Mer-tyrosine kinase: a novel susceptibility gene for SLE related end-stage renal disease

Abstract

ObjectiveLupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD.MethodsWe analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants.ResultsA genetic variant (rs56097910) within theMERTKgene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10-6. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10-4), at one CpG site (cg16333401) in close vicinity to the transcription start site ofMERTKand located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to alteredMERTKexpression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN:PRDM1(rs6924535, pmeta=1.6×10-5, OR=0.58) andAPOA1BP(NAXE) (rs942960, pmeta=1.2×10-5, OR=2.64).ConclusionWe identified a novel genetic risk locus,MERTK, associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in theMERTKgene are important for the risk of developing SLE-ESRD and suggest a role forPRDM1andAPOA1BPin proliferative LN.