Higher Genetic Risk Loads Confer More Diverse Manifestations and Higher Risk of Lupus Nephritis in Systemic Lupus Erythematosus

Objective: Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. In this study, we aimed to identify the genetic risk load using clinical and serological manifestations in SLE patients. Methods: We genotyped a total of 1,655 Korean patients with SLE (n = 1,243 as a discovery set and n = 412 as a replication set) using a customized genome-wide single-nucleotide polymorphism (SNP) array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well-validated non-HLA SNPs and HLA haplotypes of SLE-risk loci. We analyzed associations between individual wGRS and clinical SLE subphenotypes and autoantibodies using multivariable linear or logistic regression adjusted by onset age, sex, and disease duration. Results: Childhood-onset SLE (<16 years) conferred the highest genetic risk compared with adult-onset (16–50 years) or late-onset (>50 years) SLE (P = 6.8 × 10⁻⁶). High wGRS significantly increased associations with SLE manifestations, regardless of onset age, sex, and disease duration. Individual wGRS significantly correlated positively with more clinical American College of Rheumatology criteria (β = 0.143, P = 1.8 × 10⁻⁶). Subphenotype analysis revealed significant associations between the highest and lowest wGRS quartile with risk of renal disorder (hazard ratio [HR] 1.74, P = 2.2 × 10⁻⁸) and anti–Sm antibody production (HR 1.85, P = 2.8 × 10⁻⁵). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis class III or IV (HR 1.98, P = 1.6 × 10⁻⁵) and class V (HR 2.79, P = 1.0 × 10⁻³), but especially lupus nephritis class V in anti–Sm-positive SLE (area under the curve 0.68, P = 1.8 × 10⁻⁴). Conclusion: Patients with SLE and high wGRS tended to have earlier age of SLE onset, higher anti–Sm antibody positivity, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and a diverse clinical course in SLE patients.