Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension

The 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.This 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.Hypertension, defined as office blood pressure (BP) measurements of 140/90 mm Hg or greater, affects 30% of the adult population, and is a major risk factor for stroke, heart disease, and end-stage renal disease [1]. Hypertension arises as a consequence of altered activity in signal transduction pathways and interactions of complex intra- and intercellular processes [2,3]. However, the exact mechanism and causes of hypertension are unknown in 95% of the cases (essential hypertension). In the remaining 5% of cases, the cause of hypertension is secondary to various conditions including endocrine disorders as well as drug-induced hypertension [4]. Although several clinical and biochemical variables are correlated to hypertension [5-7] the causes of essential hyperten