Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population.

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. We discovered four novel SLE gene regions (<i>LCT</i>, <i>TPCN2</i>, <i>AHNAK2</i> and <i>TNFRSF13B</i>) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (p_meta <5.00×10^-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the <i>TPCN2</i> gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for <i>TPCN2</i> (P=1.38×10^-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10^-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10^-5) in ex vivo experiments. This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.