Genetic Association of the Major Histocompatibility Complex With Rheumatoid Arthritis Implicates Two Non-DRB1 Loci

Objective. The HLA-DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC region. The aim of this study was to estimate their number and location. Methods. A case-control study was performed involving 977 control subjects and 855 RA patients. The HLA-DRB1 locus was genotyped together with 2,360 single-nucleotide polymorphisms in the MHC region. Logistic regression was used to detect DRB1-independent effects. Results. After adjusting for the effect of HLA-DRB1 18 markers in 14 genes were strongly associated with RA (P < 10(-4)). Multivariate logistic regression analysis of these markers and DRB1 led to a model containing DRB1 plus the following 3 markers: rs4678, a nonsynonymous change in the VARS2L locus, similar to 1.7 Mb telomeric of DRB1; rs2442728, upstream of HLA-B, similar to 1.2 Mb telomeric of DRB1; and rs17499655, located in the 5'-untranslated region of DQA2, only 0.1 Mb centromeric of DRB1. In-depth investigation of the DQA2 association, however, suggested that it arose through cryptic linkage disequilibrium with an allele of DRB1 Two non-shared epitope alleles were also strongly associated with RA (P < 10(-4)): *0301 with anti-cyclic citrullinated peptide-negative RA and *0701 independently of autoantibody status. Conclusion. These results confirm the polygenic contribution of the MHC to RA and implicate 2 additional non-DRB1 susceptibility loci. The role of the HLA-DQ locus in RA has been a subject of controversy, but in our data, it appears to be spurious.