MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

Author:

Guo ShichengORCID,Jin YehuaORCID,Zhou JieruORCID,Zhu QiORCID,Jiang TingORCID,Bian YanqinORCID,Zhang RunrunORCID,Chang CenORCID,Xu LingxiaORCID,Shen JieORCID,Zheng XinchunORCID,Shen YiORCID,Qin YingyingORCID,Chen JihongORCID,Tang XiaorongORCID,Cheng PengORCID,Ding QinORCID,Zhang YuanyuanORCID,Liu JiaORCID,Cheng QingqingORCID,Guo MengruORCID,Liu ZhaoyiORCID,Qiu WeifangORCID,Qian YiORCID,Sun YangORCID,Shen YuORCID,Nie HongORCID,Schrodi Steven JORCID,He DongyiORCID

Abstract

AbstractObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions.Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs.Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26×10-4) and rs2620381 (miR-627, OR=0.77, P=2.55×10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0×10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0×10-5) and FDA approved drug target genes (P=0.014).Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26×10-4), rs2620381 (miR-627, P=2.55×10-3), rs4285314 (miR-3135b, P=1.10×10-13), rs28477407 (miR-4308, P=3.44×10-5), rs5997893 (miR-3928, P=5.9×10-3) and rs45596840 (miR-4482, P=6.6×10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

Publisher

Cold Spring Harbor Laboratory

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