Dipender Gill, Beben Benyamin, Luke S. P. Moore, Grace Monori, Ang Zhou, Fotios Koskeridis, Evangelos Evangelou, Mike Laffan, Ann P. Walker, Konstantinos K. Tsilidis, Abbas Dehghan, Paul Elliott, Elina Hypponen, Ioanna Tzoulaki

PLoS Medicine (2019) 16(6): e1002833

Iron is integral to many physiological processes, and variations in its levels, even within the
normal range, can have implications for health. The objective of this study was to explore
the broad clinical effects of varying iron status.

Methods and findings
Genome-wide association study (GWAS) summary data obtained from 48,972 European
individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were
used to identify 3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene
[HFE] and rs855791 in the transmembrane protease serine 6 gene [TMPRSS6]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin
levels, thus serving as instruments for systemic iron status. Phenome-wide association
study (PheWAS) of these instruments was performed on 424,439 European individuals
(54% female) in the UK Biobank who were aged 40–69 years when recruited from 2006 to
2010, with their genetic data linked to Hospital Episode Statistics (HES) from April, 1995 to
March, 2016. Two-sample summary data mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human
phenome. MR–PheWAS analysis for the 3 iron status genetic instruments was performed
separately and then pooled by meta-analysis. Correction was made for testing of multiple
correlated phenotypes using a 5% false discovery rate (FDR) threshold. Heterogeneity
between MR estimates for different instruments was used to indicate possible bias due to
effects of the genetic variants through pathways unrelated to iron status. There were 904
distinct phenotypes included in the MR–PheWAS analyses. After correcting for multiple testing, the 3 genetic instruments for systemic iron status demonstrated consistent evidence of
a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation [SD] increase in genetically
determined serum iron levels 0.72, 95% confidence interval [CI] 0.64–0.81, P = 4 × 10−8) and hypercholesterolemia (hypercholesterolemia: OR 0.88, 95% CI 0.83–0.93, P = 2 ×
10−5) and increasing risk of traits related to infection of the skin and related structures (cellulitis and abscess of the leg: OR 1.25, 95% CI 1.10–1.42, P = 6 × 10−4). The main limitations
of this study relate to possible bias from pleiotropic effects of the considered genetic variants
and misclassification of diagnoses in the HES data. Furthermore, this work only investigated
participants with European ancestry, and the findings may not be applicable to other ethnic

Our findings offer novel, to our knowledge, insight into previously unreported effects of iron
status, highlighting a potential protective effect of higher iron status on hypercholesterolemia
and a detrimental role on risk of skin and skin structure infections. Given the modifiable and
variable nature of iron status, these findings warrant further investigation.