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| © Andrew Johnson | istockphoto.com |
A landmark twin study performed in 1994 found that the relative risk of death from CHD (in males) when one's twin died of CHD before the age of 55, as compared with the risk when a twin did not die before 55, was 8.1 for monozygotic twins and 3.8 for dizygotics, suggesting that premature death from CHD is strongly associated with genetic factors.
Despite the discovery of numerous candidate genes, however, there has been no clear pattern in their consistency. Indeed, a 2007 “validation” study (in ACS) was unable to find statistical significance in 84 of 85 candidate gene variants studied, prompting the authors’ caveat that “these results emphasize the need for robust replication of putative genetic risk factors before their introduction into clinical care”.
Not until completion of the human genome project in 2003, when scientists finally had at their disposal a blueprint of the full human DNA, did huge gene scanning studies across full sets of DNA (genomes) in large populations become possible for the identification of gene variants associated with common diseases like CHD.
Several such genome-wide association studies have now been applied to CHD, and found numerous possible single letter differences in gene sequences (known as single nucleotide polymorphisms, SNPs) associated with CHD. For example, a report from Dr Nilesh Samani and colleagues from the Wellcome Trust Case Control Consortium identified several genetic loci that “individually and in aggregate, substantially affect the risk” of developing CHD. Dr Samani will speak on the “promises and problems” of genome-wide association studies at a Symposium tomorrow.
This year, five short reports published simultaneously by the journal Nature Genetics also identified clusters of genetic markers newly associated with AMI. In one of the reports, from the largest ever study of its kind, the Myocardial Infarction Genetics Consortium identified nine precise genes associated with an increased risk of MI, three of them newly discovered; the investigators said that these nine gene variants “identify 20% of the population at 2.25-fold increased risk for MI”.
With so much still at the level of basic science, what is the likelihood of genetic screening in everyday practice? For Professor Cornelia van Duijn from the Erasmus University Medical Center in Rotterdam, who will speak against routine genetic screening in a debate on population and high-risk prevention this afternoon, the complexity of such a disease as CHD may limit any opportunity for accurate prediction in asymptomatic individuals. “Unraveling the complete causal pathway may be impossible,” she says.
“There’s been rapid progress in identifying gene variants associated with type 2 diabetes, obesity and hypertension,” explains Van Duijn, “and these are helping to explain heart disease, but translating that explanation into prediction is very difficult.” It’s thus the multifactorial and subtle nature of CHD which underlines the difficulty. A disease like hormonedependent breast cancer, which is known to be directly associated with the BRCA1 and 2 genes, is much more amenable to prediction.
Nevertheless, the recent breakthroughs from genome-wide association studies in the discovery of gene variants linked to the many “causes” of CHD have been “relatively successful”, says Van Duijn, but these have been in clusters of risk factors which may explain the disease, not yet predict it.
(Genome-wide association studies in coronary artery disease: promises and problems, Monday 31 August 15:06, FPN 2714)
(Debate: Genetic screening of coronary predisposition is coming to clinical practice. Sunday 30 August 14:00-15:30, FPN 951-955)