Objective

To investigate the most susceptible genetic loci in systemic sclerosis (SSc) with genome-wide association study (GWAS).

Methods

A genome-wide association study was performed in 137 patients with systemic sclerosis and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine mapping study, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population.

Results

The SNPs (rs3128930, rs7763822, rs7764491, rs3117230 and rs3128965) of HLA-DPB1 and –DPB2 on chromosome 6 formed a distinctive peak with log p-values (p =8.16 × 10−13) for association with SSc susceptibility. Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (p = 7.61×10−8) and DPB1*0901 (p = 2.56×10−5)were the most susceptible subtypes for SSc in Koreans. In US Caucasians, two 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 anti-centromere autoantibodies (p = 1.12 × 10−3/3.2 × 10−5), respectively.

Conclusion

Our GWAS in Koreans revealed that the region of HLA-DPB1 and –DPB2 contains the most susceptible loci to Korean SSc. The confirmatory studies in US Caucasians indicated that specific SNPs of the HLA-DPB1 and/or –DPB2 were strongly associated with US Caucasian SSc patients who were positive to anti-topoisomerase I or anti-centromere autoantibodies.