Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension.
Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension.
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DOI：
10.1186/1471-2156-12-44
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发表时间：
2011-05-13
期刊：
影响因子：
2.9
通讯作者：
Jeppesen J
中科院分区：
文献类型：
--
作者：
Fenger M;Linneberg A;Jørgensen T;Madsbad S;Søbye K;Eugen-Olsen J;Jeppesen J
已经进行了几次尝试来破译未知原因的高血压的遗传学，包括大规模的全基因组关联分析（GWA），但只有少数基因被鉴定。血压调节的未解决的异质性和流行的单基因方法在多基因条件下捕获遗传效应的缺点是结果不高的主要原因。血压的水平是参与调节血管紧张性从而调节血压的可能的巨大基因网络的基因型状态的结果。最近有人提出，鞘脂代谢途径的组成部分可能在血管生理学中具有重要意义。鞘脂的基本代谢网络已经建立，但遗传变异对血压的影响尚不清楚。在这里介绍的方法中，通过两步程序阐明了鞘脂代谢中遗传变异的影响。首先，通过潜在类/结构方程建模来解决血压的生理异质性，以获得同质亚群。其次，神经酰胺从头合成的神经鞘脂代谢的遗传效应进行了分析。该模型并不假设特定的遗传模型，而是假设基因在网络中运作。研究人群的分层显示，（至少）14个不同的亚群存在不同的高血压倾向。基因在神经酰胺从头合成中的主要影响是罕见的（所有可能的0.14%）。然而，上位性是非常显着的和普遍的约70%的所有可能的两个基因的相互作用。由神经酰胺合成网络解释的表型变异在4个亚群中是实质性的，在所有受试者均为高血压的亚群中占50%以上。使用上位值构建网络显示，检测到的相互作用中只有17%是在直接代谢途径中，其余的是跳跃一个或多个中间体。本研究确定了神经酰胺/鞘氨醇-1-磷酸变阻器的组分是血压调节的核心。结果还证实，上位性是至关重要的，是最明显的变阻器网络的调节。最后，它表明，应用一个简单的病例对照方法与单基因关联分析是注定要失败的，确定一些潜在的基因与小的影响。
Several 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. 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.
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影响因子：
30.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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10.6
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