A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

Abstract

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.

Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways

“…Martin et al also described an association in the PXK locus, but this association was reported to be dependent on the SSc-related missense mutation in the DNASE1L3, rs35677470, in Mayes et al [18,136]. Finally, this report identified a novel locus for SSc that had already been reported to be associated with SLE, JAZF1 [136]. These studies confirm that, despite the clinical differences between these two systemic autoimmune disorders, the genetic susceptibility regions are greatly shared.…”

“…Additionally, a recent meta-GWAS combining SSc and SLE patients has yielded a novel common locus, KIAA0319L, for both disorders [136]. Martin et al also described an association in the PXK locus, but this association was reported to be dependent on the SSc-related missense mutation in the DNASE1L3, rs35677470, in Mayes et al [18,136]. Finally, this report identified a novel locus for SSc that had already been reported to be associated with SLE, JAZF1 [136].…”

“…This finding was not novel since the overlap between both diseases has been reported in several genetic regions [140]. Additionally, a recent meta-GWAS combining SSc and SLE patients has yielded a novel common locus, KIAA0319L, for both disorders [136]. Martin et al also described an association in the PXK locus, but this association was reported to be dependent on the SSc-related missense mutation in the DNASE1L3, rs35677470, in Mayes et al [18,136].…”

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

“…These studies have identified a substantial number of polymorphic loci associated with the risk of SSc. 7 The most prominent of these genetic associations are within the major histocompatibility complex (MHC). The great majority of the non-MHC variants associated with SSc are related to immune cell activation and function, including T and B cell signaling, along with innate immunity, type I interferon, and toll-like receptor (TLR) signaling.…”

The Contribution of Meta-Analysis of Genome-Wide Association Studies in Investigating the Genetic Susceptibility to Lupus

“…They also revealed candidate causal non-HLA SNPs, genes, and pathways involved in RA (Lee et al, 2012). In order to reveal the genetic basis of systemic sclerosis (SSc) and SLE, Martin et al (2013) performed a panmeta-analysis of two GWAS together with a replication stage. This study identified KIAA0319L as a novel susceptibility locus for SSc and SLE, and they also determined that the previously described SLE susceptibility loci PXK and JAZF1 are shared with SSc.…”