Appraising the causal relationship between thyroid function and rheumatoid arthritis: a two-sample bidirectional Mendelian randomization study

Peng Gu; Bin Pu; YangCheng Ma; Dan Yue; Qiao Xin; HaiShan Li; Teng Liu; XiaoHui Zheng; ChongZhi Ouyang

doi:10.3389/fimmu.2023.1238757

Appraising the causal relationship between thyroid function and rheumatoid arthritis: a two-sample bidirectional Mendelian randomization study

Front Immunol. 2023 Nov 28:14:1238757. doi: 10.3389/fimmu.2023.1238757. eCollection 2023.

Authors

Peng Gu^{1

2}, Bin Pu^{1

2}, YangCheng Ma², Dan Yue³, Qiao Xin⁴, HaiShan Li², Teng Liu², XiaoHui Zheng¹, ChongZhi Ouyang¹

Affiliations

¹ The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
² First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
³ College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China.
⁴ Graduated School, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.

Abstract

Background: Hypothyroidism and hyperthyroidism are observationally associated with rheumatoid arthritis (RA), but causality is unclear. To evaluate the causal relationship between thyroid function and RA, we conducted a two-Sample bidirectional Mendelian Randomization (MR) study.

Methods: Single nucleotide polymorphisms associated with six phenotypes were selected from the FinnGen biobank database, The ThyroidOmics Consortium database, and the IEU Open GWAS database. For the forward MR analysis, we selected hypothyroidism (N=213,390), Graves' disease (GD) (N=199,034), other types of hyperthyroidism (N=190,799), free thyroxine (FT4, N=49,269), and thyroid-stimulating hormone (TSH, N=54,288) as the five related thyroid function phenotypes for exposure, with RA (N=58,284) as the outcome. Reverse MR analysis selected RA as the exposure and five phenotypes of thyroid function as the outcome. The Inverse variance weighting (IVW) method was used as the primary analysis method, supplemented by weighted median (WM) and MR-Egger methods. Cochran's Q test, MR-PRESSO, MR-Egger regression methods, and leave-one-out analysis were employed to assess sensitivity and pleiotropy.

Results: Forward MR evidence indicates that genetic susceptibility to hypothyroidism is associated with an increased risk of RA (OR_Ivw=1.758, P=7.61×10^-5). Reverse MR evidence suggests that genetic susceptibility to RA is associated with an increased risk of hypothyroidism (OR_Ivw=1.274, P=3.88×10^-20), GD (OR_Ivw=1.269, P=8.15×10^-05), and other types of hyperthyroidism (OR_Ivw=1.141, P=1.80×10^-03). There is no evidence to support a forward or reverse causal relationship between genetic susceptibility to RA and FT4, TSH.

Conclusion: Our results provide genetic evidence supporting bidirectional causal relationships between thyroid function and RA. These findings inform preventive strategies and interventions targeting RA and thyroid dysfunction.

Keywords: Mendelian randomization; free thyroxine; hyperthyroidism; hypothyroidism; rheumatoid arthritis; thyroid-stimulating hormone.

MeSH terms

Arthritis, Rheumatoid* / genetics
Genetic Predisposition to Disease
Graves Disease*
Humans
Hyperthyroidism*
Hypothyroidism* / genetics
Mendelian Randomization Analysis
Thyrotropin

Substances

Thyrotropin

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.