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• W1982064176 abstract "Cardiovascular disease and its acute sequelae such as stroke and myocardial infarction (MI) are extremely prevalent in the developed world. At the root of cardiovascular disease, there is not a single identifiable cause or even a limited set of causes. More likely, the onset of cardiovascular disease is governed by many varying combinations of acquired (environmental, life style) and genetic risk factors. It sometimes seems as if each patient has his/her own private combination of risk factors. Large-scale studies such as the Framingham Heart Study, the Northwick Park study, and the Physicians and Nurses’ Health studies, to name a few, have carried out much in the way of identifying non-genetic risk factors for cardiovascular disease like unfavorable blood lipid levels, high blood pressure, smoking, obesity, and diabetes. Most modern day prevention and treatment modalities of cardiovascular disease are based on the general acceptance of these risk factors as important non-genetic determinants of cardiovascular disease and there is abundant and consistent evidence in the scientific literature to support this practice. So, what doctors do for cardiovascular patients is to identify a modifiable risk factor and to treat it. Patients who smoke are encouraged to stop smoking, unfavorable lipid profiles are improved by statin treatment, obese patients are encouraged to lose weight, and hypertension is treated with drugs that lower blood pressure, etc. Follow-up studies have shown that genetics also play an important role in these modifiable risk factors. For example, true genetic abnormalities in proteins that govern lipid metabolism and trafficking (such as the LDL receptor [1], apolipoprotein B-100 [2], lipoprotein lipase [3], and apolipoprotein CII) [3] have been identified that increase cardiovascular risk substantially and may require more aggressive treatment. It should be noted, however, that these genetic defects that have major impact on cardiovascular disease risk are relatively rare. Nevertheless, I think it is fair to say that most agree that such genetic studies, in for instance familial hypercholesterolemia, are extremely useful, in particular in a tertiary referral center [4]. In the past decade, we have witnessed the completion of the full sequence of the human genome. Aficionados of the Human Genome Project – and who is not? – have predicted that the postgenomic area will provide us with the tools to discover, within the context of cardiovascular disease, relevant interactions between all genes in the genome, including their interaction with classical environmental factors. These new genetic insights were expected to yield improved risk profiling in individual patients and better-tailored treatment. At last, we would understand why in a group of individuals with cardiovascular disease who share the same ‘classical risk profile’ some progress toward MI or stroke while others do not. Several approaches were and still are taken in the quest for novel genetic risk profiles, including family studies, genetic association studies (also in relative genetic isolates like Iceland), and studies in mice. Guided by our increasingly detailed understanding of the processes underlying cardiovascular disease and its acute events, many candidate genes have been evaluated including those encoding coagulation factors, adhesion molecules, chemokines and cytokines, and matrix metalloproteinases. In addition, genome-wide approaches were taken in an attempt to find novel markers without being biased by biological insights. For reasons that are still not totally clear the results thus far have been sobering [5]. Many of the studies using polymorphisms in candidate genes have often been difficult to replicate in subsequent studies. The same holds true for polymorphisms in genes that turned up positive in genome-wide efforts. In fact, all these efforts have not yet yielded common gene variations or combinations of gene variations that are applicable in the management of patients with cardiovascular disease [6]. Does the paper by Zee et al. [7] in this issue of JTH add more salt to the wound? In this paper, the authors have continued on the candidate gene approach. They have evaluated the role of 92 common candidate polymorphisms in genes encoding coagulation factors, cellular and matrix adhesion molecules, and molecules involved in inflammation. Their conclusion is that, after correction for multiple comparisons, the addition of genetic information had little impact on the risk prediction models for myocardial infarction. Should we accept our failure after this essentially negative study by Zee et al. and conclude that genomic testing is not the Holy Grail for prediction of cardiovascular risk? I think that it is too early for that. Firstly, one should note that the study by Zee et al., although based on the very large Physicians Health Study, is not a very powerful one. The study includes data on about 500 cases and 2000 controls, which may well be too little to detect small but clinically relevant genetic risk factors or combinations of risk factors. Secondly, there are also some recent positive results in the literature. For example, a recent study in Nature Genetics highlights that a variant of the gene encoding leukotriene A4 hydrolase, a marker that was not included in the Zee et al. paper, confers risk of myocardial infarction, in particular in Africans and Americans [8]. A study reported in PLOS Medicine has found that future Type 2 diabetes, a major risk factor for cardiovascular disease, is predicted by a combination of PPARG and CAPN genotypes in susceptible individuals with high plasma glucose and body mass index [9]. Interestingly, the PPARG polymorphism also came up positive in the Zee et al. study, but the result was rejected after correction for multiple testing. This may further attest to the fact that one should be careful in discarding genetic risk factors too easily when studies are small. It also underlines that much remains to be performed in large carefully conducted studies before genomic testing for cardiovascular disease will have a real impact on public health. Therefore, it may take another decade before cardiovascular genomics will deliver on its promise." @default.
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• W1982064176 date "2006-02-01" @default.
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• W1982064176 title "When is cardiovascular genomics delivering on its promise?" @default.
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• W1982064176 doi "https://doi.org/10.1111/j.1538-7836.2006.01798.x" @default.
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