Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank

Background The iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. In Europeans, most HH disease occurs in male HFE p.C282Y homozygotes, yet only a minority of homozygotes in the general population develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or risks for liver, diabetes or arthritis diagnoses in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. Methods 1,294 male and 1,596 female UK Biobank European-ancestry HFE p.C282Y homozygous participants with electronic medical records up to 14 years after baseline assessment were studied. Polygenic risk scores (PRS) quantified genetic effects on blood iron biomarkers and relevant diseases (identified in the general population). Analyses were repeated in 10,699 p.C282Y/p.H63D compound heterozygotes. Results In male p.C282Y homozygotes, higher iron PRS increased risk of liver fibrosis or cirrhosis diagnoses (top 20% of iron PRS had Odds Ratio 4.90: 95% Confidence Intervals 1.63 to 14.73, p=0.005 versus bottom 20%), liver cancer, and osteoarthritis, but not diabetes. The liver cirrhosis PRS also associated with increased liver cancer diagnoses, and greater type-2 diabetes PRS increased risk of type-2 diabetes. In female p.C282Y homozygotes, osteoarthritis PRS was associated with increased osteoarthritis diagnoses, and type-2 diabetes PRS with type-2 diabetes. However, the iron PRS was not robustly associated with diagnoses in p.C282Y homozygote females, or in other p.C282Y/p.H63D genotypes. Conclusions HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population. Including PRS in HH screening and diagnosis may help in estimating prognosis and treatment planning. Lay Summary Two or three sentences summarizing the main message of the article expressed in plain English to describe your findings to a non-medical audience . ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was generously funded by an award to DM by the Medical Research Council MR/S009892/1. DM and LP are supported by the University of Exeter Medical School. JA is supported by an NIHR Advanced Fellowship (NIHR301844). The funders had no input in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The North West Multi-Centre Research Ethics Committee approved the collection and use of UK Biobank data (Research Ethics Committee reference 11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available to any bone fide researcher following application to UK Biobank ([www.ukbiobank.ac.uk/register-apply][1]). Access to UK Biobank was granted under Application Number 14631. [1]: http://www.ukbiobank.ac.uk/register-apply