Investigation into the causal effect of iron metabolism on cardiovascular disease

Background: The iron-heart hypothesis, put forward in 1981, proposes that higher iron levels are responsible for an increased risk of cardiovascular disease in men and post-menopausal women compared to pre-menopausal women. However, despite 30 years of research into this suggested association, there is still no consensus regarding the causal effect of iron on CVD. Objectives: To establish the likelihood of a causal effect of iron metabolism on risk of coronary heart disease (CHD) and stroke using five markers of iron metabolism, and a combination of observational epidemiology, genetic epidemiology and causal inference methods. Results: The observational association of serum iron, ferritin, transferrin and transferrin saturation (TS) with risk of CHD and stroke was assessed in 16,906 male and 17,110 female participants of the EPIC-CVD prospective cohort. Results of this study, which is the largest prospective study to investigate the association of iron markers with CHD and stroke, indicated an inverse association of iron levels with CHD risk in men but not in women. Further, there was no evidence of a difference in risk of CHD in women by menopause status. Serum iron showed a positive association with risk of composite stroke in men and women, but there was no evidence of an association of other iron markers with stroke. Results of a Mendelian randomization (MR) analysis using established genetic variants associated with serum iron, ferritin, transferrin and TS in published genetic association studies, suggested a non-significant inverse association of iron status with risk of CHD, and no association with ischemic stroke. A genome wide association analysis in 39,000 participants of the INTERVAL blood donor trial, led to discovery of associations with genetic variants at 26 novel loci for serum iron, ferritin, transferrin, TS and soluble transferrin receptor (sTfR), providing new instruments for MR analysis. A new MR analysis of serum iron, ferritin, transferrin, TS and sTfR was performed, including up to 10 new genetic variants and an additional iron marker (sTfR). Results of this new analysis indicated a significant inverse effect of iron levels on CHD. However after exclusion of genetic variants associated with CVD risk factors, there was no longer evidence of an association of markers of iron status with risk of CHD. There was also no evidence of an association of iron markers with ischemic stroke before or after exclusion of variants associated with CVD risk factors. Conclusion: Findings from this PhD do not support a causal effect of increased iron levels on CHD. Further, the inverse association of iron markers with CHD in MR analysis appears to be the result of confounding by CVD risk factors. Results for stroke remain inconclusive due to the small numbers of cases available and should be investigated in further studies.