HLA-C∗06:02 Has the Strongest Association with PsV Risk
Unsurprisingly, when we tested the imputed variants in the MHC region for overall PsV risk (PsV-affected versus control individuals), the top association signal mapped to HLA-C (Figures 1A and 2A; Table S2). The most strongly associated variant was the classical HLA-C∗06:02 allele (p = 1.7 × 10−364), highly consistent with previous reports that HLA-C∗06:02 has the strongest association with PsV risk.7–12,17,18 We observed that no HLA-C amino acid polymorphism was more strongly associated than HLA-C∗06:02 (the smallest p value, pomnibus = 4.5 × 10−250, was at HLA-C amino acid position 156; Figure 3A). When conditioning on HLA-C∗06:02, we observed the top association signal at the four-digit classical allele of HLA-C∗12:03 (p = 2.5 × 10−25). After conditioning on HLA-C∗06:02 and HLA-C∗12:03, we found that no association exceeded the genome-wide significance threshold for the HLA-C variants (p > 5.0 × 10−8). These results suggest that multiple classical HLA-C alleles, exemplified by HLA-C∗06:02, explain the influence of HLA-C on PsV risk.