Genetic predisposition of MTHFR and TNFSF4 gene polymorphism related to hypothyroidism– A meta-analysis

Background

Autoimmune thyroid diseases (AITDs), such as hypothyroidism, result from an intricate combination of genetic and environmental influences. The relationship between genetic variations in the MTHFR and TNFSF4 genes and autoimmune illnesses has been established, but their impact on hypothyroidism has not been well investigated. This study examines the associations between specific polymorphisms in the MTHFR (rs1801133) and TNFSF4 (rs3850641 and rs7514229) genes and the risk of hypothyroidism.

Methods

The study involved 168 hypothyroid patients and 171 healthy controls, all female and aged 18 to 45, from the Department of Obstetrics and Gynecology, Chettinad Academy of Research and Education in Chennai, India. Exclusion criteria included autoimmune thyroid diseases, pregnancy, medication use, and HIV positivity. Literature from PubMed, Cochrane Library, and Google Scholar, published between 2010 and 2024, was reviewed. Keywords included ‘MTHFR,’ ‘gene,’ ‘rs1801133,’ ‘AITD,’ and ‘Hypothyroidism.’ Heterogeneity was assessed using I² statistics, and the fixed or random effects model was applied accordingly. Sensitivity and publication bias were evaluated through various tests.

Results

The GA genotype and A allele were associated with increased hypothyroidism risk (OR = 0.55, 95 % CI: 0.35–0.89; OR = 0.62, 95 % CI: 0.40–0.94). The AA genotype did not significantly affect the MTHFR rs1801133 polymorphism. The G allele was associated with reduced hypothyroidism risk (OR = 0.67, 95 % CI: 0.47–0.97). No significant effects were found for genotype distributions or genetic models in TNFSF4 rs3850641, whereas the TNFSF4 rs7514229 polymorphism, the GT genotype, and the T allele were associated with reduced hypothyroidism risk (OR = 0.46, 95 % CI: 0.23–0.92; OR = 0.48, 95 % CI: 0.25–0.94). The dominant model revealed an elevated risk with GT+TT genotypes, and in the MTHFR rs1801133 polymorphism, the allelic model showed a significant link with hypothyroidism (OR = 1.49, 95 % CI: 0.99–2.22), while other genetic models did not demonstrate persistent significant correlations. A high degree of heterogeneity was identified.

Conclusion

The research discovered a strong correlation, particularly in the GA genotype and A allele, between the MTHFR rs1801133 polymorphism and the risk of hypothyroidism. Although some TNFSF4 polymorphisms showed associations with hypothyroidism, their overall impact was modest. Future research should include more significant, more diverse populations to understand better these genetic risk factors and their implications for hypothyroidism prevention and management.