Genetics of hereditary hemochromatosis: a clinical perspective

Abstract

Hereditary hemochromatosis due to homozygosity for the C282Y mutation in the HFE gene product is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately one in 200. Cross-sectional and longitudinal studies have revealed that clinically significant iron-overload disease develops in at least 28% of male and 1% of female HFE C282Y homozygotes. The relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of hemochromatosis. Male gender is a strong genetic factor, promoting expression of clinical disease. Dietary intake of alcohol and noncitrus fruit may also act as important environmental modifiers of penetrance. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis are likely to be forthcoming.

Keywords::

• C282Y mutation
• clinical penetrance
• ferritin
• HFE hemochromatosis
• iron-overload phenotype

Financial & competing interests disclosure

The authors are supported by a National Health and Medical Research Council of Australia grant to Debbie Trinder and John K Olynyk (572601) and a practitioner fellowship to John K Olynyk; Gastroenterological Society of Australia Senior Research Fellowship to Debbie Trinder and Gastroenterological Society of Australia Postgraduate Clinical Scholarship to Eng K Gan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.