Association of hemochromatosis HFE p.C282Y homozygosity with hepatic malignancy

Abstract

Importance: Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. Objective: To estimate incidence of primary hepatic carcinomas and death by HFE variant status. Design, Setting, and Participants: Cohort study of 451,186 UK Biobank participants of European ancestries, followed from baseline assessment (2006 to 2010, aged 40-70 years) until January 2018. Exposures: Men and women with HFE p.C282Y and p.H63D genotypes, compared to those with neither HFE variants.

Main Outcomes and Measures: Two linked co-primary outcomes (incident primary liver carcinoma and deaths from any cause) were ascertained from follow-up in hospital inpatient records, national cancer registry and death certificate records, plus a subset with additional primary care data. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array and population genetics sub-structure. Kaplan Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75, by HFE genotype and sex.

Results: 451,186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% female) were followed for a median (interquartile range) of 8.9 (8.3-9.5) years. There were 1,294 male p.C282Y homozygotes, with 21 incident hepatic malignancies; 10 were in participants without baseline hemochromatosis diagnoses. Homozygote males had increased risk of hepatic malignancies (HR: 10.5, 95% CI: 6.6-16.7, p<0.001) and all-cause mortality (n=88, HR: 1.2, 95% CI: 1.0-1.5, p=0.046) compared to those with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI: 3.9-13.1) compared to 0.6% (95% CI: 0.4-0.7) with neither variant, and the risk of death was 19.5% (95% CI: 15.8-24.0) compared to 15.1% (95% CI: 14.7-15.5). Among female p.C282Y homozygotes (n=1,596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR: 2.1, 95% CI: 0.7-6.5, p=0.22) or death (HR: 1.2, CI: 0.9-1.5, p=0.20) were not statistically significant. Conclusions and Relevance: Among men with HFE p.C282Y homozygosity there was a significantly increased risk of incident primary hepatic malignancy and death compared to those without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment