The term cardiovascular disease (CVD) is frequently used interchangeably with 'heart disease', but for some medical professionals, the term CVD is used to describe only those medical conditions that lead to the narrowing or blocking of blood vessels (Mayo Clinic Staff, 2012). For others, the term CVD encompasses a number of medical conditions affecting the health of all aspects of the cardiovascular system, including blood vessels, the heart, and the autonomic circuits regulating heart rhythm (Kathiresan and Srivastava, 2012). Other terms used interchangeably with CVD include coronary artery disease (CAD) and coronary heart disease (Superko, Roberts, Garret, Pendyla, and King III, 2010; National Heart, Lung and Blood Institute, 2011). For the purposes of this review, CVD will be used in the same umbrella-like manner that Kathiresan and Srivastava (2010) have used the term, except when discussing a study that has used a different definition.
Close to 25% of all deaths in the United States are caused by CVD, which translated into 616,000 deaths in 2008 (Centers for Disease Control and Prevention [CDC], 2012). This makes CVD the number one killer of both men and women in the U.S. The resultant financial burden of this disease was estimated to be $109 billion in 2010. For these reasons, CVD prevention strategies have become a major healthcare policy issue for several U.S. agencies and organizations, including the CDC, National Institutes of Health, American Heart Association, American Stroke Association, and the Association of State and Territorial Health Officials (CDC, 2010).
Prevention strategies are at the forefront of CVD health policy, because medical interventions that treat CVD risk have cut the number of deaths due to this disease in half over the past 30 years (Viera and Sheridan, 2010). However, there is still plenty of room for improvement because two thirds of people currently at risk for developing CVD are not being treated to lower their risk. Treating risk is effective because the dominant risks are environmental and thus modifiable, such as obesity, high serum cholesterol, smoking, hypertension, sedentary lifestyle, and diabetes. The other major risk factors that are not modifiable are age and being male.
Environmental risk factors are believed to be sufficient for explaining close to 80% of CVD prevalence, which suggests heritable factors explain the remaining 20% (Thanassoulis and Vasan, 2010). This conclusion is an oversimplification of what is actually occurring, because many of associated risk factors also have a genetic component. For this reason, a family history of CVD is likely to be due to a number of environmental and genetic factors interacting in complex ways. This review will delve into what is currently understood regarding the risk that a family history confers to CVD prevalence.
The Epidemiology of Heritable CVD Risk Factors
When CVD is defined as including CAD, cardiac insufficiency, myocardial infarction, angina pectoris, and ischemic attacks, the overall prevalence of CVD events is 6.54 per 1000 person years for a Boston area community (Murabito et al., 2005). For siblings with a family history of CVD disease, the prevalence was found to be 15.27 per 1000 person years for the same community. If the analysis is adjusted for age and sex, then the odds that a sibling with a family history of CVD will develop this disease is 1.55 (95% CI, 1.19-2.03). If the analysis is further corrected for contributions from hypertension, high cholesterol, obesity, diabetes, and current smoker, the odds ratio is reduced insignificantly (OR = 1.45; 95% CI, 1.10-1.91). These results suggest that genetic factors, independent of other associated medical conditions, increase the risk of CVD by about 50%.
Early onset CVD disease was found to be a significant factor contributing to disease risk (Murabito et al., 2005). When siblings were grouped by age of onset, either before or after 48 years of age, risk was found to be significantly stratified after correcting for all confounding risk factors (OR = 2.22; 95% CI, 1.22-4.02 vs. 1.33; 95% CI, 0.98-1.08). If the analysis was limited to only those families for which parental CVD histories were known for both parents, the CVD risk for siblings increased to 1.99 (95% CI, 1.32-3.00). This suggests a family history of CVD doubles the risk for developing this disease.
One of the main unexpected results from this study was that sibling CVD represented a greater risk for disease than premature parental and sibling CVD combined (1.53; 95% CI, 0.93-2.51) (Murabito et al., 2005). The authors suggested that this difference can be explained by the higher prevalence of associated risk factors, such as hypertension (31.5%) and diabetes (12.2%), among the latter group, which would tend to suppress the odds ratio compared to that calculated for CVD siblings alone (22.3% and 5.8%, respectively).
The results of Murabito and colleagues (2005) have been confirmed by other studies and together they suggest that heritable factors distinct from those contributing to other major risk factors can increase the risk of CVD by up to 2.0-fold.
CVD Risk by Genotype
The most robust evidence for heritable CVD risk comes from genetic association studies examining Mendelian traits (reviewed by Kathiresan and Srivastava, 2012). The first to be discovered was a 5-kilobase deletion in the gene encoding low-density lipoprotein receptor (LDLR) that resulted in the loss of several exons and explained in part the prevalence of familial hypercholesterolemia. Since this discovery, mutations in five other loci, APOB, ABCG5, ABCG8, ARH, and PCSK9, have been shown to contribute to the prevalence of this disease as well. However, despite severe hypercholesterolemia being inherited in an autosomal-dominant manner the penetrance was found to be incomplete in some individuals. This suggests that expression of disease-linked loci variants can be modified by other genetic and/or environmental factors.
Marfan's syndrome is also a Mendelian disorder that affects multiple systems, including the cardiovascular system. Mutations in the fibrillin-1 gene (FBN1) causes defects in the extracellular matrix, which can lead to the development of an aortic aneurysm, dissected ascending aorta, and a prolapsed mitral valve, but the expressed phenotype is can vary considerably between individuals (reviewed by Kathiresan and Srivastava, 2012). The path towards defining the genetic contribution to a specific CVD phenotype is therefore fraught with multi-factorial contributions that interact in complex ways, leading to individual variations in the expressivity of CVD phenotypes.
In a recent genome-wide association study that examined the genetic contribution for high plasma triglycerides, seven common loci were identified (reviewed by Kathiresan and Srivastava, 2012). Resequencing of candidate loci revealed four with rare, nonsynonymous variants that segregated with individuals having high triglycerides. A statistical analysis of this data revealed that 21% of the clinical variation between individuals could be explained by the common variants and 1% by the rare variants. Together this suggests that individual variations in triglyceride levels are due to a combination of environmental factors, rare variants having a large effect, and common variants having a small effect. This implies that the overall variance in the expression of a CVD trait within a population, like plasma lipoprotein levels, cannot be fully accounted for by either Mendelian or common loci, or the combination, because Mendelian traits occur so rarely that they contribute very little to trait variance overall and common traits only cause small effects.
The degree of genetic complexity contributing to CVD risk was highlighted by a collection of studies that together conducted genome-wide association analyses on over 100,000 individuals for plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides (Kathiresan and Srivastava, 2012). Ninety-five distinct loci were found to segregate with one or more of these traits with a high degree of confidence (p < 5 x 10-8). This group of loci included several genes shown previously to contribute to variation in plasma lipoprotein levels, which are also current targets for pharmaceutical intervention (for example HMGCR and statins). A small number of the novel loci have been investigated in mice through genetic manipulation and the results are consistent with the human phenotype. However, the mechanisms by which the vast majority of novel loci affect lipoprotein metabolism have not been investigated, so there is still much to do.
Genetically-Determined Localized CVD Phenotypes
Other aspects of genetic contributions to CVD risk include the severity and extent of disease, and its morphological expression. Using myocardial infarction (MI) as the primary defining criteria for inclusion in a cohort study investigating the location of disease within the cardiovascular system, Fischer and colleagues (2005) examined the history of MI or severe CAD in 401 families. The other inclusion criteria were an MI event before the age of 60 for one sibling (index case) and at least one other sibling suffering an MI or severe CAD event before 70 years of age.
The primary differences between index cases and siblings uncovered by this study were index cases experienced their first event at a much younger age than their sibling(s) and were more often male (Fischer et al., 2005). Siblings also presented with slightly more severe disease in terms of angiogram severity scores, number of stenoses, and more…