Abstract

BACKGROUND & AIMS: Systemic iron status affects multiple health outcomes, however its net effect on life expectancy is not known. We conducted a two-sample Mendelian randomization (MR) study to investigate the association of genetically proxied iron status with life expectancy. METHODS: Using genetic data from 48,972 individuals, we identified three genetic variants as instrumental variables for systemic iron status. We obtained genetic associations of these variants with parental lifespan (n = 1,012,240) and individual survival to the 90th vs. 60th percentile age (11,262 cases and 25,483 controls). We used the inverse-variance weighted method to estimate the effect of a 1-standard deviation (SD) increase in genetically predicted serum iron on each of the life expectancy outcomes. RESULTS: We found a detrimental effect of genetically proxied higher iron status on life expectancy. A 1-SD increase in genetically predicted serum iron corresponded to 0.70 (95% confidence interval [CI] -1.17, -0.24; P = 3.00 × 10-3) fewer years of parental lifespan and had odds ratio 0.81 (95% CI 0.70, 0.93; P = 4.44 × 10-3) for survival to the 90th vs. 60th percentile age. We did not find evidence to suggest that these results were biased by pleiotropic effects of the genetic variants. CONCLUSIONS: Higher systemic iron status may reduce life expectancy. The clinical implications of this finding warrant further investigation, particularly in the context of iron supplementation in individuals with normal iron status.