Objectives 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.
Methods 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.
Results We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) 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 (pmeta <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 TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (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.
Conclusions 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.
- systemic lupus erythematosus
- gene polymorphism
- autoimmune diseases
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LW, CZ, ZZ, CY, XZ and LL contributed equally.
Handling editor Tore K Kvien
Contributors Conceived and designed the study: XJZ, YC, XYY, LDS and YS. Managed the project: LLW, LL, CHZ, ZWZ and XDZ. Sample recruitment and selection: CY, SY, APZ, NS, XY, XZ, FL, HYT, BL, YZ, YTD, RXY, KX, ZGL, JPG, XZ, CZ, YJT, MW, SXL, XF, MG, FLX, PGW, ZXW and JHX. Conducted experiments: LLW, LL, FSZ, GC, JZ, PL, CY, CHZ, ZWZ, LLT, YYC and JYS. Data process and analysis: XYY, XDZ, XBZ, JPG and YJS. Wrote manuscript: LLW, LL, XYY, XZ and YS. All the authors revised and approved the manuscript to be published.
Funding We acknowledge grant support from the National Natural Science Foundation of China (81320108016, 81130031, 81573033, 81371722, 81271747, 81370044, 31200939 and 81402590), the National Science Fund for Excellent Young Scholars (81222022), the Outstanding Talents of Organization Department of the CPC (Communist Party of China) Central Committee program, the Pre-National Basic Research Program of China (973 Plan; 2012CB722404), the National Key Basic Research Program of China (2014CB541901), the National Key Research and Development Program (No. 2016YFC0906102), the Natural Science Fund of Anhui province (1408085MKL27) and the Shenzhen Municipal Government (No. CXZZ20140904154910774).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Anhui Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.