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

BMC Genetics

Research Article

Jesper Eugen-Olsen¹  Jørgen Jeppesen²  Karen Søbye³  Mogens Fenger³  Sten Madsbad⁴  Torben, Jørgensen⁵  Allan Linneberg⁵ 

[1] Clinical Research Unit, Copenhagen University Hospital at Hvidovre, Kettegaard All 26, 2650, Hvidovre, Denmark;Deparement of Caridology Ndr, Copenhagen University Hospital at Glostrup, Ringvej 57, 2600, Glostrup, Denmark;Department of Clinical Biochemistry, Genetics, and Molecular Biology, Copenhagen University Hospital at Hvidovre, Kettegaard All 26, 2650, Hvidovre, Denmark;Department of Endocrinology, Copenhagen University Hospital at Hvidovre, Kettegaard All 26, 2650, Hvidovre, Denmark;Research Centre for Prevention and Health, Copenhagen University Hospital at Glostrup, Ndr. Ringvej 57, 2600, Glostrup, Denmark;

关键词: Systolic Blood Pressure;    Diastolic Blood Pressure;    Ceramides;    Essential Hypertension;    Brain Natriuretic Peptide;   

DOI  :  10.1186/1471-2156-12-44

 received in 2011-02-27, accepted in 2011-05-13,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Fenger et al; licensee BioMed Central Ltd. 2011