Follow-up Analysis Of Genome-wide Association Data Identifies PRKCB And 8p11.21 As Susceptibility Loci For Systemic Lupus Erythematosus

Background Systemic lupus erythematosus (SLE) (OMIM #152700) is a common systemic autoimmune inflammatory disease with complex etiology but strong clustering in families. It is characterized by dysregulated immune responses mediated by T and B cells, leading to increased production of pathogenic autoantibodies, against several self antigens. Those autoantibodies are associated with clinical manifestations in various organs.SLE affects predominantly women (prevalence ratio of men to women is 1:9), especially during the childbearing years. The genetic components have been demonstrated to play important roles in SLE. Since SLE exhibits familial clustering and 10% to 12% of SLE patients have an affected first-degree relative. The available data reveals a concordance rate for SLE between 24% and 69% for MZ twins, compared to 2% to 9% concordance for DZ twins.Over the past two decades, genetic association studies have revealed numerous susceptibility genes for SLE, su ch as HLA, STAT4, IRF5, ITGAM and PTPN22. Since 2008, 6 genome-wide association studies (GWAS) of SLE have been reported and more than 30 robust susceptibility genes and/or loci were identified. To look for additional genetic variants increasing the risk to SLE, we performed a replication study in two additional cohorts of Chinese Han based on our previous GWAS dataset (1,047 SLE cases and 1,205 controls).Objective We have performed a large scale replication study based on our previous genome wide association study (GWAS) of SLE of Chinese Han to further explore additional genetic variants affecting the susceptibility to SLE. Methods Thirty eight SNPs from our GWAS were genotyped in two additional Chinese Han cohorts (total 3,152 cases and 7,050 controls) using Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate.Results The association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4,199 cases and 8,255 controls of Chinese Han (rs16972959: OR = 0.81, 95%CI: 0.76～0.87, Pcombined = 1.35×10-9; rs12676482: OR = 1.26, 95%CI: 1.15～1.38, Pcombined = 6.68×10-7).Conclusions We identified PRKCB and 8p11.21 as novel susceptibility loci for systemic lupus erythematosus. Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21 should advance our understanding on the pathogenesis of SLE.