The genetics of familial hypercholesterolaemia

Basic molecular genetic research undertaken over the last 20 years by UCL Cardiovascular Genetics has had a significant impact on the identification and treatment of patients with familial hypercholesterolaemia (FH), developing new DNA tests and diagnostic protocols now in wide use across the UK.

The work led to the National Institute of Health and Clinical Excellence in 2008 strongly recommending DNA and cascade testing and early treatment with high-intensity statins, and furthermore, the inclusion of FH checks in the NHS's Vascular Checks programme.

Familial hypercholesterolaemia is an inherited disorder which affects one in 500 members of the general population - or approximately 120,000 people in the UK. People with FH have very high levels of cholesterol in the bloodstream from birth and are at extremely high risk of developing early heart disease. Without treatment, half of men with FH will suffer a heart attack before the age of 55, as will one-third of women by age 60. Furthermore, first-degree relatives have a 50:50 chance of having inherited an FH gene. Treatments with cholesterol-lowering statins are highly effective, and someone identified early in life and treated with statins can expect a full life expectancy - but unfortunately, only 15,000 FH patients have been identified to date and are being adequately treated. It is estimated that around 100,000 people in the UK have undiagnosed FH - around six or seven in a typically sized general practice.

Over the last 20 years, researchers at UCL have undertaken basic molecular genetic research which has better enabled the identification and treatment of patients with FH. The DNA screening methods developed have been used commonly in DNA diagnostic laboratories throughout the UK.

Population screening for FH is not practicable but tracing of close relatives of those diagnosed - 'cascade' testing - could pick up a sizeable number of those at risk. Indeed, Professor Steve Humphries (UCL Cardiovascular Genetics) has led pilot studies demonstrating the feasibility of cascade testing. These studies have also shown that, although incurring costs during implementation, a testing programme would generate savings within three years because of the reduced numbers of heart attacks. The evidence was compelling enough for the National Institute for Health and Clinical Excellence to recommend cascade testing in 2008.

In 2009/2010, Professor Humphries carried out a series of audits for the Royal College of Physicians. These showed that DNA and cascade testing had been implemented well in Scotland, Northern Ireland and Wales but almost not at all in England, where just 5% of families were being tested. It is estimated that as a result one undiagnosed FH patient suffers a heart attack every day.

Since the report was published, Professor Humphries has continued to campaign on this issue, from policy to ground level. He has worked with the National Screening Committee to include FH criteria in the NHS Vascular Checks programme to help identify further FH patients as index cases for cascade testing. He has contributed to articles on cascade testing which have appeared across the major media in the UK, and to information on FH for GPs and patients, which has been disseminated widely through charities including the British Heart Foundation and HEARTUK.