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 individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping.

Objective: To estimate the incidence of primary hepatic carcinoma and death by HFE variant status.

Design, setting, and participants: Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018.

Exposures: Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants.

Main outcomes and measures: Two linked co-primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex.

Results: A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men 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 with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), 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 = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .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 with men 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.

Figure 1.. Hazard Ratios for Incident Liver Outcomes Comparing p.C282Y Homozygous Genotype With Individuals With No HFE Variants

Hazard ratios adjusted for age, assessment center, genotyping array, and population genetics substructure using principal components. Individuals with each prevalent diagnosis at baseline only were excluded (eg, the incident liver cancer analysis included participants with baseline noncancer liver disease). The participants in the total cohort had incident diagnoses taken from Hospital Episode Statistics, the Cancer Registry, and death records (n = 451 186) (see eTables 4, 5, and 7 in the Supplement for details of all HFE genotypes). Participants in the primary care subset had primary care data available from general practices (n = 209 811).

Figure 2.. Kaplan-Meier Curve for Incidence of Diagnosed Liver Cancer in Male HFE p.C282Y Homozygotes Compared With Those With No Variants in Subset of Participants With Primary Care Data

Incident diagnosis from Hospital Episode Statistics, the Cancer Registry, death records, and primary care data (n = 209 811). Participants with prevalent liver cancer diagnosis at baseline were excluded, but those with noncancer liver disease at baseline were included. Median (interquartile range) follow-up time was 7.2 (6.5-7.8) years for p.C282Y homozygotes and 7.1 (6.5-7.7) years for those with no variants.