Lupus PRS paper of Eunji published in A&R

Dr. Eunji Ha (PhD in 2023), as a co-first author, conducted a lupus-specific polygenic risk score (PRS) analysis in patients with systemic lupus erythematosus and found association between a high genetic risk and earlier disease onset, autoantibody production, and more diverse clinical phenotypes. Her study was published in Arthritis & Rheumatology (IF= 15.483) on Apr 3rd, 2023 (https://doi.org/10.1002/art.42516). Congrats!

Title: Higher genetic risk loads confer more diverse manifestations and higher risk of lupus nephritis in systemic lupus erythematosus

Abstract

Objective: Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. 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 SNP array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well-validated non-HLA SNPs and HLA of SLE-risk loci. Associations of individual wGRS with clinical SLE sub-phenotypes and autoantibodies were analyzed using multivariable linear or logistic regression adjusted by onset-age, sex, 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 ACR criteria (β=0.143, p=1.8×10-6 ). Sub-phenotype analysis revealed significant associations between the highest and lowest wGRS-quartile 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 ). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis [class III or IV (HR=1.98, p=1.6×10-5 ); class V (HR=2.79, p=1.0×10-3 )], especially lupus nephritis class V in anti-Sm-positive SLE (AUC=0.68, p=1.8×10-4 ). Conclusion: The SLE patients with higher wGRS tended to have earlier onset-age, anti-Sm antibody, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and diverse clinical course in SLE patients.