The genetic dissection of the autoimmune diseases systemic lupus erythematosus and Sjogren's syndrome

Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are complex, heterogeneous autoimmune disorders. Prior to 2007, only 7 regions of the genome had been identified as contributing to the heritable risk of developing SLE. Recent advances in our understanding of the human genome and technological advances have ushered in a new era for discovering the genetic architecture of complex diseases. In this study, we established association of SLE risk with a novel locus at 11p13 near CD44 in a replication study (>15,000 subjects) of regions initially identified in a genome-wide association (GWA) scan not exceeding the genome-wide significance threshold (P<5x10-8). We observed independent replication in European derived SLE cases at rs2732552 (P=9.03x10 -8, OR=0.83, 95%CI=0.77-0.88) with a Pmeta=1.82x10 -9 when combined with our GWA scan results. African-American and Asian SLE cases also demonstrated association at rs2732552 (P=5x10 -3, OR=0.81, 95%C10.70-0.94 and P=4.3x10-4 , OR=0.80, 95%CI=0.70-0.91, respectively) yielding P meta=3.00x10-13.;The identification of loci contributing to risk of developing SS has lagged far behind other complex diseases. The majority of studies reported to date use candidate gene approaches and include <200 cases. We report the first GWA scan evaluating 272 SS cases and 387 controls in which ∼750,000 single nucleotide polymorphisms (SNPs) were tested for association after quality control. The most significant region associated with risk of disease was the major histocompatibility complex (MHC) with 45 SNPs exceeding a genome-wide significance threshold of P=5x10-8, all of which replicated in independent pooled samples. Within the MHC, peak significance was observed at HLA-DRA for rs9268832 (P=1.65x10 -10, OR=2.3, 95%CI=1.8-3.0). Evidence for novel genetic associations outside of the MHC was also observed at rs13282959 in both the discovery and replication cohorts (Pmeta=1.93x10-6). This SNP is located in a region of high regulatory potential near the musculin (MSC) gene, a multi-functional transcription factor involved in signaling pathways following B cell receptor activation. We also observed association with several loci established in SLE and other autoimmune diseases including the following: IRF5, TNIP1, IRF8, PRDM1, BANK1, STAT4 and 1L12B. Collectively, discovery of these genetic loci generate new opportunities for understanding disease mechanisms and improving diagnostic and therapeutic strategies for SLE and SS.