Associations Between Genetically Predicted Iron Status and Cardiovascular Disease Risk: A Mendelian Randomization Study

Abstract

Background: Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors.

Methods and results: Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P>0.05).

Conclusions: Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

Keywords: Mendelian randomization analysis; biomarkers; blood pressure; genome‐wide association study; iron; ischemic stroke; risk factors.

Figure 1. Study design and workflow.

CVD indicates cardiovascular disease; Fe, iron; IVW, inverse variance weighted; MR, Mendelian randomization; MR‐PRESSO, Mendelian randomization pleiotropy residual sum and outlier test; and MVMR, multivariate Mendelian randomization.

Figure 2. Associations between genetically predicted iron status and cardioembolic ischemic stroke using univariate and multivariate Mendelian randomization.

A, TIBC as the exposure with CES as the outcome. B, TSAT as the exposure with CES as the outcome. C, Serum iron as the exposure with CES as the outcome. MR estimates presented as OR and 95% CIs per 1‐SD unit increase in the iron exposure. ApoA indicates apolipoprotein A; ApoB, apolipoprotein B; BMI, body mass index; CES, cardioembolic stroke; DBP, diastolic blood pressure; LDL, low‐density lipoprotein; MVMR, multivariate Mendelian randomization; OR, odds ratio; TC, total cholesterol; TG, triglycerides; TIBC, total iron binding capacity; TSAT, transferrin saturation; and UVMR, univariate Mendelian randomization.

Figure 3. Associations between genetically predicted iron status and atherosclerotic cardiovascular disease outcomes using univariate and multivariate Mendelian randomization.

A, TIBC as the exposure with CHD as the outcome. B, TSAT as the exposure with CHD as the outcome. C, Serum iron as the exposure with CHD as the outcome. D, TIBC as the exposure with LAS as the outcome. E, TSAT as the exposure with LAS as the outcome. F, Serum iron as the exposure with LAS as the outcome. MR estimates presented as OR and 95% CIs per 1‐SD unit increase in the iron exposure. ApoA indicates apolipoprotein A; ApoB, apolipoprotein B; BMI, body mass index; DBP, diastolic blood pressure; CHD, coronary heart disease; LAS, large‐artery stroke; LDL, low‐density lipoprotein; MVMR, multivariate Mendelian randomization; OR, odds ratio; TC, total cholesterol; TG, triglycerides; TIBC, total iron‐binding capacity; TSAT, transferrin saturation; and UVMR, univariate Mendelian randomization.