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ABSTRACT

  • Blood pressure is a multifactorial quantitative trait showing a continuous distribution in the general population. The determinants of blood pressure variation include genetic and environmental factors, as well as demographic factors such as age, gender, and ethnicity. Multiple lines of evidence demonstrate the importance of heredity in blood pressure variation. Blood pressure aggregates within families, with greater concordance in biologic sibs than in adoptive sibs living in the same household. Monozygotic twins who share 100 percent of their genes show significantly greater concordance in blood pressure than do dizygotic twins who only share 50 percent of their genes. The impact of genetic factors on the development of hypertension is modified by environmental factors such as weight gain and sodium intake.

  • Blood pressure is regulated by the interplay between a large number of physiological variables. Physiological studies have not generally succeeded in identifying the initiating factors responsible for the development of high blood pressure. However, these studies indicate that the kidney plays an essential role in the long-term regulation of blood pressure. Maintenance of elevated blood pressure implicates a derangement in the renal pressure natriuresis mechanism, and disturbance in this system has been verified in humans with essential hypertension as well as in experimental models of the disease. At steady state, hypertension is characterized by a rightward resetting of the pressure natriuresis response, resulting in inappropriately elevated blood volume for the level of blood pressure. This signifies that derangements in salt handling are likely to participate in the development of hypertension. Genetic studies confirm these findings and demonstrate that mutations underlying all Mendelian forms of high and low blood pressure converge on a final common pathway: mutations that cause a net increase in salt reabsorption result in hypertension, whereas mutations that cause salt wasting produce hypotension.

  • Mendelian forms of hypertension: Glucocorticoid-remediable aldosteronism is caused by unequal crossing over, fusing regulatory sequences of the 11-beta hydroxylase onto coding sequences of the aldosterone synthase genes, resulting in ectopic production of aldosterone under the control of ACTH. Liddle syndrome is caused by activating mutations in genes encoding the beta and gamma subunits of the epithelial sodium channel in the distal nephron, leading to increased distal sodium reabsorption. Apparent mineralocorticoid excess is caused by 11-beta hydroxysteroid dehydrogenase deficiency that results in excessive stimulation of the mineralocorticoid receptor by cortisol. Activating mutations in the mineralocorticoid receptor cause hypertension with marked exacerbation during pregnancy. The hypertensive forms of congenital adrenal hyperplasia are caused by enzyme deficiencies in the steroid synthesis pathways that lead to accumulation of mineralocorticoid precursors. Finally, pseudohypoaldosteronism type II, characterized by hypertension and hyperkalemia, and the syndrome of hypertension with brachydactyly are two Mendelian disorders that have been mapped but whose molecular etiologies have not yet been defined.

  • Mendelian forms of hypotension: Pseudohypoaldosteronism type I features renal salt wasting with impaired secretion of potassium and hydrogen ions. Recessive and dominant PHA-I are caused by loss-of-function mutations in the genes encoding subunits of the epithelial sodium channel ...

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