Evidence for Linkage Between Essential Hypertension and a Putative Locus on Human Chromosome 17

Abstract

Abstract-Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (Pϭ0.0005) and refines the location of the blood pressure QTL. (Hypertension. 1999;34:4-7.)Key Words: hypertension, essential Ⅲ linkage Ⅲ chromosome 17 Ⅲ blood pressure Ⅲ obesity E ssential hypertension is one of the most common cardiovascular diseases, affecting 15% to 20% of the population. It is an important risk factor for heart and kidney failure, myocardial ischemia, and stroke. 1 Essential hypertension is considered a complex disease with significant genetic and environmental components that interact to play a role in blood pressure variation. 2 Many candidate genes have been reported to contribute to the susceptibility to hypertension in clinical studies. [3][4][5] The stroke-prone spontaneously hypertensive rat and the Dahl salt-sensitive hypertensive rat have proved to be useful tools in identifying quantitative trait loci (QTL) that contribute to blood pressure variations. 6 -11 Evidence of a blood pressure QTL was found on rat chromosomes 2, 10 10, 6 -11 and X. 7 The rat chromosome 10 QTL is located near the angiotensin-converting enzyme (ACE) locus. The ACE locus is an attractive candidate gene because of its role in the renin-angiotensin system and the association between several polymorphisms in the ACE locus with blood pressure levels in some studies, 12-14 although other studies failed to confirm this finding. [15][16][17] Human chromosome 17 is syntenic with rat chromosome 10, and evidence for linkage between this blood pressure QTL has been reported in French/UK hypertensive sib pairs. 18 These markers are 18 cM proximal to the ACE locus. In addition, linkage of pseudohypoaldosteronism type IIB (hypertension, hyperkalemia, and normal renal glomerular filtration) to this region has been reported in several families. 19 In this study, we tested a series of microsatellite markers near this chromosome 17 blood pressure QTL in a collection of white and black sib pairs from the United States. Evidence of linkage was found in our collection of white sib pairs. MethodsProbands were identified from hypertension clinics in Massachusetts and Texas. Extensive family histories, including medical history, risk factor information, ethnic background, and demographics, were taken. Boston Medical Center Institutional Review Board for Human Subjects approved this study, and all subjects gave informed consent. Blood samples were collected from 74 white patients and 97 of their affected sibs (125 sib pairs) and from 45 black patients...

WNK4 Intron 10 Polymorphism Is Not Associated With Hypertension

“…A locus for essential hypertension has been reported on chromosome 17 in several chromosomal microsatellite scans, [1][2][3] as had been noted for the equivalent region in the genome of genetically hypertensive rats. 4,5 Recently, interest has focused on WNK4 (chromosome 17q21.2), which encodes a serine-threonine kinase with no lysine (K), but instead has a cysteine at a key position in the active site.…”

Microarray Analysis of Rat Chromosome 2 Congenic Strains

“…15 Comparative genome analysis of rat, mouse, and human can be used to identify regions of the human genome likely to harbor genes involved in blood pressure regulation. 7,16 Julier et al 17 and Baima et al 18 provided first successful examples of comparative mapping in which a region involved in blood pressure regulation on rat chromosome 10 indicated a susceptibility locus for human hypertension on human chromosome 17q.…”

Implication of Chromosome 18 in Hypertension by Sibling Pair and Association Analyses

“…Since the identification of QTLs contributing to blood pressure variation in rat chromosome 10 in several experimental models of hypertension, 14,15 several studies have reported evidence of linkage of hypertension to the 17q syntenic region in humans. 6,10,16 Although the ACE gene, encoding the angiotensin I-converting enzyme, is located within the linked chromosomal region in rats, the human homologue is situated 18 cM proximal to the blood pressure QTL and, therefore, does not seem to overlap with the candidate region. 16 Close examination of the QTL interval at 17q12-21 discloses no obvious functional candidate genes for blood pressure variation.…”