Background Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations and unpredictable outcome. We aimed to identify the genetic contributions on clinical and serological manifestations in Korean patients with SLE.

Methods The patients with SLE were enrolled including a discovery cohort and a replication cohort from the Korean population (n = 1,655). Weighted genetic risk score (wGRS) were calculated by SLE risk loci [112 well-validated non-HLA SNPs and HLA-DRB1 haplotype] based on genome-wide association study. Individual wGRS was tested for associations with clinical sub-phenotypes of SLE by using multivariable linear regression or logistic regression.

Results Increasing wGRS was significantly associated with more diverse manifestation of SLE, regardless of onset age, sex and disease duration. The SLE patients with high wGRS-quartile were significantly associated with the risk of renal disorder (HR=1.74; p=2.2×10−8) and anti-Sm antibody production (HR=1.85; p=2.8×10−5) compared to patients with low wGRS-quartile.

We found that wGRS influenced on the development of proliferative lupus nephritis (LN) [class III or IV (HR=1.98, p=1.6×10−5)] and membranous LN [class V (HR=2.79, p=1.0×10−3)]. Moreover, increasing wGRS had the strongest effect on the development of LN class V in anti-Sm positive SLE (AUC=0.681, p= 1.8×10−4).

Conclusions The higher wGRS, which implicated in pathogenesis of SLE, increased the risk to develop lupus nephritis and anti-Sm antibody production. Our study provided that genetic risk loads could predict the clinical outcome in SLE.