Genome-wide association studies have identified >100 genetic risk factors for rheumatoid arthritis. However, the reported genetic variants could only explain less than 40% heritability of rheumatoid arthritis. The majority of the heritability is still missing and needs to be identified with more studies with different approaches and populations. In order to identify novel function SNPs to explain missing heritability and reveal novel mechanism pathogenesis of rheumatoid arthritis, 4 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. We identified 2 novel SNPs as significantly associated with rheumatoid arthritis including rs1414273 (miR-548ac, OR = 0.84, p = 8.26 × 10^-4) and rs2620381 (miR-627, OR = 0.77, p = 2.55 × 10^-3). We also identified that 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). In addition, we found that individuals who carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, p < 1.0 × 10^-6) times more risk of being affected by RA. Finally, we demonstrated that the 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). Overall, 6 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 understanding of the pathogenesis and drug development for rheumatoid arthritis.

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