Genomewide Analysis To Identify Hypertensionrelated Genes

Krushkal et al. (3) performed a genome-wide linkage analysis of systolic BP on 427 sibling pairs and identified four regions of the human genome that show statistical significant linkage. These regions are on chromosomes 2, 5, 6, and 15. These chromosomal regions include numerous potential candidates, such as phospholamban, estrogen receptor (ER), aminopeptidase N, a lB-adrenergic receptor, dopamine receptor type 1A (DR-1A), calmodulin, and sodium-calcium exchanger. However, none of these genes has been confirmed to be associated with human hypertension.

Hunt et al. (4) performed a genome-wide analysis using 2959 individuals in 500 white families from the National Heart, Lung and Blood Institute (NHLBI) family heart study and identified five regions of the genome with logarithm of odds (LOD) scores higher than 2.0 for hypertension. These included chromosomes 1, 7, 12, and 15. On the other hand, chromosome 6 showed the best evidence for linkage with systolic BP (SBP). It is important to note that angiotensinogen and renin genes are located on chromosome 1.

Kristjansson et al. (5) performed a genome-wide scan with 904 microsatellite markers using 120 extended Icelandic families with 490 hypertensive patients. After adding 5 markers, they found linkage to chromosome 18q with an allele-sharing LOD score of 4.60. These results provide evidence for a novel susceptibility gene for essential hypertension on chromosome 18q, and show that it is possible to study the genetics of essential hypertension without stratifying by subphenotypes. Although melanocortin receptor 4 is located in this region of the chromosome, it is not known whether this gene is involved in hypertension.

Rice et al. (6) performed a genome-wide scan on 317 black individuals from 114 families and 519 white individuals from 99 families using a multipoint variance-components linkage model and a panel of 509 markers. Promising results were primarily, but not exclusively, found in the black families. Linkage evidence (p < 0.0023) with baseline BP replicated other studies within a 1-LOD interval on 2p, 3p.3 and 12q.33.

Levy et al. (7) performed a genome-wide scan in the largest families from two generations of Framingham Heart study participants. Genotyping was performed on 1702 subjects from 332 large families, and BP data were available for 1585 (93%) genotyped subjects who contributed 12,588 longitudinal BP observations. For diastolic BP, LOD scores greater than 2.0 were identified on chromosome 17 (74cM, LOD 2.1) and chromosome 18 (7cM, LOD 2.1). Using a genome-wide scan, they found strong evidence for a BP quantitative trait locus on chromosome 17. The stroke-prone, spontaneously hypertensive rat and the Dahl salt-sensitive, hypertensive rat proved to be useful tools in identifying quantitative trait loci (QTL) that contribute to BP variations. Evidence of BP QTL was found on rat chromosomes 2, 10, and X. Human chromosome 17 is syntenic with rat chromosome 10, and the rat chromosome 10QTL is located near the angiotensin-converting enzyme (ACE) locus. The ACE locus is an attractive candidate gene because of its role in the renin-angtiotensin system (RAS) and the association between several polymorphisms in the ACE locus with BP levels in some studies, although other studies failed to confirm this finding. Other potential candidate genes on this segment of chromosome 17 include the Cl-HCO exchanger, phenylethanolamine N-methyltransferase, nerve growth factor receptor, and pseudohypoaldosteronism type IIB genes.

Caulfield et al. (8) recently phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families in a large white European population (BRIGHT study). Linkage analysis identified a principle locus on chromosome 6q with an LOD score of 3.21, which attained genome-wide significance (p = 0.042). The inclusion of three further loci with LOD scores higher than 1.57 (2q, 5q, and 9q) also show genome-wide significance (p = 0.017) when assessed under a locus-counting analysis. There is a region of overlap with other studies on chromosome 2 (140-170 cM). This region was linked to hypertension in Chinese sibling pairs and Finnish twins, and linkage is suggested in a discordant sibling-pair screen. In addition, linkage signals are located proximally to the BRIGHT locus on chromosome 2p, documented by two genome scans in a genome scan of families of African ancestry. Furthermore, this region has also been linked to the hypertension-associated phenotype preeclampsia in some genome-wide screens. Preliminary analysis of each region with an LOD score higher than 1.57 has identified a small number of good candidates that map to the chromosome 2 and 9 regions of interest. These candidates include the genes encoding serine-threonine kinases (STK39, STK17B, chromosome 2q), a protein kinase (PKNBETA on 9q), G protein-coupled receptors (GPR21 on 9q33, GPR107 9q, and GPR1 on 2q33) and a potassium channel (KCNJ3 on 2q24.1). Several BP QTL from hypertensive rat models exhibit homology with the BRIGHT regions of interest. For instance, rat 3q11-q23 is homologous to the human 9q region, rat 2q14-q16 with the human chromosome 5p region, and rat chromosome 9q22-q34 is homologous to the human 2q locus. Examination of databases reveals many known genes and expressed sequence tags in or near the 16cM QTL interval at 17q12-21. Although no genes that have been strongly implicated in BP variation lie in this interval, potential candidate genes in the interval include the a-1 thyroid receptors, the neuronal homolog of the amiloride sensitive epithelial sodium channel, the corticotropin-releasing hormone receptor 1, insulin-like growth factor-binding protein-4, hepatocyte nuclear factor (HNF) 1-P, and the chloride/bicarbonate exchanger AE1. In addition to the chromosome 17q12-21 interval, there were two additional regions yielding LOD scores over 2.0 in multipoint analyses. One of these lies just distal on chromosome 17, and it is possible that this locus is independent of their largest peak. This second chromosome 17 peak overlaps the locus encoding the ACE locus, a much-studied candidate gene for hypertension. The final locus that has not been previously implicated in BP variation is on chromosome 18. An interesting candidate gene in the chromosome 18 interval is the melanocortin receptor 2, which is the physiological receptor for corticotropin. Given the known effects of glucocorticoids on BP, it is of interest that receptors involved in the regulation of cortisol secretion lie in both the chromosome 17 and chromosome 18 intervals.

From this brief review it is clear that although different regions of the chromosome have been shown to be involved in the regulation of BP, these studies are often nonreproducible and genes involved in hypertension remain to be identified.

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