- Article: Four Genetic Loci Influencing Electrocardiographic Indices of Left Ventricular Hypertrophy
- UCL student Anna Rose has been awarded the Tony Jackson Memorial Prize for 2011
- A matter of priorities: Bacteria evolved way to safeguard crucial genetic material, Prof Nick Luscombe publishes in Nature
- Article: How a mother's genes can increase birth weight
- Research paper: X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development
- Direct observation of the interconversion of normal and pathogenic forms of α-synuclein, Prof Nick Wood publishes in Cell
- 4 Scholarships available for MSc in Genetics of Human Disease
- UGI's Prof Andres Ruiz-Linares reports in Nature Native Americans descend from three key migrations
- UGI's Prof Francois Balloux co-authors paper on genetics and climate reconstructions to track the global spread of modern humans out of Africa
- Vacancy: Research Associate in Statistical Genetics
- Nick Luscombe publishes in Cell
- Blood screening that is preventing heart attacks–but not in England, Prof Humphries is mentioned in a Guardian article
- Study questions effectiveness of genetic testing strategy for inherited high cholesterol, Steve Humphries publishes in The Lancet
- Nick Luscombe elected to EMBO
- BHF Grant awarded to Dr Ruth Lovering
- Mapping the effects of nature and nurture, Oliver Davis features in Wellcome Trust blog
- Congratulations to Doug Speed for being named the best FMT-BIR Young Biometrician of the year!
- Cellular resolution models for even skipped regulation in the entire Drosophila embryo - Nick Luscombe publishes in eLIFE
- UCL's Prof Hugh Gurling dies aged 63
- Research Associate - Parkinson's Biocurator position available
- Genomics—from the lab to clinical practice - BMJ Editor's Choice 30 Nov 2013
- NEW MSc Computational and Genomic Medicine 2014-15
- UGI's Oliver Davis featured in current edition of the MRC Network magazine
- UCL Genetics Institute outreach activities
- Nick Luscombe receives MRC Grant as part of the Medical Bioinformatics Initiative
- Same genes drive maths and reading ability - Oliver Davies publishes in Nature Communications
Study questions effectiveness of genetic testing strategy for inherited high cholesterol, Steve Humphries publishes in The Lancet
25 February 2013
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), according to a new paper in The Lancet.
The 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).
We propose that the clinical diagnosis of FH should be restricted to those in whom a mutation can be identified, whereas those with no detected mutation should be given the clinical diagnosis of polygenic hypercholesterolaemia.
Professor Steve Humphries, UCL Centre for Cardiovascular Genetics
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 per cent 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 per cent 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 per cent," explains Professor 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 3,020 healthy individuals (controls) from the UK Whitehall II study.
Each participant was assigned a weighted LDL-C-raising gene score based on the number of risk-associated gene copies inherited. The results were validated by repeating the analysis in a sample of over 700 patients with FH from Belgium.
The findings showed that clinically suspected, but mutation negative FH, was associated with inheritance of a greater than average number of small-effect LDL-C-raising sequence differences.
Professor Humphries says: “We propose that the clinical diagnosis of FH should be restricted to those in whom a mutation can be identified, whereas those with no detected mutation should be given the clinical diagnosis of polygenic hypercholesterolaemia. Both groups of patients will need statin therapy, but the cost effectiveness of FH cascade testing will differ depending on whether or not there is a polygenic or a single mutation cause.”
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