Population Genetics of Cardiovascular Risk

In the medical world, the focus of preventing death and disability is on the doctor and the patient. In the case of cardiovascular disease, which is the most common cause of death worldwide [1], this involves identifying, labelling and treating patients with high levels of risk factors such as blood pressure (hypertension), blood lipids (hypercholesterolemia), weight (obesity) and insulin resistance (type 2 diabetes).

In the world of public health, the approach is different. Instead of patients, there are populations and instead of treatment, there is health promotion. We are all at risk of cardiovascular disease and, therefore, we all stand to benefit if risk factor levels are reduced across the population by safe and cost-effective measures that often involve diet and lifestyle.

In pursuit of the genetic explanations for cardiovascular disease, much research has been based on the medical model, searching for genes that are associated with hypertension, obesity and so on. Yet those with such treatable high levels of risk factors account for only a portion of the cardiovascular deaths due to risk factors in a population [2]. Modest (i.e. average) levels of risk occur in many more people and although the personal risk is not great, the impact of average risk across a population is high.

Therefore, the preoccupation of genetic discovery on clinical conditions such as hypertension, obesity and hypercholesterolemia might have missed the point. It is just as important to understand why someone has average rather than low blood pressure, as it is to understand why some have high rather than normal blood pressure [3].

The Victorian Family Heart Study was established in 1990 with the aim of discovering the familial and genetic basis of cardiovascular risk in the general population [4]. The study comprises approximately 800 volunteer adult families with at minimum mother, father and one natural offspring. To increase the ability to determine genetic and environmental influences, the families were enriched with those containing monozygotic and dizygotic twins.

Simple cardiovascular risk phenotypes such as blood pressure, weight and cholesterol were measured carefully using quality controlled standardised methods. These values were the substrate of all analyses and needed to be as precise as possible.

The first phase of analyses was to define the familial patterns of risk factors and use statistical modelling to partition the components of their variation into genetic, shared environment and individual factors. Typically, genetic factors accounted for 40% to 50% of the total variation for a risk factor, while shared familial environment accounted for about 20% to 30%.

This evidence for significant genetic influence formed the basis of molecular investigation. These included studies of candidate genes such as the delineation of the involvement of the Y chromosome in blood pressure [5]. An early genome-wide linkage analysis also led to the identification of chromosomal regions influencing blood pressure [6]. One of these on chromosome 16 [7] has subsequently been identified in several other independent studies.

We have recently used high-resolution association mapping and sequencing to investigate 2 genes in this region that are known to be involved in Mendelian genetic diseases of blood pressure. One of these, the gene encoding the g-subunit of the epithelial sodium channel, is associated with blood pressure in the Victorian Family Heart Study [8]. There are 3 separate DNA variants in the non-coding DNA, each of which appears to contribute independently to blood pressure. We have replicated association of one of these variants with blood pressure in two independent populations and determined the overall magnitude of the variant on blood pressure across the population-wide distribution of the entire Victorian Family Heart Study (Büsst, unpublished observations). The variant is relatively common with a population frequency of about 25% and the magnitude of the blood pressure effect is estimated to be about 0.8 mmHg per copy of the variant.

These results reflect a pattern that is emerging in relation to the genetics of quantitative risk factors. Implicated DNA variants tend to have the following characteristics: they are found in non-coding DNA, they are relatively common and they account for about 1% or less of the variance in the risk factor. This contemporary evidence supports view that cardiovascular risk factors are determined by the combination of many polygenes, each of which has only a small contribution to the level of the risk factor. It is also likely that the mechanisms by which these variants in non-coding DNA operate is via changes in gene expression rather than major distortions of protein sequence.

The effect of individual genetic variants might be small, but there is reason to expect that their pathophysiological actions might be common. If such mechanisms can be understood, it might be possible to apply novel population-wide health promotion initiatives based on genetic causes that are widely distributed in the general community. Even small reductions in the population mean blood pressure could have a benefit equivalent to identifying and effectively treating a large proportion of hypertensive patients.As unexpected as it might be, molecular genetic research might repay its dividends in the form of simple, safe and effective public health measures for the benefit of us all.

Références

[1] Lawes C.M.M., “Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001”, Lancet, 371, 2008, 1513-18.

[2] Rose G., “Strategy of prevention: lessons from cardiovascular disease”, Br. Med. J., 282, 1981,1847-51.

[3] Harrap S.B, “Private genes, public health?”, Lancet, 349, 1997, 1338-1339.

[4] Harrap S.B., Stebbing M., Hopper J.L., Hoang H.N., Giles G.G., “Familial patterns of covariation for cardiovascular risk factors in adults – The Victorian Family Heart Study”, Am. J. Epidemiol., 152, 2000, 704-715.

[5] Ellis J.A., Stebbing M., Harrap S.B., “Association of the human Y chromosome with high blood pressure in the general population”, Hypertension, 36, 2000, 731-733.

[6] Harrap S.B., Wong Z.Y.H., Stebbing M., Lamantia A., Bahlo M., “Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes”, Physiol. Genomics, 8, 2002, 99-105.z

[7] Wong Z.Y.H., Stebbing M., Ellis J.A., Lamantia A., Harrap S.B., “Genetic linkage of the b- and g-subunits of the epithelial sodium channel with systolic blood pressure in the general population”, Lancet, 353,1999, 1222-1225.

[8] Büsst C.J., Scurrah K.J., Ellis J.A., Harrap S.B., “Selective genotyping reveals association between the epithelial sodium channel g-subunit and systolic blood pressure”, Hypertension, 50, 2007, 672-678.