC REGION USING HIGH RESOLUTION SNP AND HLA ALLELE TYPING

Abstract

Juvenile idiopathic arthritis (JIA) spans several pediatric arthropathies that involve autoimmune responses. Primary genetic risk factors for JIA have been mapped to Major Histocompatibility Complex (MHC) class I and class II genes. Recent genome-wide association studies using SNP arrays have shown that the non-HLA genetic component of JIA involves multiple low-risk loci, reinforcing the notion that JIA is a complex genetic trait with a strong HLA component. In this work, with the goal of detailed mapping and analysis of linkage disequilibrium (LD) patterns and associations with JIA in the extended MHC (xMHC) region, we combined SNP data from Affymetrix SNP Array 6.0 and Immunochip (IC) platforms with high resolution typing of 8 classical HLA genes. A cohort of about 800 affected individuals and about 500 ethnically matched controls from the Cincinnati region, as well as secondary validation cohorts of affected individuals and matched controls from Germany were used to perform the analysis, and to assess reproducibility of the results across different platforms and populations. Accurate high resolution maps of linkage with classical HLA genes and association with individual HLA alleles were generated. High concordance of results obtained using Affymetrix SNP Array 6.0 and IC was observed, with an additional resolution and improved mapping of associations provided by the latter in some regions. Several new peaks of statistically significant and reproducible association with JIA outside the regions of strong LD with classical HLA genes were observed, including one peak in the class III region, and one in the telomeric end of xMHC. Conditional analysis provided further evidence that these associations appear to be independent of classical HLA genes studied here. The results and observed association patterns are further discussed in the context of other recent studies on autoimmune diseases, including the role of HLA-DRB1 in adult Rheumatoid Arthritis.