Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank

Abstract

Objective: To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent.

Design: Cohort study.

Setting: 22 centres across England, Scotland, and Wales in UK Biobank (2006-10).

Participants: 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification.

Main outcome measure: Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women.

Results: Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest.

Conclusions: In a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.

Fig 1

Prevalent conditions in studied sample (aged 40-70 at baseline): Forest plot of associations comparing p.C282Y homozygous status with no p.C282Y mutations, irrespective of p.H63D status, in men and women. Odds ratios are from logistic regression models adjusted for age, genotyping array type, and genetic principal components. See supplementary table 2 for details

Fig 2

Percentage of participants with at least one incident diagnosis during follow-up, by age group, sex, and p.C282Y genotype. Absolute percentages and 95% confidence intervals are shown. Diagnoses included haemochromatosis, any liver disease, liver cancer, diabetes, osteoarthritis, and rheumatoid arthritis. Prevalent cases are excluded. All comparisons are with no p.C282Y mutations, irrespective of p.H63D status. See supplementary table 5 for details

Fig 3

Forest plot of associations for developing at least one p.C282Y associated incident condition (incident haemochromatosis, liver disease (including liver cancer), diabetes (type 1 or 2), rheumatoid arthritis, or osteoarthritis) by end of follow-up, stratified by genotype and sex. Hazard ratios are from time-to-event (Cox’s proportional hazards regression) models adjusted for age, genotyping array type, and genetic principal components. The homozygous and heterozygous (p.C282Y/p.C282Y and p.C282Y/−, respectively) groups are compared with participants with no p.C282Y mutations, irrespective of p.H63D status. The p.C282Y/p.H63D group are compared with participants without p.C282Y and p.H63D mutations. p.H63D/p.H63D and p.H63D/− groups are compared with participants with no p.H63D mutations. See supplementary table 4 for details