Evidence Supports Genetic Link Between Hypothyroidism, Rheumatoid Arthritis

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A new investigation demonstrated evidence of a genetic correlation, identified shared loci and suggested a causal relationship between hypothyroidism and rheumatoid arthritis (RA).¹

Using public genome-wide association studies (GWAS) summary statistics of hypothyroidism and RA, investigators identified a positive genetic association in specific genomic regions. At the same time, Mendelian randomization analysis displayed a causal effect of hypothyroidism on RA.

“This study represents the first genome-wide cross-trait analysis investigating the shared genetic basis that underlies hypothyroidism and RA,” wrote the investigative team led by Panpan Long of the center of genetics at Changsha Jiangwan Maternity Hospital.

Nearly 4 to 10% of the population is affected by hypothyroidism—the disease has been linked to cardiac dysfunction, atherosclerosis, hypertension, and coagulation disorders, potentially reducing a patient’s lifespan.² As RA affects 0.5 to 1% of the global population, with links to inflammation and structural damage of the joints, patients often experience less favorable outcomes on quality of life, morbidity, and mortality, compared with the general population.³

Although previous evidence has linked an elevated rate of hypothyroidism in patients with RA, it is not consistent in the literature, with a lack of studies on the elusive association.⁴ Long and colleagues aimed to clarify the shared genetic architecture and molecular pathways of hypothyroidism and RA, to provide a path forward for more effective interventions.¹

The analysis used public GWAS summary statistics for hypothyroidism including 462,933 individuals (22,687 cases and 440,246 controls) of European ancestry. For RA, investigators applied summary statistics for the discovery dataset from GWAS with 253,417 individuals (12,555 cases and 240,862 controls).

In the analysis, the investigative team explored the shared genetics between hypothyroidism and RA using linkage disequilibrium score regression, ρ-HESS, Pleiotropic analysis under a composite null hypothesis (PLACO), colocalization analysis, Multi-Trait Analysis of GWAS (MTAG), and transcriptome-wide association study (TWAS). Then, the team assessed the causal associations using Mendelian randomization analysis.

Bivariate linkage disequilibrium score regression methodology was used to estimate the genetic correlations between hypothyroidism and RA. Upon analysis, the results exhibited a significant positive genetic correlation (P = 6.70 x 10^-7) between hypothyroidism and RA.

After determining the significant global genetic correlation, investigators searched for specific genomic regions with local genetic correlations between hypothyroidism and RA. After multiple tests of correction, the team found strong local correlations between hypothyroidism and RA in 6 different regions.

Overlap analysis of PLACO, MTAG, Bayesian colocalization analyses, and TWAS were performed to assess the most representative genes associated with hypothyroidism and RA. The approach successfully identified TYK2, IL2RA, and IRF5 as shared risk genes for both hypothyroidism and RA. As a result, investigators noted these genes may be the most representative associated with hypothyroidism and RA.

Enrichment analyses of pleiotropic genes identified by PLACO were conducted using Functional Mapping and Annotation of GWAS (FUMA). The genetic associations between hypothyroidism and RA were enriched in various tissues, such as the spleen, lung, small intestine, adipose visceral, and blood.

Mendelian randomization analysis further validated the causal effect of hypothyroidism on RA, as the estimates remained directionally consistent across the weighted median, weighted mode, and MR Egger approaches. However, no significant effect of RA on hypothyroidism was observed in the analysis.

Long and colleagues indicated these data could have potential implications for future therapeutic strategies and risk prediction in patients with hypothyroidism and RA. However, they called for large, prospective longitudinal clinical studies to determine if hypothyroidism patients with specific genotypes are more likely to develop RA.

“In our exploratory MR analyses, we found evidence of a causal effect of hypothyroidism on RA, aligning with recent study findings,” investigators wrote. “The findings of our study suggest that hypothyroid patients can be monitored for RA risk, which will aid in early detection."

References

1. _{Peng Z, Huang W, Tang M, et al. Investigating the shared genetic architecture between hypothyroidism and rheumatoid arthritis. Front Immunol. 2024;14:1286491. Published 2024 Jan 25. doi:10.3389/fimmu.2023.1286491}
2. _{Udovcic M, Pena RH, Patham B, Tabatabai L, Kansara A. Hypothyroidism and the heart. Methodist Debakey Cardiovasc J (2017) 13:55–9. doi: 10.14797/mdcj-13-2-55}
3. _{Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. LANCET (2010) 376:1094–108. doi: 10.1016/S0140-6736(10)60826-4}
4. _{McCoy SS, Crowson CS, Gabriel SE, Matteson EL. Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis. J RHEUMATOL (2012) 39:954–8. doi: 10.3899/jrheum.111076}