Commonest genetic mutation causes much morbidity

Author: Louise Prime

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Morbidity resulting from homozygosity for the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) is common among men and women but is often mistaken for the effects of normal ageing so diagnosis is missed or late, the researchers behind a UK study* said today in the BMJ. They argued that as the associated iron overload is both preventable and treatable if started early, their findings warrant a reconsideration of options for screening.

The researchers explained that hereditary haemochromatosis is the most common genetic condition in people of European descent, and that type 1 is predominantly attributable to two HFE gene mutations, with 95% of affected people having the p.C282Y (p.Cyst282Tyr) mutation and 4% the p.C282Y/p.Hist63Asp compound heterozygote genotype.

The research team, led from the University of Exeter, analysed data from 22 centres across England, Scotland, and Wales in UK Biobank (2006-10), covering 451,243 male and female volunteers of European descent aged 40-70 years at baseline. They compared disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components.

They found that 2,890 participants (0.6%) (1,294 men and 1,596 women) were homozygous for p.C282Y; and of these, hemochromatosis was diagnosed in more than a fifth (21.7%) of men and almost one in 10 (9.8%) women, over a mean follow-up of seven years – and this was often associated with higher rates of morbidity.

Men homozygous for p.C282Y had a significantly higher prevalence of diagnosed haemochromatosis (odds ratio, OR 411.1), liver disease (OR 4.30), rheumatoid arthritis (OR 2.23), osteoarthritis (OR 2.01), and diabetes mellitus (1.53), compared with the 175,539 men with no p.C282Y mutations. During follow-up, 15.7% of homozygous men developed at least one incident associated condition, compared with 5.0% of men with no p.C282Y mutations (women 10.1% vs 3.4%).

Women homozygous for p.C282Y had a statistically significantly increased risk only for haemochromatosis (OR 438.0) and osteoarthritis (OR 1.33).

A diagnosis of haemochromatosis was also more common in p.C282Y/p.H63D compound heterozygotes, for both men and women (hazard ratio, HR 33.63 and 34.74 respectively), but excess morbidity was modest and mortality was not increased. Simple p.C282Y heterozygotes were still more likely to have a diagnosis of incident haemochromatosis (HR 3.42) compared with those with no p.C282Y or p.H63D, with no excess morbidity.

The study authors pointed out that although hereditary haemochromatosis is regarded as fitting several criteria for genetic screening, the previously reported low clinical penetrance in community p.C282Y carriers did not justify screening beyond close relatives. However, there is accumulating evidence that penetrance to clinically diagnosed morbidity in p.C282Y homozygotes is not uncommon and that many cases are missed or diagnosed only after substantial morbidity has developed.

They concluded: “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.”

*Pilling LC, Tamosauskaite J, Jones G et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ 2019; 364: k5222


Editorial team, Wilmington Healthcare

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