MicroRNA Variants and HLA-miRNA Interactions are Novel Rheumatoid Arthritis Susceptibility Factors

Shicheng Guo; Yehua Jin; Jieru Zhou; Qi Zhu; Ting Jiang; Yanqin Bian; Runrun Zhang; Cen Chang; Lingxia Xu; Jie Shen; Xinchun Zheng; Yi Shen; Yingying Qin; Jihong Chen; Xiaorong Tang; Peng Cheng; Qin Ding; Yuanyuan Zhang; Jia Liu; Qingqing Cheng; Mengru Guo; Zhaoyi Liu; Weifang Qiu; Yi Qian; Yang Sun; Yu Shen; Hong Nie; Steven J Schrodi; Dongyi He

doi:10.3389/fgene.2021.747274

MicroRNA Variants and HLA-miRNA Interactions are Novel Rheumatoid Arthritis Susceptibility Factors

Front Genet. 2021 Oct 29:12:747274. doi: 10.3389/fgene.2021.747274. eCollection 2021.

Authors

Shicheng Guo¹, Yehua Jin^{2

3}, Jieru Zhou⁴, Qi Zhu^{3

5}, Ting Jiang³, Yanqin Bian^{3

5}, Runrun Zhang^{2

3}, Cen Chang^{2

3}, Lingxia Xu^{2

3}, Jie Shen^{3

5}, Xinchun Zheng³, Yi Shen³, Yingying Qin³, Jihong Chen³, Xiaorong Tang³, Peng Cheng³, Qin Ding³, Yuanyuan Zhang³, Jia Liu³, Qingqing Cheng³, Mengru Guo³, Zhaoyi Liu³, Weifang Qiu³, Yi Qian³, Yang Sun⁵, Yu Shen⁵, Hong Nie⁶, Steven J Schrodi¹, Dongyi He^{3

5}

Affiliations

¹ Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
² Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ Department of Health Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
⁶ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

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.

Keywords: SNP; miRNA; predispose; rheumatoid arthritis; susceptibility.