Alternative titles; symbols
SNOMEDCT: 59621000; ICD10CM: I10; ICD9CM: 401, 401.9; DO: 10825;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 | ECE1 | 600423 |
| 1q23.3 | [Blood pressure regulation QTL] | 145500 | Multifactorial | 2 | RGS5 | 603276 |
| 1q24.2 | [Blood pressure regulation QTL] | 145500 | Multifactorial | 2 | ATP1B1 | 182330 |
| 1q42.2 | {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 | AGT | 106150 |
| 2p25-p24 | {Hypertension, essential, susceptibility to, 3} | 145500 | Multifactorial | 2 | HYT3 | 607329 |
| 3q24 | {Hypertension, essential} | 145500 | Multifactorial | 3 | AGTR1 | 106165 |
| 4p16.3 | {Hypertension, essential, salt-sensitive} | 145500 | Multifactorial | 3 | ADD1 | 102680 |
| 5p13-q12 | {Hypertension, essential, susceptibility to, 6} | 145500 | Multifactorial | 2 | HYT6 | 610262 |
| 7q22.1 | {Hypertension, salt-sensitive essential, susceptibility to} | 145500 | Multifactorial | 3 | CYP3A5 | 605325 |
| 7q36.1 | {Hypertension, susceptibility to} | 145500 | Multifactorial | 3 | NOS3 | 163729 |
| 12p13.31 | {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 | GNB3 | 139130 |
| 12p12.2-p12.1 | {Hypertension, essential, susceptibility to, 4} | 145500 | Multifactorial | 2 | HYT4 | 608742 |
| 15q | {Hypertension, essential, susceptibility to, 2} | 145500 | Multifactorial | 2 | HYT2 | 604329 |
| 17q | {Hypertension, essential, susceptibility to, 1} | 145500 | Multifactorial | 2 | HYT1 | 603918 |
| 20q11-q13 | {Hypertension, essential, susceptibility to, 5} | 145500 | Multifactorial | 2 | HYT5 | 610261 |
| 20q13.13 | Hypertension, essential | 145500 | Multifactorial | 3 | PTGIS | 601699 |
A number sign (#) is used with this entry because variations in many genes contribute to essential hypertension. For information on genetic heterogeneity of essential hypertension, see the MAPPING section.
The Pickering school held that blood pressure has a continuous distribution, that multiple genes and multiple environmental factors determine the level of one's blood pressure just as the determination of stature and intelligence is multifactorial, and that 'essential hypertension' is merely the upper end of the distribution (Pickering, 1978). In this view the person with essential hypertension is one who happens to inherit an aggregate of genes determining hypertension (and also is exposed to exogenous factors that favor hypertension). The Platt school took the view that essential hypertension is a simple mendelian dominant trait (Platt, 1963). McDonough et al. (1964) defended the monogenic idea. See McKusick (1960) and Kurtz and Spence (1993) for reviews. Swales (1985) reviewed the Platt-Pickering controversy as an 'episode in recent medical history.' The Pickering point of view appears to be more consistent with the observations.
Ravogli et al. (1990) measured blood pressure in 15 normotensive subjects whose parents were both hypertensive (FH+/+), 15 normotensive subjects with 1 hypertensive parent (FH +/-), and 15 normotensive subjects whose parents were not hypertensive (FH -/-); among the 3 groups, subjects were matched for age, sex, and body mass index. The measurements were made in the office during a variety of laboratory stressors and during a prolonged rest period, and ambulatory blood pressure monitoring was done for a 24-hour period. Office blood pressure was higher in the FH +/+ group than in the FH -/- group. The pressor responses were similar in the 2 groups, but the FH +/+ group had higher prolonged 24-hour blood pressure than the FH -/- group; the differences were always significant at the 5% level for systolic blood pressure. The FH +/+ group also had a greater left ventricular mass index by echocardiography than the FH -/- group. The blood pressure values and echocardiographic values of the FH +/- group tended to lie between those of the other 2 groups. Thus, the higher blood pressure shown by individuals in the prehypertensive stage with a family history of parental hypertension does not reflect a hyperreactivity to stress but an early permanent blood pressure elevation. See comments by Pickering (1990), the son of the early defender of the multifactorial hypothesis.
In a comparison of normotensive subjects who had either hypertensive or normotensive parents, van Hooft et al. (1991) found that the mean renal blood flow was lower in subjects with 2 hypertensive parents than in those with 2 normotensive parents. Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with 2 hypertensive parents. The subjects with 2 hypertensive parents had lower plasma concentrations of renin (179820) and aldosterone than those with 2 normotensive parents. The values in subjects with one hypertensive and one normotensive parent fell between those for the other 2 groups. The conclusion of van Hooft et al. (1991) was that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension.
Examination of the biochemical processes that effect blood pressure homeostasis should elucidate some of the interactive physiologic regulators that malfunction in persons with elevated pressure and show whether single genes of large effect are important in some. For example, the electrochemical gradients of cations across erythrocyte membranes are maintained by at least 7 pathways. Garay and Meyer (1979) demonstrated an abnormally low ratio of Na+ to K+ net fluxes in sodium-loading and potassium-depleted erythrocytes of human essential hypertension. This finding was absent in normotensive families and in secondary hypertension, but present in some young normotensive children of hypertensive parents.
Garay et al. (1980) found that erythrocytes have a Na, K-cotransport system (independent of the pump) that extrudes both internal Na and K and is functionally deficient in red cells of persons with essential hypertension and some of their descendants, with or without hypertension. Parfrey et al. (1981) showed that whereas young adults with a familial predisposition to hypertension behave similarly to those without such a predisposition in having a pressor response to a high sodium intake, they are peculiar in showing a depressor response to a high potassium intake. Garay (1981) found a defect in the furosemide-sensitive Na-K cotransfer mechanism in red cells of patients with essential hypertension and in some of their normotensive relatives. The same defect is found in strains of experimental animals bred for susceptibility to salt-induced hypertension or spontaneous hypertension.
Etkin et al. (1982) assessed red cell sodium transport simply by measuring the unidirectional passive influx of sodium-22 into ouabain-treated erythrocytes. In American blacks with essential hypertension, this approach failed to show the abnormal erythrocyte sodium transport that is characteristic of white persons with essential hypertension. Thus, among American blacks, essential hypertension may have a different genetic basis. De Wardener and MacGregor (1982) reviewed evidence for the hypothesis that 'the underlying genetic lesion is a renal difficulty in excreting sodium,' which sets in train a rise in the circulating concentration of a sodium-transport inhibitor.
Canessa et al. (1980) found ouabain-insensitive erythrocyte sodium-lithium countertransport (SLC) to be at least 2-fold elevated in patients. Woods et al. (1982) confirmed these results and further showed that normotensive sons of patients had significantly higher rates of countertransport than sons of normotensive controls. In patients with a positive family history, Clegg et al. (1982) found raised lithium efflux in 76% and raised red cell sodium content in 36%. Heagerty et al. (1982) measured sodium efflux rates in leukocytes in 18 normotensive subjects who had one or more first-degree relatives with essential hypertension. The total efflux rate constant was significantly lower, owing to reduced ouabain-sensitive sodium pump activity.
Woods et al. (1983) demonstrated that the rate of sodium-lithium countertransport may not be a wholly intrinsic feature of the red cell; a dialyzable plasma factor could be demonstrated. In a study of white males, Weder (1986) found that lithium clearance, a measure of proximal tubular reabsorption of sodium, was reduced and red-cell lithium-sodium countertransport was increased in hypertensives as compared with normals. Within the group of normotensive controls, lithium clearance was lower in those with at least 1 first-degree relative with hypertension than in those with no hypertensive relative. Weder (1986) concluded that enhanced proximal tubular sodium reabsorption may precede the development of essential hypertension.
Kagamimori et al. (1985) found a significant correlation in lithium-sodium countertransport and sodium-potassium cotransport rates in red blood cells in parent-offspring pairs (r = 0.52, p less than 0.01, and r = 0.46, p less than 0.01, respectively) but not in husband-wife pairs. Sodium pump rates, on the other hand, were significantly correlated in both pairs. This led them to conclude that sodium pump has a substantial environmental component whereas the genetic component predominates in the other functions. This conclusion was supported by the fact that sodium pump rates correlated significantly with sodium/creatinine and sodium/potassium ratios in casual urine. Hasstedt et al. (1988) presented evidence supporting the possibility that an allele at a major locus elevates the rate of sodium-lithium countertransport. Rebbeck et al. (1991) found evidence of both environmental and genetic factors in the determination of sodium-lithium countertransport.
Parmer et al. (1992) assessed baroreflex sensitivity in hypertensives with or without a positive family history of hypertension and in normotensives with or without a positive family history. This was done by recording cardiac slowing in response to acute phenylephrine-induced hypertension and cardiac acceleration in response to amyl nitrite-induced fall in blood pressure. Of all variables investigated, family history of hypertension was the strongest unique predictor of baroreflex sensitivity. Parmer et al. (1992) suggested that impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension.
Low birth weight is associated with the subsequent development of hypertension in adult life. Maternal malnutrition has been suggested as the cause. Edwards et al. (1993) suggested an alternative etiology, namely, increased fetal exposure to maternal glucocorticoids. Benediktsson et al. (1993) pointed out that hypertension is strongly predicted by the combination of low birth weight and a large placenta. Normally, fetal protection is afforded by placental 11-beta-hydroxysteroid dehydrogenase (218030), which converts physiologic glucocorticoids to inactive products.
Siffert et al. (1995) and Pietruck et al. (1996) demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension.
Noon et al. (1997) studied 105 men, aged 23 to 33 years, drawn at random from the population studied by Medical Research Council Working Party (1985). In hypertensive subjects with hypertensive parents, Noon et al. (1997) reported impaired dermal vasodilatation and fewer capillaries on the dorsum of the finger, as compared to these factors in hypertensive subjects with hypotensive parents or hypotensive subjects with either hypo- or hypertensive parents. No differences in other hemodynamic indices were seen among the groups. Noon et al. (1997) suggested that defective angiogenesis may be an etiological component in the inheritance of hypertension.
Salt-Sensitive Essential Hypertension
Several varieties of familial, salt-sensitive, low-renin hypertension with a proven or presumptive genetic basis have been described (Gordon, 1995). The conditions in which the molecular basis of the disorder has been identified at the DNA level include 2 forms of Liddle syndrome (177200) due to mutation in the beta subunit (600760.0001) or gamma subunit (600761.0001) of the amiloride-sensitive epithelial sodium channel; the syndrome of apparent mineralocorticoid excess (AME) due to a defect in the renal form of 11-beta-hydroxysteroid dehydrogenase (218030); and the form of familial hyperaldosteronism which is successfully treated with low doses of glucocorticoids, such as dexamethasone ('glucocorticoid-remediable aldosteronism'), which is due to a Lapore hemoglobin-like fusion of the contiguous CYP11B1 (610613) and CYP11B2 (124080) genes.
In studies in rats, Machnik et al. (2009) demonstrated that TONEBP (604708)-VEGFC (601528) signaling in mononuclear phagocytes is a major determinant of extracellular volume and blood pressure homeostasis, and that VEGFC is an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
Syndromic Forms of Hypo- and Hypertension
Lifton (1996) reviewed the molecular genetics of human blood pressure variation. He pointed out that at least 10 genes have been shown to alter blood pressure; most of these are rare mutations imparting large quantitative effects that either raise or lower blood pressure. These mutations alter blood pressure through a common pathway, changing salt and water reabsorption in the kidney. Disorders that fall into this category include glucocorticoid remediable aldosteronism (103900), the syndrome of apparent mineralocorticoid excess (218030), and Liddle syndrome (177200), which is known to be caused by a mutation in either the beta subunit or the gamma subunit of the renal epithelial sodium channel. Unlike the preceding conditions, hypotension characterizes the following mendelian disorders: pseudohypoaldosteronism type 1 (264350), which can be produced by mutation in either the alpha subunit (600228) or the beta subunit (600760) of the same epithelial sodium channel involved in Liddle syndrome; and Gitelman syndrome (263800), which is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (600968).
Lifton et al. (2001) reviewed rare syndromic forms of hyper- and hypotension showing mendelian inheritance, for some of which the underlying mutations have been identified by positional cloning and candidate gene analyses. These genes all regulate renal salt reabsorption, in accordance with the work of Guyton (1991) and others that established that the kidney plays a central role in blood pressure regulation.
Hasstedt et al. (1988) measured red cell sodium in 1,800 normotensive members of 16 Utah pedigrees ascertained through hypertensive or normotensive probands, sibs with early stroke death, or brothers with early coronary disease. Likelihood analysis suggested that RBC sodium was determined by 4 alleles at a single locus, each allele being recessive to all alleles associated with a lower mean level. The 4 resultant distributions occurred in the following frequencies: 0.8%, 89.3%, 9.7%, and 0.2% with corresponding means for sodium level (mmol/1 RBC) of 4.32, 6.67, 9.06, and 12.19, respectively. The major locus was thought to explain 29% of the variance in red cell sodium; polygenic inheritance explained another 54.6%. A higher frequency of the high red cell sodium genotype in pedigrees in which the proband was hypertensive rather than normotensive provided evidence that this major locus increases susceptibility to hypertension.
From a study of systolic blood pressure in 278 pedigrees ascertained through children enrolled in the Rochester, Minnesota, school system, Perusse et al. (1991) obtained results suggesting that variability in systolic blood pressure is influenced by major effects of allelic variation of a single gene, with gender and age dependence. They suggested that a single gene may be associated with a steeper increase of blood pressure with age among males and females.
Chromosome 1p36.1
Funke-Kaiser et al. (2003) proposed that the ECE1 gene (600423) on chromosome 1p36.1 is a candidate for human blood pressure regulation and identified 5 polymorphisms in ECE1 among a cohort of 704 European hypertensive patients. In 100 untreated hypertensive women, both the -338A (600423.0002) and -839G (600423.0003) alleles were significantly associated with ambulatory blood pressure values.
Chromosome 1q42-43
Jeunemaitre et al. (1992) presented evidence of genetic linkage between the angiotensinogen gene (AGT; 106150) and hypertension in humans, demonstrated association of AGT molecular variants with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects with different AGT genotypes. Using the affected-pedigree-member method of linkage analysis in 63 white European families in which 2 or more members had essential hypertension, Caulfield et al. (1994) found evidence of linkage and association of the AGT gene locus with essential hypertension.
Lifton (1996) commented on the fact that of the small number of candidate genes examined for possible involvement in hypertension, only the gene encoding angiotensinogen has met relatively stringent criteria supporting its role in the pathogenesis of essential hypertension. Secreted by the liver, angiotensinogen undergoes sequential cleavage by renin and angiotensin I-converting enzyme to produce the active hormone angiotensin II, which promotes the rise in blood pressure.
Chromosome 2p25-p24 (HYT3; 607329)
Angius et al. (2002) found evidence for linkage of an essential hypertension susceptibility locus, HYT3, to chromosome 2p25-p24.
Chromosome 3p14.1-q12.3 (HYT7; 610948)
By performing a metaanalysis of genomewide scans for blood pressure variation and hypertension in Caucasians using the genome-search metaanalysis method (GSMA), Koivukoski et al. (2004) found strong evidence of linkage to chromosome 3p14.1-q12.3.
Chromosome 3q21-q25
Bonnardeaux et al. (1994) identified an association between hypertension and several polymorphisms in the AGTR1A gene (106165) on chromosome 3q21-q25.
Chromosome 4p12
Missense variants in the CORIN gene (605236) that impair CORIN function have been associated with hypertensive risk in African Americans (Dries et al., 2005; Wang et al., 2008).
Dong et al. (2013) identified a missense mutation in the CORIN gene (R539C; 605236.0003) that caused impaired activity and appeared to segregate with hypertension in a Han Chinese family.
Chromosome 4p16.3
A polymorphism in the gene encoding adducin-1 (ADD1; 102680.0001) on chromosome 4p16.3 has been associated with salt-sensitive essential hypertension.
Chromosome 5p (HYT6; 610262)
Wallace et al. (2006) found evidence for linkage with hypertension and the covariates of lean body mass (HYT5; 610261) and high renal function (HYT6) on chromosomes 20q and 5p, respectively.
Chromosome 5q34
Resistance to diastolic hypertension (608622) has been associated with variation in the KCNMB1 gene (603951) on chromosome 5q34.
Chromosome 7q22.1
A polymorphism in the CYP3A5 gene (605325.0001) on chromosome 7q22.1 has been associated with salt sensitivity in patients with essential hypertension.
Chromosome 7q36
A mutation in the NOS3 gene (163729.0001) on chromosome 7q36 has been associated with resistance to conventional therapy for essential hypertension and with pregnancy-induced hypertension.
Chromosome 12p12 (HYT4; 608742)
In a genomewide scan of a large Chinese family with primary hypertension, Gong et al. (2003) reported significant linkage to chromosome 12p12.2-p12.1.
Chromosome 12p13
Siffert et al. (1998) detected a novel polymorphism (825C-T) in exon 10 of the gene encoding the beta-3 subunit of heterotrimeric G proteins (GNB3; 139130) on chromosome 12p13; see 139130.0001. The T allele was associated with the occurrence of a splice variant, GNB3-s (encoding G-beta-3-s), in which the nucleotides 498-620 of exon 9 are deleted. This in-frame deletion caused the loss of 41 amino acids and 1 WD repeat domain of the G-beta subunit. By Western blot analysis, the splice variant appeared to be predominantly expressed in cells from individuals carrying the T allele. The behavior of insect cells expressing the splice variant indicated that it is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggested a significant association of the T allele with essential hypertension.
Chromosome 15q (HYT2; 604329)
Xu et al. (1999) detected significant linkage of essential hypertension to the telomeric end of 15q in lower extreme diastolic blood pressure sib pairs.
Chromosome 17cen-q11
In an analysis of 177 affected sib pairs, Rutherford et al. (2001) provided evidence for the location of at least 1 hypertension susceptibility locus on chromosome 17. Significant excess allele sharing showed linkage to marker D17S949 on chromosome 17q22-q24; significant allele sharing was also indicated for another marker, D17S799, located close to the centromere. Since these 2 genomic regions are well separated, the results indicated that there may be more than 1 chromosome 17 locus affecting human blood pressure. Rutherford et al. (2001) concluded that the NOS2A (163730) gene, which encodes inducible nitric oxide synthase and maps to chromosome 17cen-q11, may play a role in essential hypertension. A polymorphism within the promoter of the gene showed increased allele sharing among sib pairs and positive association of NOS2A to essential hypertension.
Chromosome 17q (HYT1; 603918)
One of the principal blood pressure loci identified in experimental hereditary hypertension in the rat has been mapped to chromosome 10. Julier et al. (1997) investigated the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage (p less than 0.0001 in some analyses) near 2 closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus. The authors concluded that 17q contains a susceptibility locus (603918) for human hypertension presumably separate from ACE and argued that comparative mapping may be a useful approach for identification of such loci in humans.
By testing a series of microsatellite markers in the region identified by Julier et al. (1997), Baima et al. (1999) confirmed the location of a blood pressure QTL on 17q in a collection of both white and black sib pairs in the U.S.
In an analysis of 177 affected sib pairs, Rutherford et al. (2001) provided evidence for the location of at least 1 hypertension susceptibility locus on chromosome 17. Significant excess allele sharing showed linkage to marker D17S949 on chromosome 17q22-q24; significant allele sharing was also indicated for another marker, D17S799, located close to the centromere. Since these 2 genomic regions are well separated, the results indicated that there may be more than 1 chromosome 17 locus affecting human blood pressure. Rutherford et al. (2001) concluded that the NOS2A (163730) gene, which encodes inducible nitric oxide synthase and maps to chromosome 17cen-q11, may play a role in essential hypertension. A polymorphism within the promoter of the gene showed increased allele sharing among sib pairs and positive association of NOS2A to essential hypertension.
Chromosome 18q21 (HYT8; 611014)
In a case-control study of essential hypertension showing linkage to chromosome 18q21 in Spanish patients, Guzman et al. (2006) observed significant overrepresentation of a 2-SNP MEX3C (611005) haplotype, G at rs1941958 and T at rs1893379, in hypertensive patients compared with controls. Guzman et al. (2006) concluded that MEX3C contributes to essential hypertension in Spanish patients.
Chromosome 20q (HYT5; 610261)
Wallace et al. (2006) found evidence for linkage with hypertension and the covariates of lean body mass and high renal function on chromosomes 20q (HYT5) and 5p (HYT6; 610262), respectively.
Chromosome 20q13
Nakayama et al. (2002) identified a mutation in the PTGIS gene (601699.0001), which maps to chromosome 20q13, in 3 sibs with essential hypertension.
Pending Linkage and Association Studies
Chromosome 1p36.3-p36.2
Tumor necrosis factor receptor-2 (TNFRSF1B; 191191) has been implicated in insulin resistance and metabolic syndrome disorders such as hypertension. Glenn et al. (2000) tested markers in and near the TNFR2 locus for linkage and association with hypertension as well as hypercholesterolemia and plasma levels of the shed soluble receptor (sTNF-R2). Using sib-pair analysis, they reported a sharp, significant linkage peak centered at TNFRSF1B (multipoint maximum lod score = 2.6 and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively). In a case-control study, they demonstrated a possible association of TNFRSF1B with hypertension by haplotype analysis. Plasma sTNF-R2 was significantly elevated in hypertensives and showed a correlation with systolic and diastolic blood pressure. A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low, and high density lipoprotein cholesterol, and diastolic blood pressure was also observed. The authors proposed a scheme for involvement of TNF (see 191160) and its receptors in hypertension and hypercholesterolemia.
Chromosome 1p33
Gainer et al. (2005) found an association between the 8590C variant of the CYP4A11 gene (601310) on chromosome 1p33 and essential hypertension in white individuals.
Chromosome 1q23
By genomewide linkage and candidate gene-based association studies, Chang et al. (2007) demonstrated a replicated linkage peak for blood pressure regulation on human chromosome 1q23, homologous to mouse and rat quantitative trait loci (QTLs) for BP, that contains at least 3 genes associated with blood pressure levels in multiple samples: ATP1B1 (182330), RGS5 (603276), and SELE (131210). Chang et al. (2007) viewed the probable relationship between each of these genes and blood pressure regulation.
Chromosome 1q32
In a Chinese population in Taiwan, Chiang et al. (1997) found an association between the renin gene (179820) HindIII polymorphism on chromosome 1q32 and hypertension.
Chromosome 1q43
Zhang et al. (2004) studied 726 hypertensive Chinese patients and their families for the association between the asp919-to-glu (D919G) polymorphism of the MTR gene (156570) on chromosome 1q43 and the antihypertensive effect of the angiotensin-converting enzyme (ACE; 106180) inhibitor benazepril. Compared to the 919D allele, both population-based and family-based association tests demonstrated that the 919G allele was associated with a significantly less diastolic blood pressure reduction. No significant association was found between the extent of systolic blood pressure reduction and benazepril therapy.
Chromosome 5q15
Yamamoto et al. (2002) screened the ALAP gene (ERAP1; 606832) gene for mutations in 488 unrelated Japanese individuals and identified one polymorphism, lys528 to arg (K528R), that showed an association with essential hypertension. The estimated odds ratio for essential hypertension was 2.3 for presence of the arg allele at codon 528, in comparison with presence of the lys/lys genotype (p of 0.004).
Chromosome 6q24.3
As a complement to linkage and candidate gene association studies, Zhu et al. (2005) carried out admixture mapping using genome scan microsatellite markers among the African American participants in the U.S. National Heart, Lung, and Blood Institute's Family Blood Pressure Program. This population was assumed to have experienced recent admixture from ancestral groups originating in Africa and Europe. Zhu et al. (2005) used a set of unrelated individuals from Nigeria to represent the African ancestral population and used the European Americans in the Family Blood Pressure Program to provide estimates of allele frequencies for the European ancestors. They genotyped a common set of 269 microsatellite markers in the 3 groups at the same laboratory. The distribution of marker location-specific African ancestry, based on multipoint analysis, was shifted upward in hypertensive cases versus normotensive controls, consistent with linkage to genes conferring susceptibility. This shift was largely due to a small number of loci, including 5 adjacent markers on chromosome 6q and 2 on chromosome 21q. The most significant markers that were increased in hypertensive African Americans in 3 different samples and that showed excess of African ancestry among hypertensive cases compared with controls were GATA184A08 on chromosome 6q24 (lod score = 4.14) and D21S1437 on chromosome 21q21 (lod score = 4.34). Zhu et al. (2005) concluded that chromosome 6q24 and chromosome 21q21 may contain genes influencing risk of hypertension in African Americans.
In a large-scale admixture scan for genes contributing to hypertension risk in 1,670 African Americans and 387 control individuals, Deo et al. (2007) identified no candidate genes or linkage peaks that appeared to contribute substantially to the differential risk between African and European Americans. They did observe nominal association at the chromosome 6q24 location (p = 0.16) identified by Zhu et al. (2005). They noted that the study sample used by Zhu et al. (2005) with multiple affected family members may explain the difference in the findings.
Chromosome 8p
Wu et al. (1996) studied the distribution of blood pressure in 48 Taiwanese families with noninsulin-dependent diabetes mellitus and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. They obtained significant evidence for linkage of systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (238600) locus on 8p. Allelic variation around the LPL gene locus was estimated to account for as much as 52 to 73% of the total interindividual variation in systolic blood pressure levels.
Chromosome 11q24.1
Rutherford et al. (2007) identified a quantitative trait locus (QTL) on chromosome 11q24.1 that influenced change of blood pressure measurements over time in Mexican Americans of the San Antonio Family Heart Study. Significant evidence of linkage was found for rate of change in systolic blood pressure (lod = 4.15) and for rate of change in mean blood pressure (lod = 3.94) near marker D11S4464. Rutherford et al. (2007) presented results from fine mapping the chromosome 11 QTL with use of SNP-associated analysis within candidate genes identified from a bioinformatic search of the region and from whole genome transcriptional expression data. The results showed that the use of longitudinal blood pressure data to calculate the rate of change in blood pressure over time provides more information than do the single-time measurements, since they reveal physiologic trends in subjects that a single-time measurement could never capture.
Chromosome 12q
Frossard and Lestringant (1995) carried out association studies at a candidate locus, the pancreatic phospholipase A2 gene (PLA2A; 172410), located on chromosome 12q. Positive associations were found between the presence of a TaqI dimorphic site located in the first intron of this gene and hypertension in 3 populations sampled: 2 from USA and 1 from Germany. The results indicated that a QTL (quantitative trait locus) implicated in determining an individual's genetic susceptibility to hypertension may be present within up to 30 cM of the PLA2A gene. Phospholipase A2 is a rate-limiting enzyme in eicosanoid production. It is coupled to angiotensin II receptors and acts, upon activation by increased intracellular calcium, to release esterified arachidonic acid from membrane phospholipids.
Chromosome 14
Von Wowern et al. (2003) performed a 10-cM genomewide scan in Scandinavian sib pairs (243 patients among 91 sibships) with early onset primary hypertension. After fine mapping of the loci, significant linkage was obtained on chromosome 14 (p = 0.0002 at 41 cM), nearest to marker D14S288 (Z = 2.7).
Chromosome 18p11
Studies in hypertensive humans and rats, as well as in familial orthostatic hypotensive syndrome (143850), suggested that chromosome 18 may have a role in hypertension. In a study using 12 microsatellite markers spanning human chromosome 18 in 177 Australian Caucasian hypertensive sib pairs, Rutherford et al. (2004) found that there was significant excess allele sharing of the D18S61 marker. The adenylate cyclase-activating polypeptide-1 gene (ADCYAP1; 102980) is involved in vasodilation and maps to the same region (18p11) as the D18S59 marker. Testing a microsatellite marker in the 3-prime untranslated region of ADCYAP1 in age- and gender-matched hypertensive and normotensive individuals showed possible association with hypertension.
Chromosome 21q21
As a complement to linkage and candidate gene association studies, Zhu et al. (2005) carried out admixture mapping using genome scan microsatellite markers among the African American participants in the U.S. National Heart, Lung, and Blood Institute's Family Blood Pressure Program. This population was assumed to have experienced recent admixture from ancestral groups originating in Africa and Europe. Zhu et al. (2005) used a set of unrelated individuals from Nigeria to represent the African ancestral population and used the European Americans in the Family Blood Pressure Program to provide estimates of allele frequencies for the European ancestors. They genotyped a common set of 269 microsatellite markers in the 3 groups at the same laboratory. The distribution of marker location-specific African ancestry, based on multipoint analysis, was shifted upward in hypertensive cases versus normotensive controls, consistent with linkage to genes conferring susceptibility. This shift was largely due to a small number of loci, including 5 adjacent markers on chromosome 6q and 2 on chromosome 21q. The most significant markers that were increased in hypertensive African Americans in 3 different samples and that showed excess of African ancestry among hypertensive cases compared with controls were GATA184A08 on chromosome 6q24 (lod score = 4.14) and D21S1437 on chromosome 21q21 (lod score = 4.34). Zhu et al. (2005) concluded that chromosome 6q24 and chromosome 21q21 may contain genes influencing risk of hypertension in African Americans.
In a large-scale admixture scan for genes contributing to hypertension risk in 1,670 African Americans and 387 control individuals, Deo et al. (2007) identified no candidate genes or linkage peaks that appeared to contribute substantially to the differential risk between African and European Americans, including the chromosome 21q21 locus identified by Zhu et al. (2005).
Genomewide Linkage Studies
To search systematically for chromosomal regions containing genes that regulate blood pressure, Xu et al. (1999) scanned the entire autosomal genome using 367 polymorphic markers. The study population, selected from a blood pressure screen of more than 200,000 Chinese adults, comprised rare but highly efficient extreme sib pairs (207 discordant, 258 high concordant, and 99 low concordant) and all but 1 parent of these sibs. By virtue of the sampling design, the number of sib pairs, and the availability of genotyped parents, this study represented one of the most powerful of its kind. Although no regions achieved a 5% genomewide significance level, maximum lod scores were greater than 2.0 for regions of chromosomes 3, 11, 15, 16, and 17.
Exclusion Linkage Studies
Jeunemaitre et al. (1992) could demonstrate no linkage between hypertension and the angiotensin I-converting enzyme locus (ACE; 106180) on chromosome 17. Wu et al. (1996) studied the distribution of blood pressure in 48 Taiwanese families with noninsulin-dependent diabetes mellitus and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. They found no evidence for linkage of the ACE gene on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures.
In a review, Garbers and Dubois (1999) identified a number of important blood pressure regulatory genes, including their loci in the human, mouse, and rat genomes. Phenotypes of gene deletions and overexpression in mice were summarized, and a detailed discussion of selected gene products was included.
De Mendonca et al. (1980) found the same changes as those reported by Garay and Meyer (1979) in 3 varieties of genetically transmitted hypertension in the rat: an abnormally low ratio of Na+ to K+ net fluxes in sodium-loading and potassium-depleted erythrocytes.
Kurtz and Morris (1985) found that recently weaned Dahl rats (Dahl et al., 1962) already had a higher than normal blood pressure and greater heart weight to body weight ratio than did normal rats. Thus, the hypertension that develops with salt challenge is superimposed on an already extant difference in blood pressure between strains. Rapp et al. (1989) found that Dahl rats sensitive to hypertension with salt administration had a different RFLP in the renin gene than did Dahl rats resistant to hypertension. They found, furthermore, that when the sensitive and the resistant rats were crossed, the renin RFLP cosegregated with blood pressure in the F2 generation. One dose of the 'sensitive' renin allele was associated with an increment of blood pressure approximately 10 mm Hg, and 2 doses increased blood pressure approximately 20 mm Hg. Rapp et al. (1989) concluded that in the rat the renin gene is, or is closely linked to, 1 of the genes regulating blood pressure.
In a study of crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain, Hilbert et al. (1991) localized 2 genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F-2 generation. The 2 genes were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicated that the human homolog of BP/SP-1 could reside on chromosome 17q in a region that also contains the angiotensin I-converting enzyme gene. Since ACE1 encodes a key enzyme of the renin-angiotensin system, it is a prime candidate gene in primary hypertension. A rat microsatellite marker of the gene was mapped to rat chromosome 10 within the region containing BP/SP-1. In precisely the same cross prepared by the same investigators, Jacob et al. (1991) likewise mapped a gene they called Bp1 to rat chromosome 10 and demonstrated close linkage to the rat gene for angiotensin I-converting enzyme. They also identified significant, albeit weaker, linkage to a locus, Bp2, on chromosome 18 of the rat. Phenylethanolamine N-methyltransferase (PNMT; 171190), which catalyzes the synthesis of epinephrine from norepinephrine, is encoded by a gene on human chromosome 17 and rat chromosome 10 and is, therefore, also a candidate gene for hypertension in the rat model.
Kreutz et al. (1995) reported further characterization of the BP/SP-1 locus, using a congenic strain of rats carrying a 6-cM chromosomal fragment genotypically identical with the segment on chromosome 10 in the stroke-prone spontaneously hypertensive rat (SHRSP) in whom the BP/SP-1 locus was originally identified. This segment was 26 cM away from the ACE locus. From breeding experiments they concluded that a QTL, termed BP/SP-1a, lies within the SHRSP-congenic region and is linked to basal blood pressure, whereas a second locus on chromosome 10, termed BP/SP-1b, that maps closer to the ACE locus cosegregates predominantly with blood pressure after exposure to excess dietary NaCl. Through the study of inbred Dahl salt-sensitive rats, Gu et al. (1996) demonstrated 2 blood pressure QTLs on rat chromosome 1.
Benediktsson et al. (1993) found that rat placental 11-beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolized by 11-beta-OHSD) had lower birth weights and higher blood pressure when adults than did offspring of control rats.
Cicila et al. (1993) found a difference between Dahl salt-hypertension sensitive (S) and resistant (R) strains of rats, namely, a polymorphism of 11-beta hydroxylase (202010) that cosegregated with the capacity of the adrenal to synthesize 18-hydroxy-11-deoxycorticosterone (18-OH-DOC). They found that the R rat carries an 11-beta hydroxylase allele that is associated with uniquely reduced capacity to synthesize 18-OH-DOC and encodes an 11-beta-hydroxylase protein with 5 amino acid substitutions. The gene for 11-beta-hydroxylase is located on rat chromosome 7. Dubay et al. (1993) showed that in the Lyon hypertensive rat strain different loci are involved in the regulation of steady-state (diastolic pressure) and pulsatile (systolic minus diastolic, or pulse pressure) components of blood pressure. Significant linkage was established between diastolic blood pressure and a microsatellite marker of the renin gene on rat chromosome 13, and between pulse pressure and the carboxypeptidase B gene (114852) on rat chromosome 2. Deng et al. (1994) localized a blood pressure QTL on rat chromosome 2 between 2 candidate loci. They estimated that the particular QTL accounted for 9.2% of the total variance and 26% of the genetic variance.
End-stage renal disease, coronary artery disease, and stroke are complications of hypertension. Why some patients develop complications is unclear, but susceptibility genes may be involved. To test this notion, Brown et al. (1996) studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. They were able to localize 2 genes, designated Rf1 and Rf2 by them, which were responsible for about half of the genetic variation in key indices of renal impairment. In addition, they localized another gene, called Bpfh1, which was responsible for about 26% of the genetic variation in blood pressure. Rf1 strongly affected the risk of renal impairment, but had no significant effect on blood pressure. The results showed that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.
Vincent et al. (1997) presented evidence that genetic factors may influence the response to antihypertensive drugs. In a backcross population derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, they used microsatellite markers to identify a QTL on rat chromosome 2 that specifically influences the systolic and diastolic blood pressure responses to administration of a dihydropyridine calcium antagonist. The locus accounted for 10.3% and 10.4% of the total variances in the systolic and diastolic responses to the drug, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of trimetaphan, a ganglionic blocking agent, or of losartan, an angiotensin II subtype 1 receptor (106165) antagonist.
Churchill et al. (1997) tested the role of genetic factors in determining hypertension-induced renal damage by developing a new experimental animal model. Two genetically distinct yet histocompatible kidneys were chronically and simultaneously exposed to the same blood pressure profile and metabolic environment in the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats that carried the major histocompatibility complex of the Brown Norway strain. After 25 days of severe hypertension induced by deoxycorticosterone acetate (DOCA) and salt, Brown Norway donor kidneys, but not spontaneously hypertensive rat kidneys, developed proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury. Control experiments showed that strain differences in renal damage were not related to transplantation-induced renal injury, immunologic rejection, or preexisting strain differences in blood pressure. These studies demonstrated that differences in susceptibility to hypertension-induced renal damage are genetic in these rat strains and established the feasibility of using organ-specific genome transplants to map genes expressed in the kidney. Brown Norway rats showed no blood pressure response to DOCA-salt, showing additional genetic differences in hypertension.
Tanaka et al. (1997) found that in SHRSP rats on a normal NaCl diet, supplementing dietary potassium with KCl exacerbated hypertension, whereas supplementing either K-bicarbonate or K-citrate (KB/C) attenuated hypertension. Supplemental KCl but not KB/C induced stroke in all and only those rats in the highest quartiles of both blood pressure and plasma renin activity. Plasma renin activity was higher with KCl than with KB/C. These observations were interpreted as showing that the severity of hypertension and frequency of stroke in SHRSP rats were selectively Cl(-)-sensitive and Cl(-)-determined.
Lifton et al. (1991) excluded APNH (107310) as a candidate gene for susceptibility to essential hypertension.
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