Impact of TMPRSS6 Genetic Variants on Maternal Iron Status in Pregnancy: A Systematic Review

Abstract

Objective: The TMPRSS6 gene encodes matriptase-2, a serine protease that negatively regulates hepcidin and thus governs systemic iron homeostasis. Common polymorphisms have been implicated in altered iron indices in normal populations. To date, no systematic review has comprehensively assessed the impact of TMPRSS6 on maternal iron status and pregnancy outcomes. This review aims to elucidate the molecular mechanisms and clinical impact of TMPRSS6 variants on maternal iron status and obstetric complications. Methods: A systematic review was conducted in accordance with PRISMA guidelines. English-language articles published between 2015 and 2024 were retrieved from PubMed, Crossref, OpenAlex, and Google Scholar. Eligible studies assessed TMPRSS6 genotypes in relation to iron biomarkers and obstetric complications. Seven studies met inclusion criteria. Results: Of 1243 articles identified, seven studies (n = 1094 pregnant participants) met inclusion criteria. The rs855791 T-allele and rs4820268 G-allele consistently correlated with lower serum iron, reduced transferrin saturation, and elevated unsaturated iron-binding capacity. These variants increased risks of iron-deficiency anemia, gestational diabetes mellitus, and preeclampsia. Functional analyses indicated that altered matriptase-2 activity leads to inappropriately high hepcidin, impaired dietary iron absorption, and downstream metabolic disturbances. Conclusion: TMPRSS6 polymorphisms play a central role in disrupting iron regulation and contribute to obstetric complications. Incorporating TMPRSS6 genotyping into prenatal care may facilitate personalized risk stratification and optimized iron supplementation strategies.