Evidence for a genetic mechanism of the chromogranin A and phenylethanolamine-N-methyltransferase genes in the pathogenesis of hypertension in the spontaneously hypertensive rat.

摘要

Dissection of the genetic basis of human essential hypertension is greatly hindered by the inherent complexity of the disorder. Indeed, susceptibility genes are estimated to contribute ∼20-30% to development of essential hypertension, and gene actions are confounded by environmental variables, such as diet and exercise, and the diverse heterozygosity of the human population. In contrast, identification of susceptibility genes in the Spontaneously Hypertensive Rat (SHR) model of human essential hypertension is greatly enhanced by the purely genetic basis of hypertension in the SHR and the ability to strictly control the environment. The large gap in physiology between the immediate action of susceptibility genes and the ultimate development of hypertension, however, looms large, even in the SHR. The objective of the dissertation, therefore, is to identify polymorphisms within candidate genes for hypertension in the SHR that manifest as intermediate phenotypes for the ultimate hypertensive disease state. Differential expression of adrenal mRNA is proposed as a novel intermediate phenotype for hypertension in the SHR. Initially, a comparison of adrenal gene expression between the SHR rat and BPH mouse, two independent models of human essential hypertension, was performed to uncover common genetic mechanisms of hypertension across mammalian species. A diverse set of differentially expressed genes and biochemical systems within and between the SHR and BPH strains was identified, reinforcing the complexity of the disease. Next, candidate genes for hypertension in the SHR were identified using a method to integrate adrenal gene expression data with blood pressure QTL data. Seven candidate genes were identified and resequenced. Polymorphisms discovered in the promoter and/or 3'-untranslated region of the chromogranin A (Chga) and phenylethanolamine-N-methyltransferase (Pnmt ) genes were hypothesized to contribute to differential expression of Chga (1.73-fold overexpressed) and Pnmt (0.67-fold underexpressed) adrenal mRNA in the SHR. Finally, luciferase assays were used to demonstrate that promoter polymorphisms are likely to contribute to the adrenal differential mRNA expression of Chga and Pnmt in vivo. The crucial role of Chga and Pnmt in the biosynthesis and exocytosis of catecholamines makes them strong candidate genes for hypertension in the SHR. More importantly, the association of Chga and Pnmt with human essential hypertension makes them potential therapeutic targets as well.