Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Abstract

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

“…We did not find significant heterogeneity of odds-ratios at most of the risk loci between Asian and European cohorts, consistent with published results (5,42). To understand the contribution of the loci to SLE inheritance, we estimated the percentage of explained heritability of 78 loci (four loci were monomorphic in Asians).…”

The Histidine Transporter SLC15A4 Coordinates mTOR-Dependent Inflammatory Responses and Pathogenic Antibody Production

“…We next asked whether SLC15A4 plays a role in autoantibody production, because SLC15A4 is implicated in the pathogenesis of human SLE (Han et al, 2009;He et al, 2010;Wang et al, 2012). We used a mouse model with a lupus-like disease induced by 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) .…”

“…This SLC15A4-dependent pDC function contributes to the pathogenesis of lupus-like disease (Baccala et al, 2013). Genome-wide analyses show that SLC15A4 is closely associated with inflammatory diseases such as type 2 diabetes , systemic lupus erythematosus (SLE) (Han et al, 2009;He et al, 2010;Wang et al, 2012), and inflammatory bowel disease (IBD) (Lee et al, 2009). These observations indicate that SLC15A4 might be a key regulator in autoimmune diseases.…”

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

“…Studies suggest an essential role of Aiolos at later stages of B cell differentiation (61,63). Numerous studies have identified polymorphisms in IKZF1 and IKZF3 to be associated with a risk for development of SLE (64)(65)(66)(67)(68)(69)(70)(71). Thus, modulation of Aiolos and Ikaros expression has the potential to correct multiple aspects of the immune dysregulation mediated by B cells and differentiation into autoantibody-secreting cells associated with SLE.…”