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 groups.
CONCLUSIONS: 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.