HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome-wide association study in Koreans with replication in North Americans

Objective To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. Methods A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. Results The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA–DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P = 8.16 × 10−13). Subtyping analysis of HLA–DPB1 showed that DPB1*1301 (P = 7.61 × 10−8) and DPB1*0901 (P = 2.55 × 10−5) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti–DNA topoisomerase I (P = 7.58 × 10−17/4.84 × 10−16) or anticentromere autoantibodies (P = 1.12 × 10−3/3.2 × 10−5), respectively. Conclusion The results of our genome-wide association study in Korean subjects indicate that the region of HLA–DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA–DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti–DNA topoisomerase I or anticentromere autoantibodies.