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

Abstract

ObjectiveAlthogh 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=8.26x10-4) and rs2620381 (miR-627, OR=0.77, P=2.55x10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0x10-6) 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=2.0x10-5) and FDA approved drug target genes (P=0.014). Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26x10-4), rs2620381 (miR-627, P=2.55x10-3), rs4285314 (miR-3135b, P=1.10x10-13), rs28477407 (miR-4308, P=3.44x10-5), rs5997893 (miR-3928, P=5.9x10-3) and rs45596840 (miR-4482, P=6.6x10-3) 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.