Genetics of Iron Metabolism and Premenstrual Symptoms: A Mendelian Randomization Study

Background: Many women of reproductive age experience adverse psychological and physiological premenstrual symptoms. These symptoms may last for most of the reproductive years and can negatively affect the quality of life of many women. Some studies have examined the role of micronutrients in premenstrual symptoms, but the research on iron has been limited.

Objectives: The objective of this study was to evaluate the effects of genetic predictors of iron overload and low iron status on premenstrual symptoms using Mendelian randomization.

Methods: We examined 254 White females aged 20-29 y from the Toronto Nutrigenomics and Health Study. DNA was isolated from peripheral white blood cells and genotyped for the homeostatic regulatory iron gene (HFE; rs1800562 and rs1799945), transmembrane protease serine 6 (TMPRSS6; rs482026), transferrin receptor 2 (TFR2; rs3811647), and transferrin (TF; rs738584) polymorphisms. Risk of iron overload or low iron status was determined based on combined genotypes. Binomial logistic regressions were carried out to examine the association between genetic risk of iron overload or low iron status and the presence of premenstrual symptoms.

Results: Compared with participants with typical risk of iron overload, those with an elevated risk of iron overload were less likely to experience premenstrual symptoms of confusion (OR: 0.13; 95% CI: 0.02, 1.00), headaches (OR: 0.28; 95% CI: 0.08, 0.98), and nausea (OR: 0.13; 95% CI: 0.02, 0.99) after adjusting for BMI, age, and vitamin C and calcium intake. No associations were seen with the other symptoms. There were also no associations between low iron status genotypes and premenstrual symptoms.

Conclusions: This Mendelian randomization study demonstrates that women with an elevated risk of iron overload may have a lower risk of experiencing some premenstrual symptoms (headache, confusion, and nausea), suggesting that iron status could impact the risk of certain premenstrual symptoms.