Abstract
This chapter provides an overview of the genetics of hypertension, reviewing what is known about rare Mendelian forms of hypertension, which can be explained by mutations in single genes, as well as the genetics of primary hypertension. Different approaches such as candidate gene approaches, linkage studies, and genome-wide association studies are discussed. It is hoped that this chapter will provide a concise primer for reading the literature in the area of genetics and hypertension.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
Introduction
More than 12 years have elapsed since the publications in February 2001 that provided the first maps of the human genome [1, 2]. While genes involved in a number of rare, monogenic forms of hypertension have been identified, the genetics of primary hypertension has eluded delineation, likely because it has multiple genetic determinants. However, many recently developed tools are available to reveal the genetic aspects of primary hypertension, and a growing number of studies have identified many genetic associations with the condition, which is widely viewed as a polygenic disorder. This chapter discusses both monogenic and polygenic aspects of hypertension. We also discuss the current clinical implications of genetic studies and information in our approach to hypertension [3].
Monogenic Forms of Human Hypertension
Genes for a number of monogenic forms of human hypertension have been identified via positional cloning [in the past called “reverse genetics”] [4–6]. In this approach, large kindreds with many affected family members are phenotyped, and the mode of inheritance determined – that is, is the disease autosomal recessive, autosomal dominant, sex linked, and codominant, in its clinical transmission. Subsequently, linkage analysis is performed using highly polymorphic genetic markers such as microsatellite markers that occur widely throughout the genome, evenly spaced at approximately 10 centimorgan [cM] intervals. Since most people (about 70 %) are heterozygous, the inheritance of alleles can be traced through large pedigrees. In a successful linkage analysis, a specific chromosomal region in the genome linked to the trait is identified. A LOD [logarithm of the odds] score describes the presence of such a region. The generally accepted LOD score indicating linkage is greater than 3.3 [corresponding to a significance level genome wide of 4.5 × 10−5 [4]]. Once linkage is identified, a search for known candidate genes in the area of putative linkage commences. A search using additional highly polymorphic markers may also narrow the area of interest, leading to sequences of possible genes within the area.
A number of monogenic forms of hypertension have been identified to date. A number are due to gain-of-function mutations [7–9], most of which involve the renal handling of salt and/or the overproduction of mineralocorticoids or increased mineralocorticoid activity. Severe hypertension, often from early life – even infancy – is not unusual in such conditions. Clinical hallmarks include apparent volume expansion and suppressed plasma renin activity with variable hypokalemia. An approach to evaluation of those forms of hypertension associated with hypokalemia and suppressed renin activity is shown in Fig. 6.1 [10].
Gain-of-function mutations in transporters in the distal renal tubules result in hypertension via salt and water retention [11]. (While mutations and polymorphisms in the genes of various components of the renin-angiotensin-aldosterone system [RAAS] may lead to excessive renal sodium retention, no single RAAS polymorphism causes monogenic hypertension.) Phenotypically, most monogenic hypertension can be divided into disorders caused by mutations that lead to overproduction of mineralocorticoids or increased mineralocorticoid activity and those that result in abnormalities of electrolyte transport, focusing attention on the role of the kidney in hypertension (Table 6.1) [7]. Additionally, some mutations in proto-oncogenes and genes that involve response to hypoxia have been linked to chromaffin tumors (Table 6.2) [12]. Information about the most common forms of monogenic hypertension [13] follows.
Glucocorticoid-Remediable Aldosteronism or Familial Hyperaldosteronism Type 1 [OMIM #103900]
Glucocorticoid-remediable aldosteronism (GRA) or familial hyperaldosteronism type 1, an autosomal dominant disorder, is considered the most common type of monogenic hypertension and presents in early infancy in some patients [14–18]. GRA has been recognized since the 1960s, when Sutherland et al. [19] and New et al. [20] reported patients with severe hypertension accompanied by suppressed renin and increased aldosterone secretion that were found to be treatable with dexamethasone. (GRA is listed in the Online Mendelian Inheritance in Man index [OMIM] as #103900 [OMIM can be accessed at http://www.ncbi.nlm.nih.gov/Omim]; note that the OMIM numbers for other Mendelian disorders will also be listed for other disorders when available.) The hypertension in GRA is moderate to severe, owing to increased aldosterone secretion driven by adrenocorticotropic hormone (ACTH).
A chimeric gene containing the 5′ regulatory sequences of 11 beta hydroxylase [which confers ACTH responsiveness] fused with the distal coding sequences of aldosterone synthase causes ACTH rather than angiotensin II or potassium as the main controller of aldosterone secretion [21, 22]. Both serum and urine aldosterone levels tend to be elevated, though not invariably. The chimeric gene product converts cortisol to 18-hydroxy and 18-oxo metabolites [23–25], which can be detected in urine and are pathognomonic. The elevations of urinary cortisol metabolites TH18oxoF and 18-hydroxycortisol and an elevated ratio of TH18oxoF/THAD metabolites may distinguish GRA patients from others with AME or Liddle syndrome [26]. However, specific genetic testing, which is both sensitive and specific, has largely supplanted the urinary testing when the condition is suspected.
Not all affected members of GRA families develop hypertension in childhood [27–29]. Dluhy et al. [27] assessed 20 children in 10 unrelated GRA pedigrees and observed that 16 of the 20 developed hypertension, as early as 1 month of age. However, four children were normotensive. Monotherapy using glucocorticoid suppression or aldosterone receptor and epithelial sodium cotransporter (ENaC) antagonists was sufficient to control BP in half of the hypertensive children, though the others required polypharmacy, and three had uncontrollable hypertension [27].
Cerebral hemorrhage at an early age (mean age, 32 years) is common in GRA pedigrees. And almost half of reported pedigrees [48 %] and 18 % of individual GRA patients have been noted to develop cerebrovascular complications [7, 8, 21].
Familial Hyperaldosteronism Type 2 OMIM #605635
This form of hyperaldosteronism, which appears to be autosomal dominant, is distinct from type 1 and is associated with hyperplasia of the adrenal cortex, an adenoma producing aldosterone or both [30–33]. It has been estimated to be fivefold more common than GRA [33]. Dexamethasone fails to suppress the hypertension. To date, no mutation has been identified, though linkage studies have identified a five megabase locus on chromosome 7p22. The Stowasser group [33] has examined a number of candidate genes within 7p22, many of which involve cell growth, but has still not yet definitively identified the gene responsible.
Familial Hyperaldosteronism Type 3 [OMIM# 613677]:
FH type 3 is very rare and is also called Geller syndrome; it is now known that a heterozygous mutation in the KCNJ5 gene, which is on chromosome 11q24, leads to familial hyperaldosteronism type III [33–37].
Apparent Mineralocorticoid Excess [AME] [OMIM # 218030]
Low-renin hypertension, often severe and accompanied by hypokalemia and metabolic alkalosis [38], is the hallmark of apparent mineralocorticoid excess [AME], first described in 1977 by New et al. [39, 40]. Spironolactone is often effective initially, but patients often become refractory to this drug. In AME, 11β-hydroxysteroid dehydrogenase (11β-HSD) is absent, resulting in hypertension in which cortisol acts as if it were a potent mineralocorticoid. The microsomal enzyme, 11β-hydroxysteroid dehydrogenase, interconverts active 11-hydroxyglucocorticoids to inactive keto-metabolites. Cortisol, as well as aldosterone, has an affinity for the mineralocorticoid receptor. Normally, 11β-HSD is protective, preventing binding of cortisol to the mineralocorticoid receptor, but in AME, the slower-than-normal metabolism of cortisol to cortisone results in cortisol acting as a potent mineralocorticoid [39, 40], while metabolism of cortisone to cortisol is normal.
Persons with classic AME usually develop symptoms in early childhood, often presenting with failure to thrive, severe hypertension, and persistent polydipsia. Affected patients appear volume expanded and respond to dietary sodium restriction. Plasma renin activity is very low. Affected children are at high risk for cardiovascular complications, and some develop nephrocalcinosis and renal failure [41]; early therapy may lead to better outcome. A high cortisol: cortisone ratio in plasma or an abnormal urinary ratio of tetrahydrocortisol/tetrahydrocortisone (THF/THE), in which THF predominates and makes the diagnosis.
Several variants of AME have been reported, including a mild form in a Mennonite kindred in which there is a P227L mutation in the HSD11B2 gene [42, 43], a coactivator defect with resistance to multiple steroids [44], and hypertension without the characteristic findings of AME in a heterozygous father and homozygous daughter who have mutations in 11 β HSD2 [45]. Coeli et al. reported a Brazilian child with a homozygous missense mutation p.R186C in the HSD11B2 gene [46].
The hypertension in AME appears renally mediated, but recent evidence suggests that ultimately, the disorder changes from one with increased sodium resorption to a vascular form of hypertension [47].
Mineralocorticoid Receptor Gain-of-Function Mutation
A novel form of monogenic hypertension due to a gain-of-function mutation in the mineralocorticoid receptor, causing it to remain bound to its steroid ligands, has also been described. The first known case was a teenage boy with hypertension, who had low renin and aldosterone levels, as well as mild hypokalemia [48]. In toto, 11 persons in the patient’s family had a point mutation, which influences an important binding region of the receptor – a serine at amino acid 810 in the mineralocorticoid receptor is changed to leucine (S810L)
Affected persons have refractory hypertension, and women with this mutation have severely elevated BP during pregnancy [49, 50]. Early death due to heart failure occurred in the index family [48].
It appears that the S810L mutation leads to a conformational change in the receptor that heightens the stability of steroid-receptor complexes. The mutation thus results in a steric hindrance resulting in a bending of the molecule that makes it difficult for known agonists and antagonists to act normally. Some antagonists that cannot act on the normal [“wild type”] receptor work in this mutation: these include RU 486, 5-pregnane-20-one, and 4,9-androstadiene-3,17-dione [51].
Steroidogenic Enzyme Defects Leading to Hypertension
Rare autosomal recessive defects in steroidogenesis associated with hypertension were recognized well before the genomic era. Cortisol is normally synthesized under the control of ACTH in the zona fasciculata, while aldosterone is synthesized largely under the influence of angiotensin II and potassium in the zona glomerulosa. Aldosterone synthesis is not normally controlled by ACTH, but if any of the several enzymes that are involved in cortisol biosynthesis is abnormal, the usual feedback loop is interrupted. Consequently, plasma ACTH will increase in an attempt to produce cortisol, and aberrant products will accumulate, some of which lead to hypertension. This is discussed in more detail in Chap. 25.
The inherited defects of steroid biosynthesis – all autosomal recessive – are, as a group, termed congenital adrenal hyperplasia (CAH), and each results in a characteristic clinical and biochemical profile [52–54]. Any enzyme in the pathways of steroidogenesis may contain a mutation; the most commonly affected is 21-hydroxylase. Mutations in 21-hydroxylase are not, however, generally associated with hypertension. Enzyme mutations that are associated with hypertension include [in order of frequency] 11β-hydroxylase > 3β-hydroxysteroid dehydrogenase> 17α-hydroxylase and cholesterol desmolase. Patients with the 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase defects have a tendency to retain salt, becoming hypertensive. It is also important to remember that any person with CAH may develop hypertension owing to overzealous replacement therapy.
Steroid 11β-Hydroxylase Deficiency
The mineralocorticoid excess in 11β-hydroxylase deficiency [52–58], a form of CAH accompanied by virilization, leads to decreased sodium excretion with resultant volume expansion, renin suppression, and hypertension. Elevated BP is not invariant in 11β-hydroxylase deficiency and most often is discovered in later childhood or adolescence, often with an inconsistent correlation to the biochemical profile [52–58]. Hypokalemia is variable, but total body potassium may be markedly depleted in the face of normal serum or plasma potassium. Renin is generally decreased, but aldosterone is increased.
Therapy of 11β-hydroxylase deficiency should focus on normalizing steroids. Administered glucocorticoids should normalize cortisol and reduce ACTH secretion and levels to normal, thus stopping over secretion of deoxycorticosterone (DOC). Hypertension generally resolves with such therapy [53]. When hypertension is severe, antihypertensive therapy should be used instituted until the BP is controlled; such therapy can be tapered later.
Additional mutations can cause this syndrome. For example, a patient with 11β-hydroxylation inhibition for 17α-hydroxylated steroids but with intact 17-deoxysteroid hydroxylation has been reported [58]. Multiple mutations affecting the CYP11B1 gene have been described; these include frameshifts, point mutations, extra triplet repeats, and stop mutations [38, 59–62].
Steroid 17α-Hydroxylase Deficiency
Abnormalities in 17α-hydroxylase affect both the adrenals and gonads, since a dysfunctional 17α-hydroxylase enzyme results in decreased synthesis of both cortisol and sex steroids [63–66]. Affected persons appear phenotypically female [or occasionally have ambiguous genitalia], irrespective of their genetic sex, and puberty does not occur. Consequently, most cases are discovered after a girl fails to enter puberty [65]. An inguinal hernia is another mode of presentation. Hypertension and hypokalemia are characteristic, owing to impressive overproduction of corticosterone [compound B].
Glucocorticoid replacement is an effective therapy. However, should replacement therapy fail to control the hypertension, appropriate therapy with antihypertensive medication(s) should be instituted to achieve BP control.
Mutations in Renal Transporters Causing Low-Renin Hypertension
Pseudohypoaldosteronism Type II: Gordon Syndrome [OMIM#145260]
Pseudohypoaldosteronism type II, Gordon syndrome, or familial hyperkalemia (OMIM #145260), an autosomal dominant form of hypertension associated with hyperkalemia, acidemia, and increased salt reabsorption by the kidney, is caused by mutations in the WNK1 and WNK 4 kinase family [67–71]. Though the physiology and response to diuretics suggested a defect in renal ion transport in the presence of normal glomerular filtration rate, the genetics have only recently been delineated.
Affected persons have low-renin hypertension and improve with thiazide diuretics or with triamterene [71]. Aldosterone receptor antagonists do not correct the observed abnormalities.
PHAII genes have been mapped to chromosomes 17, 1, and 12 [67, 68]. One kindred was found to have mutations in WNK1 – large intronic deletions that increase WNK1 expression. Another kindred with missense mutations in WNK4, which is on chromosome 17, has been described. While WNK 1 is widely expressed, WNK4 is expressed primarily in the kidney, localized to tight junctions. WNKs alter the handling of potassium and hydrogen in the collecting duct, leading to increased salt resorption and increased intravascular volume by as yet unknown means.
Liddle Syndrome [OMIM # 177200]
In 1963, Liddle [72] described the early onset of autosomal dominant hypertension in a family in whom hypokalemia, low renin, and aldosterone concentrations were noted in affected members. Inhibitors of renal epithelial sodium transport such as triamterene worked well in controlling the hypertension, but inhibitors of the mineralocorticoid receptor did not. A general abnormality in sodium transport seemed apparent, as the red blood cell transport systems were not normal [73]. A major abnormality in renal salt handling seemed likely when a patient with Liddle syndrome underwent a renal transplant and hypertension and hypokalemia resolved posttransplant [74].
While the clinical picture of Liddle syndrome is one of aldosterone excess, aldosterone levels as well as renin levels are very low [10]. Hypokalemia is not invariably present. A defect in renal sodium transport is now known to cause Liddle syndrome. The mineralocorticoid-dependent sodium transport within the renal epithelia requires activation of the epithelial sodium channel [ENaC], which is composed of at least three subunits normally regulated by aldosterone. Mutations in the beta and gamma subunits of the ENaC have been identified [both lie on chromosome 16] [75, 76]. Thus, the defect in Liddle syndrome leads to constitutive activation of amiloride-sensitive epithelial sodium channels (ENaC) in distal renal tubules, causing excess sodium reabsorption. Additionally, these gain-in-function mutations prolong the half-life of ENaCs at the renal distal tubule apical cell surface, resulting in increased channel number [77].
Pheochromocytoma-Predisposing Syndromes
A variety of RET proto-oncogene mutations and abnormalities in tumor-suppressor genes are associated with autosomal dominant inheritance of pheochromocytomas, as summarized in Table 6.2 [12, 78–83]. A number of paraganglioma and pheochromocytoma susceptibility genes inherited in an autosomal dominant pattern appear to convey a propensity toward developing such tumors [12]. Both glomus tumors and pheochromocytomas derive from neural crest tissues, and the genes identified in one type of tumor may appear in the other [84]. For instance, germ-line mutations have been reported both in families with autosomal dominant glomus tumors [as well as in registries with sporadic cases of pheochromocytoma] [85]. In addition, other pheochromocytoma susceptibility genes include the proto-oncogene RET (multiple endocrine neoplasia syndrome type 2 [MEN-2]), the tumor-suppressor gene VHL seen in families with von Hippel-Lindau disease and the gene that encodes succinate dehydrogenase subunit B (SDHB).
The genes involved in some of these tumors appear to encode proteins with a common link involving tissue oxygen metabolism [86–88]. In von Hippel-Lindau disease, there are inactivating [loss-of-function] mutations in the VHL suppressor gene, which encodes a protein integral to the degradation of other proteins – some of which, such as hypoxia-inducible factor, are involved in responding to low oxygen tension. Interestingly, the mitochondrial complex II, important in O2 sensing and signaling, contains both SDHB [succinate dehydrogenase subunit B] and SDHD [succinate dehydrogenase subunit D]. Thus, mutations in the VHL gene and SDHB and SDHD might lead to increased activation of hypoxic signaling pathways leading to abnormal proliferation.
In multiple endocrinopathy-2 (MEN-2) syndromes, mutations in the RET proto-oncogene lead to constitutive activation [activating mutations] of the receptor tyrosine kinase. The end result is hyperplasia of adrenomedullary chromaffin cells [and in the parathyroid, calcitonin-producing parafollicular cells]. In time, these cells undergo a high rate of neoplastic transformation. It now also appears that apparently sporadic chromaffin tumors may contain mutations in these genes as well.
Hypertension with Brachydactyly [OMIM #112410]
Hypertension with brachydactyly, also called brachydactyly, type E, with short stature and hypertension (Bilginturan syndrome), was first described in 1973in a Turkish kindred [89]. Affected persons have shortened phalanges and metacarpals, as well as hypertension. Linkage studies performed in the 1990s mapped this form of hypertension to a region on chromosome 12p, in the region 12p12.2 to p11.2 [90, 91].
Patients with this form of hypertension have normal sympathetic nervous system and renin-angiotensin system responses. In 1996, some abnormal arterial loops were noted on MRI examinations of the cerebellar region. There was speculation that this abnormality could lead to compression of neurovascular bundles that would lead to hypertension [92]. Another family, in Japan, also had similar findings, and a deletion in 12p was reported in that family [93].
There are several candidate genes in the region – a cyclic nucleotide phosphodiesterase (PDE3A) and a sulfonylurea receptor, SUR2, which is a subunit of an ATP-sensitive potassium channel. It was hypothesized that there could be “a chromosomal rearrangement between the candidate genes PDE3A/SUR2/KCNJ8 for hypertension and SOX5 for the skeletal phenotypes, separated by several megabases” (summarized in reference [94]). It then appeared, in studies using bacterial artificial chromosomes, that there was an inversion, deletion, and reinsertion in this region. It appears currently that rather than a mutation in a single gene, this form of hypertension is caused by the chromosomal rearrangement.
Other Forms of Mendelian Hypertension
In addition, there have been reports of severe insulin resistance, diabetes mellitus, and elevated BP caused by dominant-negative mutations in human peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor [95].
PPARγ is important in the differentiation of adipocytes (reviewed in Meirhaeghe and Amouyel [95]). Mutations in PPARγ have been linked to a group of symptoms, including hypertension. Only eight persons have been described to date and have point mutations that are heterozygous (V290M, R425C, P467L, and F388L) [95–99]. The affected patients have had marked insulin resistance, then develop type 2 diabetes, and have dyslipidemia, as well as hypertension. The finding of these patients has been taken widely as a demonstration of the importance of PPARG in metabolic syndrome and in blood pressure control.
There has also been a description of hypertension, hypomagnesemia and hypercholesterolemia due to an abnormality in mitochondrial tRNA. In this case, there is impaired ribosomal binding due to a missense mutation in the mitochondrial tRNA [100].
When to Suspect Monogenic Hypertension
Table 6.3 lists those situations in which the astute clinician should consider monogenic hypertension [8]. These include both clinical and laboratory findings that should point toward further evaluation. Significant among these are a strong family history of hypertension and early onset of hypertension, particularly when the BP is difficult to control within the family. Low plasma renin activity, along with hypokalemia, should also point toward the possibility that a defined form of hypertension may be present.
Non-Mendelian, Polygenic Hypertension
The genetic contribution to a prevalent condition such as essential [primary] hypertension is widely considered to involve multiple genes and is thus termed polygenic. The possibility for determining the genes that are involved seems far more feasible in the current genomic era, yet clear identification has proved elusive, in part because BP is a continuous variable, and the contribution of any one gene appears to be small. Relevant background for considering the genetic factors predisposing toward hypertension follows:
Experimental Hypertension as a Tool to Investigate Polygenic Hypertension
Many studies in inbred experimental animals, mainly rats and mice, have aimed to identify genes controlling BP (see Chap. 8). In the 1980s, it was estimated that 5–10 genes control BP [101]. In 2000, Rapp summarized available research and estimated that 24 chromosomal regions in 19 chromosomes were associated with hypertension in various rat strains [102]. A recent review by Delles et al. [103] notes that candidate QTLs (quantitative trait loci) have been identified on nearly every chromosome. Studies using inbred rat strains, however, did not identify polygenes and their associated alleles [104].
A large number of chromosomal regions and some candidate genes have also been suggested from experimental studies in mice. For example, targeted gene deletion studies have shown an effect on BP in more than a dozen genes, among which are endothelial nitric oxide synthase, insulin receptor substrate, the dopamine receptor, apolipoprotein E, adducin-alpha, the bradykinin receptor, and the angiotensin type 2 receptor, as well as other members of the RAAS [105].
Genetic manipulation in mice has been successful in exploring contributions of various candidate genes (reviewed in [106]), most notably those of the RAAS through two approaches, overexpression of a given gene [with “transgenic” animals [102]] and deleting gene function [with “knockouts”]. An additional approach is to use gene targeting in embryonic stem [ES] cell cultures [107–109].
Inbred strains rather than transgenic or knockouts have led to important findings [109–112]. A number of studies, notably those of Jacob et al. [109] and Hilbert et al. [110], found linkage in a rat model of hypertension that pointed to the angiotensin-converting enzyme (ACE) gene as important in determining hypertension. Since those reports of more nearly 20 years ago, a large number of clinical studies have suggested a link between ACE polymorphisms in humans and hypertension. See a recent commentary on the value of studies in the rat model [103, 111].
Human Hypertension
A variety of studies have pointed to a link between human hypertension and genes of the RAAS (summarized in references [112, 113]). However, in common diseases such as hypertension, it may be more productive to consider susceptibility alleles rather than disease alleles per se. Furthermore, some people carrying a particular susceptibility allele may not have the disease, either because they do not have the environmental exposure that causes the condition to develop or because they lack another allele [or alleles] that are needed to cause a given clinical problem. Because there are multiple potential interactions, and susceptibility alleles are generally common, following a given allele through pedigrees is difficult. In such a circumstance, segregation analysis is difficult, particularly if a given susceptibility allele has a small effect. Indeed, to date, linkage has been reported on most chromosomes in humans [114–129].
While linkage analysis may constitute an initial step (3–6), it is not as powerful a tool in polygenetic conditions as it is in Mendelian diseases, because many people without the disease may carry the susceptibility allele. Using affected siblings [sib pairs] may be helpful to gain more understanding of the possible genetics (see Fig. 6.2). Siblings who are both affected with a given problem such as hypertension would be anticipated to share more than half their alleles near or at the susceptibility locus, and the chance of this occurrence is then calculated (3–6). A LOD score of greater than 3.6 is taken as evidence of a linked locus, which is often very large (in the range of 20–40 cM). Once a putative linkage is confirmed in a replicate study, finer mapping can be performed to hone in on the genetic region that contains the putative gene. This is done via linkage disequilibrium or association testing between disease and genetic markers, often with single-nucleotide polymorphisms (SNPs). SNPs occur roughly every 1,000 base pairs and lend themselves to automated testing. Using SNPs, a broad region (10–40 cM) can be narrowed to a far smaller region of roughly 1 × 106 base pairs [121, 122].
Genome-wide screens of the human genome aiming to discover hypertension genes have suggested many loci of interest [123, 124]. These genome-wide screens have included subjects with diverse phenotypes and ethnicity; furthermore, selection criteria have varied. The numbers and composition of families have ranged from single, large pedigrees to more than 2,000 sib pairs from 1,500 or so families [123]. Using genomic scan data from four partner networks the US Family Blood Pressure Program (FBPP) [124] sought to use phenotypic strategies that reflect the ethnic demography of the USA. A 140–170 cM region of chromosome 2 was linked to hypertension in several populations – Chinese sibling pairs [120] and Finnish twins [115], as well as a discordant sibling-pair screen. Recently Caulfield et al. phenotyped 2,010 sib pairs drawn from 1,599 families with severe hypertension as part of the BRIGHT study [Medical Research Council BRItish Genetics of HyperTension] and performed a 10 cM genome-wide scan [125]. Their linkage analysis identified a locus on chromosome 6q with a LOD score of 3.21 and genome-wide significance of 0.042. However, this locus is at the end of chromosome 6, and the end of a chromosome may generate errors; thus, caution is required in drawing conclusions from these findings. The Caulfield group also found three other loci with LOD scores above 1.57 [125]. One of these loci was the same as that found in the Chinese and Finnish studies [125].
Within the last few years, there have been further genome-wide association studies (GWAS) concerning hypertension reported [130, 131]. In 2007 Levy et al. used an Affymetrix 100 k chip platform and performed a GWAS with the Framingham cohort, yet the initial analysis did not find significance for any single gene [132]. Using the Wellcome Trust Case Control Consortium [WTCCC] and an Affymetrix 500 k chip, another GWAS was reported in 2007, and it, too, did not reach genome-wide significance for any gene [133]. However, a study in which the subjects were from the Korean general population most recently reported genome-wide significance, though a very small effect for the ATPase, Ca++-transporting, plasma membrane 1 (ATP2B) gene [134]. These rather disappointing results from GWAS studies on hypertension are discussed to indicate the complexity of primary hypertension.
Two consortiums have reported some more encouraging results. The Global BPgen group examined 2.5 million genotyped or imputed SNPs in 34,433 persons of European background and found eight regions that reached genome-wide significance. These regions were associated with hypertension and lie in close proximity to genes for CYP17A1, CYP1A2, FGF5, SH2B3, MTHFR, ZNF652, and PLCD3 and to the chromosome 10 open reading frame 107 (c10orf107) [135]. Further, the so-called CHARGE consortium [136] looked at 29,136 participants and studied 2.5 million genotyped or imputed SNPs; they reported significant associations with hypertension for 10 SNPs and with systolic BP for 13 SNPs and for diastolic BP with 20 SNPs. Their findings plus those of Global BPgen were then subjected to a meta-analysis, and this led to findings of genome-wide significance for a number of genes associated with elevated BP or with systolic or diastolic BP [135]. These included the ATP2B gene, as well as CYP17A1 (steroid 17-alphamonooxygenase), CSK-ULK3 (adjacent to c-src tyrosine kinase and unc-51- like kinase 3 loci), TBX3-TBX5 (adjacent to T-box transcription factor TBX3 and T-box transcription factor TBX5 loci), ULK4 ( unc-51-like kinase 4), PLEKHA7 (pleckstrin homology domain containing family A member 7), SH2B3 (SH2B adaptor protein 3), and CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) [135].
Candidate Genes
Another approach in assessing polygenic hypertension is to use candidate genes – genes that already have a known or suspected role in hypertension – that are present near the peak of observed genetic linkage. If the full sequence of the candidate gene is known, then it is relatively easier to go forward.
In the Caulfield study [125], for example, there are a number of candidate genes that are within the linkage analysis-identified areas on chromosomes 2 and 9. Genes that encode serine-threonine kinases, STK39, STK17B are on chromosome 2q; PKNBETA, a protein kinase, is on chromosome 9q; G protein-coupled receptors on chromosome 9 – GPR107 9q and GPR21 on 9q33; and on 2q24.1 there is a potassium channel, KCNJ3.
Use of microarrays to identify differential expression of expressed sequences in tissues from affected and unaffected persons has become common. These arrays are available either as full-length cDNAs or as expressed sequence tags (ESTs)
Candidate Susceptibility Genes
A number of genes have become candidates as susceptibility genes, particularly those of the RAAS. A number of such genes were associated with hypertension and cardiovascular regulation in the pre-genomic era. Many associations have been described or imputed, including not only members of the RAAS but many other genes. For example, Izawa et al. [128] chose 27 candidate genes based on reviews of physiology and genetic data that looked at vascular biology, leukocyte and platelet biology, and glucose and lipid metabolism. They then also selected 33 SNPs of these genes, largely related in promoter regions, exons, or spliced donor or acceptor sites in introns and looked at their relationship to hypertension in a cohort of 1,940 persons. They found that polymorphisms in the CC chemokine receptor 2 gene were associated with hypertension in men and the TNF-alpha gene was associated with it in women [117]. In a GWAS in African Americans, Adeyemo et al. [137] suggested that pathway and network approaches might be helpful in identifying or prioritizing various loci.
Variants or Subphenotypes
If a particular variant of a complex disease is clinically distinct, then analysis of so-called subphenotypes via positional cloning may be potentially illuminating [3–5, 118, 120]. In such an instance, there may be fewer susceptibility genes involved. However, subphenotypes may be difficult to study, as the physiology involved may be intricate. An example would be salt-sensitive hypertension [118]. In order to study subjects, it is necessary to perform careful metabolic studies that confirm the subphenotype [hypertension with salt sensitivity] and also is standard during testing.
Present Implications for Pediatric Hypertension
A search for monogenic forms of hypertension is clearly indicated in an infant, child, or teenager with elevated BP and history or signs compatible with one of these diagnoses. If a child is found to have one of the rare forms of monogenic hypertension, there will be specific therapy. Few data, however, exist to guide the clinician in terms of the roles polygenic hypertension in children at the present time. Current approaches, summarized in Fig. 6.2 and in recent reviews [138–144], would still indicate that the concept of a complex set of interactions leads to most cases of hypertension.
Another approach worth mentioning is that of genome-wide admixture mapping – mapping by admixture linkage disequilibrium (MALD), which is used to detect genes in populations that are mixed, for example, where one group’s ancestors have more of a given disease than another group [139]. Using a moderate number single-nucleotide polymorphisms (SNPs), this method determines regions in the genome that contain more SNPs from one ancestral group as compared to the others. Then honing down on the area, genes of interest may be found. This approach is very appealing as a means by which to study hypertension in African Americans [145, 146]. For example, MALD was used to find a linkage peak in persons with African ancestry, which has turned up two apolipoprotein L1 (APOL1) variants in the coding region, as well as an adjacent area in the myosin heavy chain 9 gene (MYH9), which are associated with focal segmental glomerulosclerosis and hypertension.
There is no doubt that varied genetic mechanisms that lead to primary hypertension remain to be delineated. In the future gene-environment interactions, pathways that involve multiple gene products, as well as epigenetic phenomena, will be explored. Ultimately, there may be pharmacogenetic approaches by which therapy for hypertension may be individualized.
References
Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291:1304–51.
International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.
Delles C, Padmanabhan S. Genetics and hypertension: is it time to change my practice. Can J Cardiol. 2012;28:296–304.
Bogardus C, Baier L, Permana P, Prochazka M, Wolford J, Hanson R. Identification of susceptibility genes for complex metabolic diseases. Ann NY Acad Sci. 2002;967:1–6.
Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–7.
Wang DG, Fan J-B, Siao C-J, et al. Large-scale identification, mapping and genotyping of single-nucleotide polymorphisms in the human genome. Science. 1998;280:1077–82.
Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–56.
Dluhy RG. Screening for genetic causes of hypertension. Curr Hypertens Rep. 2002;4:439–44.
Wadei HM, Textor SC. The role of the kidney in regulating arterial blood pressure. Nat Rev Nephrol. 2012;8:602–9.
Yiu VW, Dluhy RG, Lifton RP, Guay-Woodford LM. Low peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol. 1997;11:343–6.
Wilson H, Disse-Nicodeme S, Choate K, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107–11.
Dluhy RG. Pheochromocytoma: the death of an axiom. N Engl J Med. 2002;346:1486–8.
Melcescu E, Phillips J, Moll G, Subauste JS, Koch CA. Syndromes of mineralocorticoid excess. Horm Metab Res. 2012;44:867–78.
Miura K, Yoshinaga K, Goto K, et al. A case of glucocorticoid-responsive hyperaldosteronism. J Clin Endocrinol Metab. 1968;28:1807.
New MI, Siegal EJ, Peterson RE. Dexamethasone-suppressible hyperaldosteronism. J Clin Endocrinol Metab. 1973;37:93.
Biebink GS, Gotlin RW, Biglieri EG, Katz FH. A kindred with familial glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab. 1973;36:715.
Grim CE, Weinberger MH. Familial dexamethasone-suppressible hyperaldosteronism. Pediatrics. 1980;65:597.
Oberfield SE, Levine LS, Stoner E, et al. Adrenal glomerulosa function in patients with dexamethasone-suppressible normokalemic hyperaldosteronism. J Clin Endocrinol Metabl. 1981;53:158.
Sutherland DJA, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966;95:1109.
New MI, Peterson RE. A new form of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1967;27:300.
Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. Chimeric 11β-hydroxylase/aldosterone synthase gene causes GRA and human hypertension. Nature. 1992;355:262–5.
Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthetase. Nat Genet. 1992;2:66–74.
Ulick S, Chu MD. Hypersecretion of a new cortico-steroid, 18-hydroxycortisol in two types of adrenocortical hypertension. Clin Exp Hypertens. 1982;4(9/10):1771–7.
Ulick S, Chu MD, Land M. Biosynthesis of 18-oxocortisol by aldosterone-producing adrenal tissue. J Biol Chem. 1983;258:5498–502.
Gomez-Sanchez CE, Montgomery M, Ganguly A, Holland OB, Gomez-Sanchez EP, Grim CE, et al. Elevated urinary excretion of 18-oxocortisol in glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab. 1984;59:1022–4.
Shackleton CH. Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research. J Steroid Biochem Mol Biol. 1993;45:127–40.
Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R. Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood. J Pediatr. 2001;138:715–20.
Kamrath C, Maser-Gluth C, Haag C, Schulze E. Diagnosis of glucocorticoid-remediable aldosteronism in hypertensive children. Horm Res Paediatr. 2011;76(2):93–8.
Fallo F, Pilon C, Williams TA, Sonino N, Morra Di Cella S, Veglio F. Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism. J Hum Hypertens. 2004;18:47–51.
Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). Med Genet. 2000;37:831–5.
Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharm Physiol. 1992;19:319–22.
Torpy DJ, Gordon RD, Lin JP, Huggard PR, Taymans SE, Stowasser M, et al. Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene. J Clin Endocr Metab. 1998;83:3214–8.
Jeske YW, So A, Kelemen L, Sukor N, Willys C, Bulmer B, et al. Examination of chromosome 7p22 candidate genes RBaK, PMS2 and GNA12 in familial hyperaldosteronism type II. Clin Exp Pharmacol Physiol. 2008;35:380–5.
Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, et al. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab. 2012;97:E1567–72.
Stowasser M, Pimenta E, Gordon RD. Familial or genetic primary aldosteronism and Gordon syndrome. Endocrinol Metab Clin N Am. 2011;40:343–68.
Geller DS, Zhang J, Wisgerhof MV, et al. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93:3117–23.
Choi M, Scholl UI, Bjorklund P, et al. K1 channel mutations in adrenal aldosterone producing adenomas and hereditary hypertension. Science. 2011;331:768–72.
Cerame BI, New MI. Hormonal hypertension in children: 11b-hydroxylase deficiency and apparent mineralocorticoid excess. J Pediatr Endocrinol. 2000;13:1537–47.
New MI, Levine LS, Biglieri EG, Pareira J, Ulick S. Evidence for an unidentified ACTH-induced steroid hormone causing hypertension. J Clin Endocrinol Metab. 1977;44:924–33.
New MI, Oberfield SE, Carey RM, Greig F, Ulick S, Levine LS. A genetic defect in cortisol metabolism as the basis for the syndrome of apparent mineralocorticoid excess. In: Mnatero F, Biglieri EG, Edwards CRW, editors. Endocrinology of hypertension, Serono Symposia, vol. 50. New York: Academic; 1982. p. 85–101.
Moudgil A, Rodich G, Jordan SC, Kamil ES. Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome. Pediatr Nephrol. 2000;15(1–2):60–2.
Mercado AB, Wilson RC, Chung KC, Wei J-Q, New MI. J Clin Endocrinol Metab. 1995;80:2014–20.
Ugrasbul F, Wiens T, Rubinstein P, New MI, Wilson RC. Prevalence of mild apparent mineralocorticoid excess in Mennonites. J Clin Endocrinol Metab. 1999;84:4735–8.
New MI, Nimkarn S, Brandon DD, Cunningham-Rundles S, Wilson RC, Newfield RS, Vandermeulen J, Barron N, Russo C, Loriaux DL, O’Malley B. Resistance to multiple steroids in two sisters. J Ster Biochem Molec Biol. 2001;76:161–6.
Li A, Li KXZ, Marui S, Krozowski ZS, Batista MC, Whorwood C, Arnhold IJP, Shackleton CHL, Mendonca BB, Stewart PM. Apparent mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state. J Hypertens. 1997;15:1397–402.
Coeli FB, Ferraz LF, Lemos-Marini SH, Rigatto SZ, Belangero VM, de Mello MP. Apparent mineralocorticoid excess syndrome in a Brazilian boy caused by the homozygous missense mutation p.R186C in the HSD11B2 gene. Arq Bras Endocrinol Metabol. 2008;52:1277–81.
Bailey MA, Paterson JM, Hadoke PW, Wrobel N, Bellamy CO, Brownstein DG, Seckl JR, Mullins JJ. A switch in the mechanism of hypertension in the syndrome of apparent mineralocorticoid excess. J Am Soc Nephrol. 2008;19:47–58. Epub 2007 Nov 21.
Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;289:119–23.
Rafestin-Oblin ME, Souque A, Bocchi B, Pinon G, Fagart J, Vandewalle A. The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related. Endocrinology. 2003;144:528–33.
Kamide K, Yang J, Kokubo Y, Takiuchi S, Miwa Y, Horio T, Tanaka C, Banno M, Nagura J, Okayama A, Tomoike H, Kawano Y, Miyata T. A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes. Hypertens Res. 2005;28:703–9.
Pinon GM, Fagart J, Souque A, Auzou G, Vandewalle A, Rafestin-Oblin ME. Identification of steroid ligands able to inactivate the mineralocorticoid receptor harboring the S810L mutation responsible for a severe form of hypertension. Mol Cell Endocrinol. 2004;217:181–8.
New MI, Wilson RC. Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess. PNAS. 1999;96:12790–7.
New MI, Seaman MP. Secretion rates of cortisol and aldosterone precursors in various forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1970;30:361.
New MI, Levine LS. Hypertension of childhood with suppressed renin. Endocrinol Rev. 1980;1:421–30.
New MI. Inborn errors of adrenal steroidogenesis. Mol Cell Endocrinol. 2003;211(1–2):75–83.
Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23:181–92.
Mimouni M, Kaufman H, Roitman A, Morag C, Sadan N. Hypertension in a neonate with 11 beta-hydroxylase deficiency. Eur J Pediatr. 1985;143:231–3.
Zachmann M, Vollmin JA, New MI, Curtius C-C, Prader A. Congenital adrenal hyperplasia due to deficiency of 11-hydroxylation of 17a-hydroxylated steroids. J Clin Endocrinol Metab. 1971;33:501.
White PC, Dupont J, New MI, Lieberman E, Hochberg Z, Rosler A. A mutation in CYP11B1 [Arg448His] associated with steroid 22-beta-hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest. 1991;87:1664–7.
Curnow KM, Slutker L, Vitek J, et al. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7 and 8. Proc Natl Acad Sci USA. 1993;90:4552–6.
Skinner CA, Rumsby G. Steroid 11 beta-hydroxylase deficiency caused by a 5-base pair duplication in the CYP11B1 gene. Hum Mol Genet. 1994;3:377–8.
Helmberg A, Ausserer B, Kofler R. Frameshift by insertion of 2 base pairs in codon 394 of CYP11B1 causes congenital adrenal hyperplasia due to steroid 11beta-hydroxylase deficiency. J Clin Endocrinol Metab. 1992;75:1278–81.
Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency. J Clin Invest. 1966;45:1946.
New MI. Male pseudohermaphroditism due to 17-alpha-hydroxylase deficiency. J Clin Invest. 1970;49:1930.
Mantero F, Scaroni C. Enzymatic defects of steroidogenesis: 17-alpha –hydroxylase deficiency. Pediatr Adol Endocrinol. 1984;13:83–94.
Rosa S, Duff C, Meyer M, Lang-Muritano M, Balercia G, Boscaro M, et al. P450c17 deficiency: clinical and molecular characterization of six patients. J Clin Endocrinol Metab. 2007;92:1000–7.
Mansfield TA, Simon DB, Farfel Z, Bia M, Tucci JR, Lebel M, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21. Nat Genet. 1997;16:202–5.
Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. Human hypertension caused by mutations in WNK Kinases. Science. 2001;293:1107–12.
Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wildtype but not mutant WNK4. Proc Natl Acad Sci USA. 2003;100:680–4.
Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003;111:1039–45.
Erdogan G, Corapciolgu D, Erdogan MF, Hallioglu J, Uysal AR. Furosemide and dDAVP for the treatment of pseudohypoaldosteronism type II. J Endocrinol Invest. 1997;20:681–4.
Liddle GW, Bledsoe T, Coppage WS. A familial renal disorder simulating primary aldosteronism with negligible aldosterone secretion. Trans Assoc Phys. 1963;76:199–213.
Wang C, Chan TK, Yeung RT, Coghlan JP, Scoggins BA, Stockigt JR. The effect of triamterene and sodium intake on renin, aldosterone, and erythrocyte sodium transport in Liddle’s syndrome. J Clin Endocrinol Metabol. 1981;52:1027–32.
Botero-Velez M, Curtis JJ, Warnock DG. Brief report: Liddle’s syndrome revisited- a disorder of sodium reabsorption in the distal tubule. N Engl J Med. 1994;330:178–81.
Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, et al. Liddle’s syndrome: heritable human hypertension caused y mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79:407–14.
Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995;11:76–82.
Rossier BC. 1996 Homer Smith Award Lecture: cum grano salis: the epithelial sodium channel and the control of blood pressure. J Am Soc Nephrol. 1997;8:980–92.
Eng C, Crossey PA, Milligan LM, et al. Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet. 1995;32:934–7.
Erickson D, Kudva YC, Ebersold MJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001;86:5210–6.
Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–51.
Gimm O, Armanios M, Dziema H, Neumann HPH, Eng C. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res. 2000;60:6822–5.
Aguiar RC, Cox G, Pomeroy SL, Dahia PL. Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J Clin Endocrinol Metab. 2001;86:2890–4.
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381–3.
Neumann HPH, Berger DP, Sigmund G, Blum U, Schmidt D, Parmer RJ, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993;329:1531–8.
Neumann HPH, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–66.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5.
Scheffler IE. Molecular genetics of succinate: quinone oxidoreductase in eukaryotes. Prog Nucleic Acid Res Mol Biol. 1998;60:267–315.
Ackrell BA. Progress in understanding structure-function relationships in respiratory chain complex II. FEBS Lett. 2000;466:1–5.
Bilginturan N, Zileli S, Karacadag S, Pirnar T. Hereditary brachydactyly associated with hypertension. J Med Genet. 1973;10:253–9.
Schuster H, Wienker TF, Bahring S, Bilginturan N, Toka HR, Neitzel H, et al. Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nat Genet. 1996;13:98–100.
Gong M, Zhang H, Schulz H, Lee A-A, Sun K, Bahring S, et al. Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum Molec Genet. 2003;12:1273–7.
Bahring S, Schuster H, Wienker TF, Haller H, Toka H, Toka O, et al. Construction of a physical map and additional phenotyping in autosomal-dominant hypertension and brachydactyly, which maps to chromosome 12. (Abstract). Am J Hum Genet. 1996; 59 (suppl.): A55 only.
Nagai T, Nishimura G, Kato R, Hasegawa T, Ohashi H, Fukushima Y. Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia-like syndrome. Am J Med Genet. 1995;55:16–8.
Bähring S, Kann M, Neuenfeld Y, Gong M, Chitayat D, Toka HR, et al. Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA. Hypertension. 2008;51:426–31.
Meirhaeghe A, Amouyel P. Impact of genetic variation of PPARgamma in humans. Mol Genet Metab. 2004;83:93–102.
Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3.
Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes. 2003;52:910–7.
Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408–11.
Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002;51:3586–90.
Wilson FH, Hariri A, Farhi A, Zhao H, Petersen KF, Toka HR, et al. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science. 2004;306:1190–4.
Harrap SB. Genetic analysis of blood pressure and sodium balance in the spontaneously hypertensive rat. Hypertension. 1986;8:572–82.
Rapp JP. Genetic analysis of inherited hypertension in the rat. Physiol Rev. 2000;80:135–72.
Delles C, McBride MW, Graham D, Padmanabhan S, Dominiczak A. Genetics of hypertension: from experimental animals to humans. Biochim Biophys Acta 2009 Dec 24. doi:10.1016/j.bbadis.2009.12.006 [epub ahead of print].
Doris PA. Hypertension genetics, SNPs, and the common disease: common variant hypothesis. Hypertension. 2002;39(Part 2):323–31.
Cvetkovic B, Sigmund CD. Understanding hypertension through genetic manipulation in mice. Kidney Int. 2000;57:863–74.
Gordon JW, Ruddle FH. Gene transfers into mouse embryos: production of transgenic mice by pronuclear integration. Methods Enzymol. 1983;101:411–33.
Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.
Capecchi MR. Altering the genome by homologous recombination. Science. 1989;244:1288–92.
Jacob HJ, Lindpaintner K, Lincoln SE, Kusumi K, Bunker RK, Mao YP, Ganten D, Dzau VJ, Lander ES. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991;67:213–24.
Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Soubrier F, Dubay C, Cartwright P, De Gouyon B, Julier C, Takahasi S, et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991;353:521–9.
Saavedra JM. Opportunities and limitations of genetic analysis of hypertensive rat strains. J Hypertens. 2009;27:1129–33.
Lalouel J-M, Rohrwasser A, Terreros D, Morgan T, Ward K. Angiotensinogen in essential hypertension: from genetics to nephrology. J Amer Soc Nephrol. 2001;12:606–15.
Zhu X, Yen-Pei CC, Yan D, Weder A, Cooper R, Luke A, et al. Associations between hypertension and genes in the renin-angiotensin system. Hypertension. 2003;41:1027–34.
Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, et al. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec family study. Circulation. 2000;102:1956–63.
Perola M, Kainulainen K, Pajukanta P, Terwillinger JD, Hiekkalinna T, Ellonen P, et al. Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings. J Hypertens. 2000;18:1579–85.
Pankow JS, Rose KM, Oberman A, Hunt SC, Atwood LD, Djousse L, et al. Possible locus on chromosome 18q influencing postural systolic blood pressure changes. Hypertension. 2000;36:471–6.
Krushkal J, Ferrell R, Mockrin SC, Turner ST, Sing CF, Boerwinkle E. Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation. 1999;99:1407–10.
Levy D, DeStefano AL, Larson MG, O’Donnell CJ, Lifton RP, Gavras H, et al. Evidence for a gene influencing blood pressure on chromosome 17: genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension. 2000;36:477–83.
Sharma P, Fatibene J, Ferraro F, Jia H, Monteith S, Brown C, et al. A genome-wide search for susceptibility loci to human essential hypertension. Hypertension. 2000;35:1291–6.
Xu X, Rogus JJ, Terwedow HA, Yang J, Wang Z, Chen C, et al. An extreme-sib-pair genome scan for genes regulating blood pressure. Am J Hum Genet. 1999;64:1694–701.
Wang DG, Fan J-B, Siao C-J, Berno A, Young P, Sapolsky R, et al. Large-scale identification, mapping and genotyping of single-nucleotide polymorphisms in the human genome. Science. 1998;280:1077–82.
The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928–33.
Harrap SB. Where are all the blood pressure genes? Lancet. 2003;361:2149–51.
Province MA, Kardia SLR, Ranade K, et al. A meta-analysis of genome-wide linkage scans for hypertension: the National Heart Lung and Blood Institute Family Blood Pressure Program. Am J Hypertens. 2003;16:144–7.
Caulfield M, Munroe P, Pembroke J, Samani N, Dominiczak A, Brown M, et al. Genome-wide mapping of human loci for essential hypertension. Lancet. 2003;361:2118–23.
Ehret GB, Morrison AC, O’Connor AA, Grove ML, Baird L, Schwander K, et al. Replication of the Wellcome Trust genome-wide association study of essential hypertension: the Family Blood Pressure Program. Eur J Hum Genet. 2008;16:1507–11.
Hong KW, Jin HS, Cho YS, Lee JY, Lee JE, Cho NH, et al. Replication of the Wellcome Trust genome-wide association study on essential hypertension in a Korean population. Hypertens Res. 2009;32:570–4.
Izawa H, Yamada Y, Okada T, Tanaka M, Hirayama H, Yokota M. Prediction of genetic risk for hypertension. Hypertension. 2003;41:1035–40.
Binder A. A review of the genetics of essential hypertension. Curr Opin Cardiol. 2007;22:176–84.
Hamet P, Seda O. The current status of genome-wide scanning for hypertension. Curr Opin Cardiol. 2007;22:292–7.
Martinez-Aguayo A, Fardella C. Genetics of hypertensive syndrome. Horm Res. 2009;71:253–9.
Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, et al. Framingham Heart study 100 k project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet. 2007;8 Suppl 1:S3.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527–34.
Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–76.
Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A. Genome-wide association of blood pressure and hypertension. Nat Genet. 2009;41:677–87.
Adeyemo A, Gerry N, Chen G, Herbert A, Doumatey A, Huang H. A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet. 2009;5:e1000564.
Delles C, McBride MW, Graham D, Padmanabhan S, Dominiczak AF. Genetics of hypertension: from experimental animals to humans. Biochim Biophys Acta. 1802;2010:1299–308.
Simino J, Rao DC, Freedman BI. Novel findings and future directions on the genetics of hypertension. Curr Opin Nephrol Hypertens. 2012;21(5):500–7.
Padmanabhan S, Newton-Cheh C, Dominiczak AF. Genetic basis of blood pressure and hypertension. Trends Genet. 2012;28:397–408.
Braun MC, Doris PA. Mendelian and trans-generational inheritance in hypertensive renal disease. Ann Med. 2012;44 Suppl 1:S65–73.
Hiltunen TP, Kontula K. Clinical and molecular approaches to individualize antihypertensive drug therapy. Ann Med. 2012;44 Suppl 1:S23–9.
Cowley AW, Nadeau JH, Baccarelli A, Berecek K, Fornage M, Gibbons GH, et al. Report of the NHLBI working group on epigenetics and hypertension. 2012; 59: 899–905
El Shamieh S, Visvikis-Siest S. Genetic biomarkers of hypertension and future challenges integrating epigenomics. Clin Chim Acta. 2012;414:259–65.
Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 2008;40:1175–84.
Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329:841–5.
New MI, Crawford C, Virdis R. Low Renin hypertension in childhood. In: Lifshitz F, editor. Pediatric endocrinology, Third Edition, Ch 53, p776
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ingelfinger, J.R. (2013). Monogenic and Polygenic Contributions to Hypertension. In: Flynn, J., Ingelfinger, J., Portman, R. (eds) Pediatric Hypertension. Clinical Hypertension and Vascular Diseases. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-490-6_6
Download citation
DOI: https://doi.org/10.1007/978-1-62703-490-6_6
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-489-0
Online ISBN: 978-1-62703-490-6
eBook Packages: MedicineMedicine (R0)