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Identification of new susceptibility loci associated with rheumatoid arthritis
  1. Rui-Xue Leng1,2,
  2. Dong-Sheng Di1,2,
  3. Jing Ni3,
  4. Xiao-Xiao Wu1,2,
  5. Lin-Lin Zhang1,2,
  6. Xu-Fan Wang1,2,
  7. Rui-Shan Liu1,2,
  8. Qian Huang1,2,
  9. Yin-Guang Fan1,2,
  10. Hai-Feng Pan1,2,
  11. Bin Wang1,2,
  12. Dong-Qing Ye1,2
  1. 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
  2. 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
  3. 3Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
  1. Correspondence to Dong-Qing Ye, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; ydq{at}ahmu.edu.cn

Abstract

Objectives The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).

Methods We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.

Results We identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta <5.00E−08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets.

Conclusion This study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

  • arthritis
  • rheumatoid
  • polymorphism
  • genetic
  • therapeutics
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Footnotes

  • Handling editor Josef S Smolen

  • R-XL, D-SD and JN contributed equally.

  • Contributors D-QY coordinated and supervised the overall study. R-XL conceived, designed the study and drafted the manuscript. D-SD, R-SL, QH, X-XW, L-LZ and X-FW prepared samples, collected the demographic and clinical data. R-XL and JN performed data imputation, the association analysis and bioinformatic analysis. BW, H-FP and Y-GF commented and helped in revising the manuscript. All authors reviewed and approved the final manuscript.

  • Funding This study was funded by the Chinese national high level personnel special support plan.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the medical ethics committee of Anhui Medical University. All procedures involved in this study were performed in accordance with the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. Data request should be sent to ydq@ahmu.edu.cn.

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