Hypothyroidism and rheumatoid arthritis: a two-sample Mendelian randomization study

Area of Science:

• Genetics and Immunology
• Endocrinology

Background:

• The causal link between hypothyroidism and rheumatoid arthritis (RA) risk is debated, despite existing genome-wide association studies (GWAS).
• This research aimed to rigorously test the hypothesis of a causal relationship between hypothyroidism and RA.

Approach:

• Employed a two-sample Mendelian randomization (TSMR) analysis across European and Asian ancestries to assess causality.
• Integrated functional annotations and variant prediction frameworks to identify and interpret instrumental variables (IVs).

Key Points:

• Inverse variance weighted (IVW) analysis revealed a significant causal relationship between hypothyroidism and RA risk in European ancestry (OR = 1.96, p < 0.001).
• Consistent results were observed across multiple MR methods (MR-Egger, weighted median) and validated in an independent Asian dataset.
• The SNP rs4409785 was identified as a potential causal variant, influencing CTCF-cohesin binding and immune cell function.

Conclusions:

• This study provides robust evidence for a significant causal association between hypothyroidism and an elevated risk of RA.
• Identified potential causal genetic variants, advancing the understanding of RA's underlying mechanisms.