Brief Report: Influence of HLA–DRB1 Susceptibility Alleles on the Clinical Subphenotypes of Systemic Lupus Erythematosus in Koreans

Objective To investigate the association between HLA–DRB1 alleles and systemic lupus erythematosus (SLE) susceptibility and features of SLE, such as clinical manifestations and autoantibody profiles, in a Korean population. Methods We tested the genetic associations between HLA–DRB1 alleles and SLE susceptibility and clinical subphenotypes in 1,089 patients with SLE and 2,161 control subjects, including a discovery set (475 patients and 1,119 controls) and a replication set (614 patients and 1,042 controls). We used a relative predispositional effects (RPEs) method to examine the independent effect of each allele associated with SLE or its subphenotypes. Results We identified 4 HLA–DRB1 alleles that were associated with increased susceptibility to SLE, 2 of which had been detected previously (*15:01; P for RPE = 1.11 × 10−13, odds ratio [OR] 1.88) and *09:01 (P for RPE = 1.59 × 10−5, OR 1.46), and 2 of which were novel alleles (*08:03 [P for RPE = 8.80 × 10−8, OR 1.62]) and *07:01 (P for RPE = 1.14 × 10−6, OR 1.57)]. In addition, protective effects on the development of SLE were observed for 2 novel alleles (HLA–DRB1*12:02 [P for RPE = 6.35 × 10−4, OR 0.49]) and *11:01 [P for RPE = 1.24 × 10−3, OR 0.59]). The SLE risk alleles had an additive genetic effect, as demonstrated by the finding that double copies of these alleles (OR 3.38) had larger risk effects size compared with single copies (OR 1.95) and no copy (OR 1 [reference]). In a subphenotype analysis, various HLA–DRB1 alleles (including SLE risk alleles) were observed to have significant predispositional effects on diverse clinical manifestations. In particular, HLA–DRB1*15:01 (OR 2.30), *09:01 (OR 2.46), *07:01 (OR 2.61), and *08:03 (OR 2.97) were strongly associated with the risk of anti‐Sm antibody production. Conclusion We detected 6 HLA–DRB1 alleles that were associated with SLE in Koreans. The SLE risk alleles promoted the production of autoantibodies, including anti‐Sm, and diverse clinical manifestations.