Familial Hypercholesterolaemia patients often inherit small-effect changes in several genes rather than a large-effect mutation in a single gene

Published on February 22, 2013 at 7:12 AM · No Comments

Research published Online First in The Lancet provides new evidence that a substantial proportion of individuals with a clinical diagnosis of Familial Hypercholesterolaemia (FH) inherit a combination of small-effect changes in several genes (polygenic) rather than a large-effect mutation in a single gene (monogenic). These findings  have implications for the majority of national guidelines on family screening for FH, that advocate testing relatives of all individuals with a clinical diagnosis of FH, including those of the UK National Institute for Health and Clinical Excellence (NICE).

“Cascade [family] testing of the roughly 40% of patients with a clinical diagnosis of FH and an identifiable causative mutation would eliminate staff and screening costs associated with screening relatives of the remaining 60% of patients without an identifiable mutation. This is very likely to be more cost-effective, but proving this will require a more detailed analysis”, says British Heart Foundation Professor Steve Humphries from University College London, who led the research.

FH is one of the most common inherited disorders affecting over 12 million people worldwide (1 in 500 of the general population). It causes very high levels of low-density lipoprotein cholesterol (LDL-C) or “bad cholesterol” in the blood, and if untreated, results in a five to eight times greater risk of early coronary heart disease (CHD).  Identification of patients with FH needs to be improved because at least 75% of cases remain undetected, untreated, or improperly treated, despite good evidence that early detection and treatment with statins can significantly improve life expectancy

DNA-based cascade screening to identify other family members with FH, who would  benefit from treatment, has been recommended by NICE on the presumption of a monogenic inheritance of the disorder, where first-degree relatives would have a 50:50 chance of having the condition. However, 60% of people with clinically suspected FH have no identifiable mutation in any of the three genes (LDLR, APOB, or PCSK9) known to cause FH.

“The current study was designed to investigate whether individuals who inherit many, small-effect, LDL-cholesterol raising sequence differences in a wide range of genes might have received a clinical diagnosis of FH, which would influence the efficacy of any cascade screening programme since the odds of finding relatives with grossly elevated LDL-C in such cases would be less than the expected 50%”, explains Humphries.

Recent genetic studies have identified many common genetic variants associated with a small increment in LDL-C levels. Genotyping for 12 of these single nucleotide polymorphisms (SNPs) was done on blood samples from 321 mutation-negative UK patients with FH, as well as 319 UK patients with FH with a known mutation, and 3020 healthy individuals (controls) from the UK Whitehall II study.

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