Frontiers in Genetics (Oct 2021)
MicroRNA Variants and HLA-miRNA Interactions are Novel Rheumatoid Arthritis Susceptibility Factors
- Shicheng Guo,
- Yehua Jin,
- Yehua Jin,
- Jieru Zhou,
- Qi Zhu,
- Qi Zhu,
- Ting Jiang,
- Yanqin Bian,
- Yanqin Bian,
- Runrun Zhang,
- Runrun Zhang,
- Cen Chang,
- Cen Chang,
- Lingxia Xu,
- Lingxia Xu,
- Jie Shen,
- 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,
- Dongyi He
Affiliations
- Shicheng Guo
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Yehua Jin
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yehua Jin
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jieru Zhou
- Department of Health Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Qi Zhu
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Qi Zhu
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Ting Jiang
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yanqin Bian
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yanqin Bian
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Runrun Zhang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Runrun Zhang
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Cen Chang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Cen Chang
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Lingxia Xu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Lingxia Xu
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jie Shen
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jie Shen
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Xinchun Zheng
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yi Shen
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yingying Qin
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jihong Chen
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Xiaorong Tang
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Peng Cheng
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Qin Ding
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yuanyuan Zhang
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Jia Liu
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Qingqing Cheng
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Mengru Guo
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Zhaoyi Liu
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Weifang Qiu
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yi Qian
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Yang Sun
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Yu Shen
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Hong Nie
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Steven J. Schrodi
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Dongyi He
- Department of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Dongyi He
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- DOI
- https://doi.org/10.3389/fgene.2021.747274
- Journal volume & issue
-
Vol. 12
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