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Cardiovascular genetics: are we there yet?
  1. A C Sturm
  1. Correspondence to:
 Mrs A C Sturm
 Division of Human Genetics, Department of Internal Medicine, The Ohio State University, 2050 Kenny Road, 8th Floor Tower, Columbus, OH 43210;

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Cardiovascular genetics

Since 1900, cardiovascular disease has been the number one killer in the United States every year except 1918, the year of the great influenza pandemic. Cardiovascular disease claims more lives each year than the next five leading causes of death combined, which are cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza and pneumonia.1 Cardiovascular disease is also the leading cause of death in Europe, accounting for over 4 million deaths each year and, according to World Health Organization estimates, 16.6 million people around the globe die of cardiovascular disease each year.2 Based on the United States National Heart, Lung, and Blood Institute Family Heart Study, in its 44 year follow up of participants and a 20 year follow up of their offspring, coronary artery disease accounts for more than half of all cardiovascular events in men and women under the age of 75. Further, coronary artery disease is the single largest killer of men and women in America.1


Coronary artery disease has a complex aetiology, involving multiple genetic and environmental influences and interactions. In a recent review, Lusis estimates the total number of genes involved in cardiovascular disease by considering the risk factors for cardiovascular disease that are under genetic control.3 Some of these risk factors with a significant heritability include cholesterol levels, triglyceride levels, hypertension, obesity, diabetes, and the metabolic syndrome, all of which themselves have many genes involved in their susceptibility.3,4 Therefore, at least hundreds of genes are involved in the susceptibility to cardiovascular disease.3 The identification and characterisation of these genes has been a major undertaking and challenge for researchers. A recent call to arms from Sing et al5 makes recommendations for what needs to be done to cope with these complexities, including developing new statistical methods to analyse the exponentially increasing amount of data generated by contemporary technology as well as training scientists for a “biocomplex future” and encouraging collaborations between researchers that help to study “how the parts are put together” in complex traits.


Much about the genetic basis of coronary artery disease remains unknown and the search for genes that cause major susceptibility in the development of coronary artery disease has been frustrating. In a recent Science report, Wang et al6 described a large family segregating an autosomal dominant form of coronary artery disease. Thirteen individuals in this family displayed coronary artery disease and nine of these thirteen patients developed acute myocardial infarction. A genome wide linkage scan identified a significant linkage to chromosome 15q26, a region containing approximately 93 genes, 43 of which were known genes.

A member of the myocyte enhancer factor 2 transcription factors, MEF2A, became a strong candidate, since its mRNA has been detected in blood vessels during early mouse development.7 In all 10 living affected family members, a 21 base pair deletion in exon 11 of MEF2A was identified. Further, this deletion was not present in family members with normal phenotypes nor was it present in 119 individuals with normal angiograms. Wang et al6 also showed evidence that the deletion is a functional mutation that probably acts by a dominant negative mechanism, and immunostaining revealed a strong MEF2A protein signal within the endothelial cell layer of coronary arteries. However, Wang and his colleagues also reported that three other large families with coronary artery disease or myocardial infarction are not linked to this locus, and 50 patients, of unknown ages, with sporadic coronary artery disease or myocardial infarction did not have an MEF2A mutation. Therefore, MEF2A may only be a rare cause of coronary artery disease and myocardial infarction, accounting for only a small percentage of incidences of the disease overall.

Optimists would like to think that MEF2A may be as important as the BRCA1 and BRCA2 genes in the development of the hereditary breast and ovarian cancer syndromes. Pessimists, on the other hand, will counter that this may only be a private mutation found in just one single family. Possibly, MEF2A will fall somewhere in between these two extremes. Future studies will be necessary to determine the prevalence of patients having coronary artery disease or myocardial infarction with MEF2A mutations as well as whether single nucleotide polymorphisms within this gene with smaller effects may be associated with common coronary artery disease and myocardial infarction.


Whether you are an optimist or a pessimist, the discovery of the first autosomal dominant gene for coronary artery disease and myocardial infarction is truly exciting. To date, there have been just four other published studies that have identified loci linked to cardiovascular disease. Linkage to two loci likely to contribute to premature coronary artery disease, one on chromosome 2q21.1–22 and another on Xq23–26, were found using a Finnish population.8 A susceptibility locus for coronary artery disease on chromosome 16p13.3 was identified in Indo-Mauritians.9 A whole genome scan in 513 western European families found evidence for linkage to myocardial infarction in a region on chromosome 14q11.2–12.10 And the acute coronary syndrome, consisting of myocardial infarction and unstable angina, has been linked to 2q36–q37.3.11


Although the above linkage reports provide a definitive starting place for the identification of potential candidate genes, and the availability of the genomic sequence for these starting places should facilitate gene identification, the specific genes have yet to be found. In fact, up until the Wang et al6 report, the majority of genes known to be involved in coronary artery disease have been identified using association studies, either using a candidate gene approach or by conducting whole genome association studies that take advantage of the hundreds of thousands of single nucleotide polymorphisms that span our genome.

Critics have conceded that findings from many genetic association studies are inconsistent and cannot be replicated, and that these studies should be restricted to the study of polymorphisms that have been shown to have a direct effect on gene function.12 In fact, in a recent review of genetic association studies, Hirschhorn et al13 found that over 600 positive associations between common gene variants and disease have been reported. Of the putative associations which have been studied three or more times, only 3.6% have been consistently replicated.

Many have offered their assessment of association studies, and of why type 1 errors (false positives) seem to abound.13–15 There are several reasons for the inability to replicate genetic associations. These include population stratification, modification of the association by other genetic or environmental factors that vary between groups studied, genotyping error rates that differ between cases and controls, absence of power leading to false negative results, failure to exclude chance as an explanation for association in some studies, and publication bias, where several studies are undertaken but only positive results are reported, which some claim is the most likely reason for failure to replicate.14


While there are definite reasons to be pessimistic about association studies, a number of them have provided strong evidence that genome wide case control studies are powerful tools in the identification of genes related to common diseases such as coronary artery disease.

One recent large scale case control study identified a candidate gene, lymphotoxin-α, associated with susceptibility to myocardial infarction and two genetic variants within this gene were proven to affect its expression level and biological function.16 Further, a number of other genes have exhibited consistent evidence of association with coronary artery disease or its known risk factors. Now, in this issue of Journal of Medical Genetics, McCarthy et al17 extend these findings with an analysis of 111 candidate genes underlying premature coronary artery disease, currently the only large scale association study using a case control design for coronary artery disease in white Americans. Before now, there have been three other similar studies, one an interim report on 62 candidate genes by this group18 and two others, which assessed Japanese individuals with myocardial infarction.16,19 To improve the power of their study, McCarthy et al17 selected cases that were genetically loaded, having early onset coronary artery disease (onset<45 in men and <50 in women) and coming from high risk families with hypertension, high body mass index, and diabetes.

The strongest association found was with the A387P variant in thrombospondin-4, conferring a greater than twofold increase in the odds of myocardial infarction. This association was also reported in this group’s previous report18 and has since been replicated in a number of studies.19–22 Further, functional genomic studies performed by this group (currently in press) have shown that this variant is a gain of function mutation that interferes with endothelial cell adhesion and proliferation, and is therefore biologically relevant.23

While McCarthy et al17 also report on novel genetic associations with coronary artery disease in this manuscript, the validity of these associations remains to be seen and will require future replicative studies. So, while criticisms of association studies are ever present, the authors’ conclusion that case control association studies are effective in generating hypotheses for candidate genes in coronary artery disease rings true.


Finally, then, the question remains: are we there yet? The answer to this question depends on what your own definition of “there” is. No, not every susceptibility gene or single nucleotide polymorphism within these susceptibility genes associated with coronary artery disease is known. However, we must ask ourselves, what is the primary goal of all this genomic research? And we must answer this question by stating that the reason for this research is to reduce the morbidity and mortality caused by the disease in question. Importantly, 50% of men and 63% of women who died suddenly from coronary artery disease had no previous symptoms of this disease.1 For this reason alone, the utility of cardiovascular genetics clinics whose main goals are identification of those at increased risk, subsequent modification of this risk, and therefore prevention of coronary artery disease, must be recognised. Obtaining a comprehensive family history should be an integral component of any disease prevention programme.24 The significance of the familial occurrence of coronary artery disease has been a focus of research for at least 50 years,26 with a positive family history of coronary artery disease emerging as an independent predictor of risk in the development of coronary artery disease even when other risk factors are considered.27–30

Applying what we know now about cardiovascular genetics in a clinical setting to prevent this leading cause of death is a reality. In a recent review from Scheuner,31 the components that should be included in a genetic evaluation for coronary artery disease are recommended, including genetic risk assessment, risk factor modification, early detection strategies, and genetic counselling and education. Risk assessment includes pedigree analysis, personal medical history, physical examination, laboratory testing, and early detection techniques, which not only serve to help in risk stratification, but also serve to screen those individuals already in greater than average risk categories based on family history.

These techniques will allow aggressive risk factor modification when necessary or, when unnecessary, may lead to patient reassurance, comparative to colonoscopy in screening for colon cancer.31 The goal of the genetic evaluation for coronary artery disease then is to provide the patient, through genetic counselling and education, with an individualised strategy for early detection and prevention that fits with their preferences, and potentially includes both lifestyle changes involving diet, weight control, exercise, and smoking cessation, as well as targeted drug therapy in appropriate cases.


So, while we may not be completely “there” yet in terms of understanding the complex genetics of cardiovascular disease, there are definite ways in which morbidity and mortality due to cardiovascular disease can be reduced by genetic counselling of at risk individuals in cardiovascular genetics clinics. Because of the high prevalence of cardiovascular disease, the moment we are “there”, genetic counsellors, cardiovascular geneticists, and cardiologists should expect a tidal wave of demand, one that would dwarf that for even clinical cancer genetics. Now would therefore be the time to think of viable strategies to involve primary caregivers in helping with the 21st century practice of molecular based cardiovascular risk assessment and management.

Cardiovascular genetics


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  • Conflicts of interest: none declared.

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