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The genetics of blood pressure and hypertension: the role of rare variation.

ABSTRACT: The role of heredity in influencing blood pressure and risk of hypertension is well recognized. However, progress in identifying specific genetic variation that contributes to heritability is very limited. This is in spite of completion of the human genome sequence, the development of extraordinary amounts of information about genome sequence variation and the investigation of blood pressure inheritance in linkage analysis, candidate gene studies and, most recently genome-wide association studies. This paper considers the progress of this research and the obstacles that have been encountered. This work has made clear that the genetic architecture of blood pressure regulation in the population is not likely to be shaped by commonly occurring genetic variation in a discrete set of blood pressure-influencing genes. Rather heritability may be accounted for by rare variation that has its biggest impact within pedigrees rather than on the population at large. Rare variants in a wide range of genes are likely to be the focus of high blood pressure genetics for the next several years and the emerging strategies that can be applied to uncover this genetic variation and the problems that must confronted are considered.

SUBMITTER: Doris PA

PROVIDER: S-EPMC3562708 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The genetics of blood pressure and hypertension: the role of rare variation.

Doris Peter A PA

Cardiovascular therapeutics 20101206 1

The role of heredity in influencing blood pressure and risk of hypertension is well recognized. However, progress in identifying specific genetic variation that contributes to heritability is very limited. This is in spite of completion of the human genome sequence, the development of extraordinary amounts of information about genome sequence variation and the investigation of blood pressure inheritance in linkage analysis, candidate gene studies and, most recently genome-wide association studie ...[more]

PMID: 21129164

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Project description:BackgroundSeveral attempts to decipher the genetics of hypertension of unknown causes have been made including large-scale genome-wide association analysis (GWA), but only a few genes have been identified. Unsolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition are the main reasons for the modest results. The level of the blood pressure is the consequence of the genotypic state of the presumably vast network of genes involved in regulating the vascular tonus and hence the blood pressure. Recently it has been suggested that components of the sphingolipid metabolism pathways may be of importance in vascular physiology. The basic metabolic network of sphingolipids has been established, but the influence of genetic variations on the blood pressure is not known. In the approach presented here the impact of genetic variations in the sphingolipid metabolism is elucidated by a two-step procedure. First, the physiological heterogeneity of the blood pressure is resolved by a latent class/structural equation modelling to obtain homogenous subpopulations. Second, the genetic effects of the sphingolipid metabolism with focus on de novo synthesis of ceramide are analysed. The model does not assume a particular genetic model, but assumes that genes operate in networks.ResultsThe stratification of the study population revealed that (at least) 14 distinct subpopulations are present with different propensity to develop hypertension. Main effects of genes in the de novo synthesis of ceramides were rare (0.14% of all possible). However, epistasis was highly significant and prevalent amounting to approximately 70% of all possible two-gene interactions. The phenotypic variance explained by the ceramide synthesis network were substantial in 4 of the subpopulations amounting to more than 50% in the subpopulation in which all subjects were hypertensive. Construction of the network using the epistatic values revealed that only 17% of the interactions detected were in the direct metabolic pathway, the remaining jumping one or more intermediates.ConclusionsThis study established the components of the ceramide/sphingosine-1-phosphate rheostat as central to blood pressure regulation. The results in addition confirm that epistasis is of paramount importance and is most conspicuous in the regulation of the rheostat network. Finally, it is shown that applying a simple case-control approach with single gene association analysis is bound to fail, short of identifying a few potential genes with small effects.

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The genetics of blood pressure and hypertension: the role of rare variation.

Publications

The genetics of blood pressure and hypertension: the role of rare variation.

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