Genetically predicted iron status and cardiovascular function and structure: a Mendelian randomization study

Area of Science:

• Cardiovascular Genetics
• Iron Metabolism
• Mendelian Randomization

Background:

• Iron level imbalances are associated with cardiovascular outcomes.
• Lifelong higher iron levels may impact cardiovascular health.
• Confounding factors can bias observational studies on iron and cardiovascular disease.

Purpose of the Study:

• To assess the association between genetically predicted lifelong higher iron levels and cardiovascular outcomes.
• To utilize a two-sample Mendelian randomization (MR) approach to minimize confounding biases.
• To investigate the role of specific iron biomarkers and related genes in cardiovascular structure and function.

Main Methods:

• Employed a two-sample Mendelian randomization (MR) approach.
• Utilized genetic variants associated with iron biomarkers (ferritin, serum iron, TIBC, TSAT) from six cohort studies (N=257,953).
• Examined associations with cardiac structure and function parameters (LVEDV, LVESV, LVEF, LVM, LVMVR) using UK Biobank data.

Main Results:

• A one standard deviation (SD) increase in genetically predicted serum iron was associated with lower left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV).
• A one SD increase in genetically predicted transferrin saturation (TSAT) was associated with higher left ventricular mass-to-end-diastolic volume ratio (LVMVR).
• No significant heterogeneity, pleiotropy, or bidirectional effects were observed; associations were linked to HFE, TMPRSS6, TF, and TFR2 genes.

Conclusions:

• Provides Mendelian randomization evidence that both lower and higher iron status can alter cardiovascular function and structure.
• Highlights the significant role of HFE, TMPRSS6, TF, and TFR2 genes in the observed iron-cardiovascular associations.
• Suggests a complex relationship between iron homeostasis and cardiovascular health.