Meta-analysis on the association of the COMT Val158Met variant with preeclampsia risk

Catecholamine-O-methyl transferase (COMT) catalyzes the O-methylation of catechol-structured compounds such as catecholamines and catecholestrogens. A genetic variation in the human COMT gene (rs4680 or Val158Met) significantly reduces three-to-four-fold catecholamine metabolism and influences neurotransmitter levels, thereby modulating preeclampsia (PE) susceptibility. The present meta-analysis was conducted to evaluate the link between the COMT Val158Met variant and PE risk. Case-control studies published until November 20, 2025 were systematically searched from PubMed, Google Scholar, and Web of Science databases. To assess the association between the COMT Val158Met variant and PE, Odds ratios and 95% confidence intervals were calculated under three genetic models. The results indicated no significant association between the COMT Val158Met variant and PE risk across three genetic models, including the allele (Met vs. Val: Overall OR 1.19, 95% CI 1.00-1.43, P = 0.052), recessive (Met/Met + Met/Val vs. Val/Val: Overall OR 1.16, 95% CI 0.95-1.40, P = 0.137), and dominant (Met/Met vs. Met/Val + Val/Val OR 1.39, 95% CI 0.97-2.00, P = 0.075) models. Furthermore, subgroup analyses based on ethnicity also indicated no association between the Val158Met variant and PE risk in Caucasian and Asian populations. Sensitivity analyses conducted using the leave-one-out method revealed that the results are robust. Asymmetry observed in Begg's funnel plot indicated a significant publication bias in the dominant model (P = 0.012). In summary, results showed that the COMT Val158Met variant is not associated with PE risk. As this meta-analysis contradicts the biological plausibility that COMT alleles influence catecholamine neurotransmitters and PE, the results warrant careful interpretation and further investigation.