Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy

• Published in: JAMA : the journal of the American Medical Association 2020-11, Vol.324 (20), p.2048-2057
• Main Authors: Atkins, Janice L, Pilling, Luke C, Masoli, Jane A. H, Kuo, Chia-Ling, Shearman, Jeremy D, Adams, Paul C, Melzer, David
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Alanine Transaminase - blood; Aspartate Aminotransferases - blood; Biological Specimen Banks; Cancer; Cohort Studies; Death; Diagnosis; Female; Genetics; Genotypes; Genotyping; Genotyping Techniques; Hemochromatosis; Hemochromatosis - blood; Hemochromatosis - complications; Hemochromatosis - genetics; Hemochromatosis - mortality; Hemochromatosis Protein - genetics; Homozygosity; Homozygote; Homozygotes; Humans; Liver; Liver cancer; Liver Neoplasms - etiology; Male; Malignancy; Men; Middle Aged; Mortality; Mutation; Original Investigation; Polycythemia - etiology; Population genetics; Risk; Sex Factors; Statistical analysis; Substructures; Women
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2020.21566

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