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• W2029552785 abstract "Computer screens of endless strings of four-lettered DNA can be translated to twenty-lettered proteins, but other as yet unknown translations will be necessary to convert this alphabetical soup to biology1.Fields S. The future is function.Nature Genet. 1997; 15: 325-327Crossref PubMed Scopus (0) Google Scholar. This review is addressed to clinical nephrologists with the aim of clarifying the breakthroughs that genetics may make in the understanding of essential hypertension. We summarize some of the research performed in genetic animal models of hypertension as well as in human hypertension, and compare the rat with the human data in an attempt to draw some general conclusions. A summary of the modern genetic strategies is provided that may be used to identify the genes responsible for essential hypertension, together with an explanation of the genetic terminology the non-specialist reader may find in dealing with the genetics of complex diseases (and specifically hypertension). Simple genetic diseases are not that simple, and hypertension is far more complex Though remarkable progress has been made in human genetics, it is becoming clearer each day that even the simplest genetic trait, that is, one caused by a monogenic disease, exhibits a bewildering complexity2.Alper J.S. Genetic complexity in single gene diseases. No simple link between genotype and phenotype.Brit Med J. 1996; 312: 196-197Crossref Google Scholar. Just as examples, three prototype diseases are briefly described. (1) Phenylketonuria, an inherited disease associated with severe mental retardation, is caused by a defect in the gene coding for phenylalanine hydroxylase. However, the enzyme deficiency is not enough to cause the disease. Exposure to dietary phenylalanine is also required. In fact, mental retardation does not occur if either factor (diet and abnormal enzyme) is missing3.Dilella A.G. Woo S.L.C. Molecular basis of phenylketonuria and its clinical applications.Mol Biol Med. 1987; 4: 183-192PubMed Google Scholar. Thus, an interaction with the appropriate environment is crucial for presentation of the phenotype. (2) Over 400 mutations of the cystic fibrosis gene have been described4.Wolf U. The genetic contribution to phenotype.Hum Genet. 1995; 95: 127-148Crossref PubMed Google Scholar, and while some are benign and of no clinical relevance, others cause more or less severe forms of the disease. This means that not all the mutations in the gene cause the disease and that different mutations in the same gene may cause a different severity of the disease. (3) Hereditary spastic paraplegia in its autosomal dominant form is a clinically homogeneous, inherited degenerative disorder of the motor system, but is genetically heterogeneous because in different families the disease-causing locus is attributed to different chromosomes, some still not identified. This suggests that there is a common pathway on which the different abnormal gene products must act. Any interruption of such a pathway by any of such defective genes may cause the same phenotypic expression of the disease5.Dubé M.P. Mlodzienski M.A. Kibar Z. Farlow M.R. Ebers G. Harper P. Klodny E.H. Rouleau G.A. Figlewicz D.A. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.Am J Hum Genet. 1977; 60: 625-629Google Scholar. More than 40 years of epidemiological studies have identified different environmental concomitants associated with the development of essential hypertension, and analysis of blood pressure in families has demonstrated that a substantial proportion of blood pressure variation among individuals is determined by genetic factors. There is no agreement on the proportion of blood pressure variability explained by genetic factors, but the general estimate is around 30 to 40%. However, simple biometric calculations by Cavalli Sforza and Bodmer demonstrated that it may be as much as 70 to 80%, about 40% of it due to dominance effect, which should indicate the existence of some major gene effect over a polygenic background6.Cavalli Sforza L.L. Bodmer W.F. The Genetics of Human Populations. WH Freeman Company, South San Francisco1971: 534-536Google Scholar. While much is understood about environmental factors, the genetic factors are still largely unknown. On the other hand, genetics (and molecular biology) permit the detection of the primary pathogenetic mechanisms of diseases by identification of the specific DNA segment that carries the pathogenic mutation, which should eventually allow reconstruction of the entire sequence of events from DNA mutation to the disease. The classical approach in a search for the pathogenetic mechanism of a disease is to go from the top of complexity, at the whole organism level, down to the DNA level by dissecting the disease phenotype into several intermediate phenotypes at the different levels of biological organization7.Camussi A. Bianchi G. Genetics of essential hypertension. From the unimodal-bimodal controversy to molecular technology.Hypertension. 1988; 12: 620-628Crossref PubMed Google Scholar. This top down approach (from the complexity of the phenotype to the simple DNA sequence alteration) has been fruitful, as it has led to the discovery of many genes that cause rare monogenic disorders. The situation is considerably more complicated in the case of common, complex diseases such as essential hypertension for several reasons. (1) Hypertension is caused by many genes with locus heterogeneity or inheritance that is polygenic or oligogenic. While there is general agreement that essential hypertension is caused by many genes, two alternatives are possible. Different forms of essential hypertension share only the same final phenotype but have different pathogenetic mechanisms. In this case only any one of the many possible mutated genes is needed to express the disease, as in the case of monogenic forms of hypertension8.Lifton R.P. Molecular genetics of human blood pressure variation.Science. 1996; 272: 676-680Crossref PubMed Google Scholar. Alternatively, more than one gene with at least one deleterious allele must be simultaneously present in an individual to cause essential hypertension. In the first case we are dealing with locus heterogeneity, in the second with polygenic or oligogenic inheritance. Both alternatives may be true for essential hypertension, although it is highly likely that it is polygenic and heterogeneous. In other words, the phenotype is determined by allelic variation at more than one gene at a time. Moreover, different sets of allelic variation of different genes may cause a similar final phenotype. To further complicate the picture, multigenic inheritance may be additive or epistatic. (2) Environmental factors. The environment can alter the sequence of events that lead from the primary DNA mutation to the final phenotype, and act at all the different levels of biological organization. (3) Compensatory factors. No biological function operates in a closed system, so any malfunctioning protein may influence (by inducing or inhibiting) transcription of other proteins, which in their turn may have an effect on the final phenotype, so that the pathogenic mutation of any gene may be obscured by the redundancy of compensatory mechanisms and the disease phenotype may be determined only by compensatory overexpression or inhibition of another gene, whose DNA sequence is indeed normal. Though the complexity of the picture may appear discouraging due to the large number of potential candidate genes and possible confounding interactions, among the many physiological and/or biochemical mechanisms that affect blood pressure only a relatively few are involved in its long-term control9.Guyton A.C. Hall J.E. Coleman T.J. Manning R.D.J. The dominant role of the kidneys in the long-term regulation of arterial pressure in normal and hypertensive states,.in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis and Management. Raven Press, New York1990: 1029-1052Google Scholar. Whatever the initiating event, some alteration in kidney function must occur to produce a permanent blood pressure increase. Guyton called this phenomenon the “overriding role of the kidney on blood pressure control”9.Guyton A.C. Hall J.E. Coleman T.J. Manning R.D.J. The dominant role of the kidneys in the long-term regulation of arterial pressure in normal and hypertensive states,.in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis and Management. Raven Press, New York1990: 1029-1052Google Scholar. Recent findings on the genetics of essential hypertension seem to support this notion. Among the few loci or genes associated with blood pressure regulation in humans or rats found thus far, most are directly or indirectly involved in the renal control of sodium balance8.Lifton R.P. Molecular genetics of human blood pressure variation.Science. 1996; 272: 676-680Crossref PubMed Google Scholar. Of course, this does not exclude the possibility that other genetic defects operating through non-renal mechanisms may be discovered in the future, but it underlines the importance of the renal genetic-molecular mechanisms of essential hypertension. This importance is also supported by the overwhelming amount of data, collected over a period of more than 30 years, that deal with the crucial interaction between body sodium and renin in determining the final level of blood pressure and kidney function. Careful studies of sodium handling by the kidney, the renin-angiotensin system, the pressor response to sodium load or depletion, or to other aspects of renal function under different experimental conditions may help to cluster hypertensive patients into discrete subgroups whose members should should all have the same, more clearly identifiable renal genetic-molecular mechanisms10.Sharma A.M. Salt sensitivity as a phenotype for genetic studies of human hypertension.Nephrol Dial Transplant. 1996; 11: 927-929Crossref Google Scholar. This consideration underlines the crucial role that the clinical and experimental nephrologist may play in clarifying the pathogenetic mechanisms of essential hypertension. STRATEGIES FOR IDENTIFYING THE GENETIC MECHANISMS OF ESSENTIAL HYPERTENSION How to search and what to search for When two alleles of two different genes are located in close proximity on the same chromosome, there is only a small chance that recombination will occur between them and thay are said to be in linkage dysequilibrium (or to be associated). The position of a gene on a chromosome is called its “locus.” In modern terminology a locus comprises not only genes but also genetic units without a known function. The concept of linkage dysequilibrium can also be applied to phenotypes. When two phenotypes occur together in the same individual more often than expected by chance, as for the type A blood group and cancer of the stomach11.Beckman L. Ängqvist K.A. On the mechanism behind association between ABO blood groups and gastric carcinoma.Hum Hered. 1987; 37: 140-143Crossref Scopus (10) Google Scholar, they are said to be associated or to be in linkage dysequilibrium. One of several possibilities is tight linkage of the two genes that determine the two associated phenotypes. Taken in its broadest sense, the term linkage dysequilibrium is now currently employed to indicate that a certain locus is associated with a certain disease [reviewed in12.Ott J. Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore and London1991Google Scholar. When used in this way, it indicates that the occurrence of a particular genotype for a locus occurs more often than expected when the disease under investigation is present. This only signifies that the locus is of interest, that is, that a gene possibly involved in the pathogenesis of the disease is located in proximity to the identified locus, whereas the observed genotype is only a “genetic” marker of the disease but does not allow any speculation on which is the gene that determines the disease. A genetic marker is thus any identifiable DNA segment that may be in linkage dysequilibrium with the disease of interest. A marker can be a particular variant or allele of any DNA segment or gene that is in tight linkage with the disease allele. Currently the most used DNA markers are anonymous polymorphic DNA markers that are widely and homogeneously distributed across the whole genome. They are derived from repetitive sequence elements based either on short (microsatellite) or longer (minisatellite) domains that are repeated in tandem. There are numerous possible alleles for such markers (up to 30 to 40), which are thus highly polymorphic. Such a large number of alleles has a practical utility for geneticists, as they provide the possibility of observing transmission of the marker with that of the phenotype under investigation. Two conceptually different approaches may be employed in the study of genetic determinants of essential hypertension. The first is the candidate gene approach, which takes advantage of polymorphism in genes that encode proteins of known or suspected importance in blood pressure regulation. The cosegregation with blood pressure of a candidate gene variant or of an allele of any kind of DNA marker (allele of any known gene, RFLP, mini- or microsatellite) mapping within or very close to the candidate gene is considered good evidence for a pathogenic role of the gene under investigation, particularly when functional alteration of the candidate gene function is also demonstrated. The second approach, random genome scanning, also may use anonymous polymorphic DNA markers as well as known variants of known genes, but it tests many markers in the same population without previous assumptions on which is or where is the disease gene. An identified genetic locus influencing a quantitative trait such as blood pressure is called quantitative trait locus (QTL)13.Rapp J.P. Deng A.Y. Detection and positional cloning of blood pressure quantitative trait loci: Is it possible?.Hypertension. 1995; 25: 1121-1128Crossref PubMed Google Scholar. It is important to remember that when blood pressure QTLs are being sought by genome scanning, a very large number of loci are evaluated in the same experimental unit. To avoid numerous false positives, such experiments should set a significance level in the range of P < 10-514.Lander E. Kruglyak L. Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results.Nature Genet. 1995; 11: 241-247Crossref PubMed Google Scholar, although there is no general consensus on such stringent criteria. At present no agreement exists as to the most suitable kind of sample to study and genetic strategy to adopt in order to identify the genes that cause essential hypertension. Two distinct general strategies are available: linkage analysis and association analysis. Each one has specific advantages and drawbacks. Both linkage and association methodologies are powerful and useful to detect and map genes potentially responsible for many human disorders. There are major differences in the particular “material” used as linkage analyses are applied to families and associations to the general population. Although linkage studies are powerful methods for detecting disease loci, they depend heavily on the a priori hypothesis that a single major locus is responsible for susceptibility to the disease and, moreover, they are sensitive to errors in parameters used in the genetic model, unless nonparametric approaches are used. On the other hand, as essential hypertension is a multifactorial disease, the genetic association strategy has the advantage of being able to detect not only major gene effects but also minor ones, which may not be revealed by linkage analyses. A conspicuous drawback of association analysis is that it is much more sensitive to increases in genetic distance of the marker from the disease locus, making it more suitable to test candidate genes than to perform a complete genome scan, which would require an immensely large (and dense) number of markers15.Kidd K.K. Associations of disease with genetic marker: Déjà vu all over again.Am J Med Genet. 1993; 48: 71-73Crossref PubMed Google Scholar. Furthermore, particularly in the case of essential hypertension, precise definition of the control sample is critical. This is the weakest point of any association study, as the gross phenotypic definition of “healthy” or “not affected” may not be precise enough due to the heterogenous polymorphic etiology of a complex, multifactorial trait. Genetic analysis of essential hypertension, as that of any other complex disease, suffers from three fundamental complications. (1) Each gene may have only a small quantitative effect on the disorder. This implies that the relative risk for the genotype, that is, the increased chance that an individual with a particular genotype for a particular allele has the disease, is small and that a substantial number of nonaffected individuals can be found with the genotype of the affected ones. Risch and Merikangas recently considered this problem in detail and concluded that linkage analysis has only a limited power to detect genes of modest effect such as those that are implicated in the pathogenesis of essential hypertension. Their argument is that, for alleles occurring with a relatively high frequency in the population and yet confer a relatively small genotype risk, linkage analysis provides few chances to identify disease loci because the number of families required, several hundreds to thousands, is currently far beyond anyone's ability16.Risch N. Merikangas K. The future of genetic studies of complex human diseases.Science. 1996; 273: 1516-1517Crossref PubMed Google Scholar. (2) It is likely that essential hypertension is genetically heterogeneous. However, all linkage methods focus on a single locus at one time in the expectation (hope) that if that locus “accounts for a high enough proportion of cases it can be detected”17.Kidd K.K. Can we find genes for schizophrenia?.Am J Med Genet (Neuropsych Genet. 1977; 74: 104-111Crossref Google Scholar. Statistical tests for heterogeneity should thus be used before rejecting the hypothesis of linkage for a candidate gene. (3) Epistasis is very likely to be present in essential hypertension. Frankel and Schork have recently discussed two examples of epistatic interaction in determining cancer susceptibility in mice18.Frankel W.N. Schork N.J. Who's afraid of epistasis?.Nature Genet. 1996; 14: 371-373Crossref PubMed Google Scholar. In both cases, there was evidence for a two-locus system in which neither locus had an effect per se, and neither would be detectable with standard linkage designs19.Fijneman R.J.A. De Vries S.S. Jansen R.C. Demant P. Complex interactions of new quantitative trait loci, Sulc1, Sulc2, Sulc3, Sulc4, that influence the susceptibility to lung cancer in the mouse.Nature Genet. 1996; 14: 465-467Crossref PubMed Scopus (0) Google Scholar,20.Van Vezel T. Stassen A.P.M. Moen C.J.A. Hart A.A.M. Van der Valk M.A. Demant P. Gene interaction and single gene effects in colon tumor susceptibility in mice.Nature Genet. 1996; 14: 468-470Crossref Scopus (113) Google Scholar. Monogenic forms of human hypertension Monogenic forms of human hypertension are very rare syndromes in which mutations in single genes are sufficient to produce large blood pressure changes. Although this review is concerned with essential hypertension, a brief description of monogenic forms of hypertension is included, as knowledge of these forms may provide new insights into blood pressure regulation. A recent review on this topic is in8.Lifton R.P. Molecular genetics of human blood pressure variation.Science. 1996; 272: 676-680Crossref PubMed Google Scholar. Liddle's syndrome. Liddle's syndrome is an autosomal dominant form of salt-sensitive hypertension characterized by early onset, hypokalemia, and low renin and aldosterone levels. It can be treated by salt restriction and amiloride (the selective inhibitor of the epithelial Na channel). A linkage study in Liddle's original pedigree demonstrated linkage to a segment of chromosome 16 containing two genes, the β and γ subunits of the epithelial Na channel, which were considered plausible candidates because sodium reabsorption through this channel is one of the major determinants of tubular sodium reabsorption21.Shimkets R.A. Warnock D.G. Bositis C.M. Nelson-Williams C. Hansson H.H. Schambelan M. Gill J.R. Ulick S. Milora R.V. Findling J.V. Canessa C.M. Rossier B.C. Lifton R.P. Liddle's syndrome: Heritable human hypertension caused by mutations in the b subunit of the epithelial sodium channel.Cell. 1994; 79: 407-414Abstract Full Text PDF PubMed Scopus (986) Google Scholar. Different mutations causing truncation of the cytoplasmic C-terminus of the β or γ subunit have subsequently been described as responsible for Liddle's syndrome in different pedigrees22.Hansson J. Nelson-Williams C. Suzuki H. Schild L. Shimkets R. Lu Y. Canessa C. Iwasaki T. Rossier B. Lifton R. Hypertension caused by a truncated epithelial sodium channel γ subunit: Genetic heterogeneity of Liddle's syndrome.Nature Genet. 1995; 11: 76-80Crossref PubMed Scopus (580) Google Scholar, 23.Hansson J. Schild L. Lu Y. Wilson T. Gautschi I. Shimkets R. Canessa C. Nelson-Williams C. Rossier B. Lifton R. A de novo missense mutation of the β subunit of the epithelial sodium channel causes hypertension and Liddle's syndrome and identifies a proline riche segment of the protein critical for regulation of channel activity.Proc Natl Acad Sci USA. 1995; 92: 11495-11499Crossref PubMed Scopus (277) Google Scholar, 24.Jeunemaitre X. Bassilana F. Persu A. Dumont C. Chamigny G. Lanzdunski M. Corvol P. Barbry P. Genotype-Phenotype analysis of an newly discovered family with Liddle's syndrome.J Hypertens. 1997; 15: 1091-1100Crossref PubMed Scopus (67) Google Scholar. In all cases, premature truncation of the cytoplasmic C-terminus of either the β or γ subunit results in constitutive activation of the channel (that is, loss of normal negative regulation of the channel, and hence increased net renal sodium reabsorption). The critical role of the epithelial Na channel in maintaining salt and extracellular fluid balance and controlling blood pressure is confirmed by the finding of different mutations in both the α or β subunits, either of which cause pseudohypoaldosteronism type I, a rare autosomal recessive disease characterized by neonatal salt wasting, low blood pressure, hyperkalemia and metabolic acidosis. Sodium is lost as the mutations cause a striking decrease in the opening time of the Na channel (and hence of the sodium reabsorbed)25.Grunder S. Firsov D. Chang S.S. Jaeger N.F. Gautschi I. Schild L. Lifton R.P. Rossier B.C. A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel.EMBO J. 1997; 16: 899-907Crossref PubMed Scopus (138) Google Scholar. Pseudohypoaldosteronism type II or Gordon's syndrome. This is another rare form of dominant familial hypertension with low renin, high serum K, normal glomerular filtration rate and good response to salt restriction and/or thiazide diuretic treatment. Linkage analysis demonstrated locus heterogeneity, with in some families significant linkage to chromosome 17q2126.Mansfield T.A. Simon D.B. Farfel Z. Bia M. Tucci J.R. Lebel M. Gutkin M. Vialettes B. Christofilis M.A. Kauppinen-Makelin R. Mayan H. Risch N. Lifton R.P. Multilocus linkage of familial hyperkalaemia and hypertension. pseudohypoaldosteronism type II, to chromosomes 1q31–42 and 17p11–q21.Nature Genet. 1997; 16: 202-205Crossref PubMed Scopus (164) Google Scholar, which is syntenic with a segment of rat chromosome 10 that contains at least one or two blood pressure QTLs (see below). Apparent mineralocorticoid excess. Apparant mineralocorticoid excess (AME) is an autosomal recessive form of hypertension, phenotypically similar to Liddle's syndrome (low renin and low aldosterone levels) but responsive to mineralocorticoid (type 1) receptor inhibition by spironolactone. Different mutations in the gene of the 11β-hydroxysteroid dehydrogenase kidney isozyme cause different degrees of loss of function of the enzyme. The kidney isozyme of 11β-hydroxysteroid dehydrogenase is expressed in distal and cortical collecting tubules, where the mineralocorticoid receptor is also present. It converts cortisol to cortisone, which has no mineralocorticoid activity, at the pre-receptor level. When the enzymatic activity is defective, normal circulating cortisol can thus produce a large mineralocorticoid effect by direct stimulation of the mineralocorticoid receptor27.Mune T. Rogerson F.M. Nikkila H. Agarwal A.K. White P.C. Human hypertension caused by mutations in the kidney isozyme of 11Β-hydroxysteroid dehydrogenase.Nature Genet. 1995; 10: 394-399Crossref PubMed Google Scholar,28.Mune T. White P.C. Apparent mineralocorticoid excess. Genotype is correlated with biochemical phenotype.Hypertension. 1996; 27: 1193-1199Crossref PubMed Google Scholar. Due to the enzyme defect, affected patients have an elevated urinary tetrahydrocortisol + allo-tetrahydrocortisol to tetrahydrocortisone ratio. Recently, a heterozygous hypertensive father of an affected homozygous proband has been described in a Brazilian kindred29.Li A. Li K.X.Z. Marui S. Krozowski Z.S. Batista M.C. Whorwood Z.S. Arnhold I.J.P. Schackelton C.H.L. Mendonca B.B. Stewart P.M. Apparent mineralocorticoid excess in a Brazilian kindred: Hypertension in the heterozygote state.J Hypertens. 1997; 15: 1397-1402Crossref PubMed Scopus (58) Google Scholar. The interest of this case is that the father, who also has an altered urinary steroid ratio, had previously been defined as having essential hypertension, although with low renin and aldosterone levels and a suboptimal response to conventional antihypertensive treatment (diuretics + β-blockers). As the urinary steroid ratio has also been reported as abnormal in some essential hypertensive individuals30.Soro A. Ingram M.C. Tonolo G. Glorioso N. Fraser R. Evidence of coexisting changes in 11Β-hydroxysteroid dehydrogenase and 5α-reductase activity in patients with untreated essential hypertension.Hypertension. 1995; 25: 67-70Crossref PubMed Google Scholar, it is possible that subtle defects in 11β-hydroxysteroid dehydrogenase activity also play a role in essential hypertension. Glucocorticoid remediable aldosteronism. Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant form of hypertension with low renin but high aldosterone levels, whose secretion is controlled by ACTH and not by angiotensin II. The disease is caused by unequal crossing-over of chromosome 8 between the aldosterone synthase and 11β-hydroxylase genes, which are tightly linked. The crossing-over produces a novel chimeric gene, which contains the proximal (regulatory) sequence of 11β-hydroxylase and the distal (coding) sequence of aldosterone synthase. In this way the chimeric gene is under the control of ACTH but its gene product has aldosterone synthase activity31.Lifton R.P. Dluhy R.G. Powers M. Rich G.M. Cook S. Ulick S. Lalouel J.M. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.Nature. 1992; 1355: 262-265Crossref Scopus (765) Google Scholar,32.Lifton R.P. Dluhy R.G. Powers M. Rich G.M. Gutkin M. Fallo F. Gill J.R. Feld L. Ganguly A. Laidlaw J.C. Murnaghan D.J. Kaufman C. Stockgit J.R. Ulick S. Lalouel J.M. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.Nature Genet. 1992; 2: 66-74Crossref PubMed Google Scholar. The rat as a reductionist model for human hypertension For a long time research on the pathogenetic mechanisms of hypertension focused only on the search for biochemical/physiological differences between hypertensive and normotensive humans or between spontaneously hypertensive rats and their respective normotensive control strains. Many differences were found and many biochemical/physiological mechanisms for hypertension have been proposed. Probably much of that work did not yield meaningful conclusions because, in the case of humans, the population of hypertensives is too heterogeneous and, in the case of rats, many of the observed differences between hypertensive and control strains were simply due to chance selection and fixation of specific biochemical/physiological traits rather than real causal differences relevant to the pathogenesis of hypertension. Modern genetic strategies are thus based on the search for QTLs, that is, not for the disease gene itself but for an indication of its approximate location. Unfortunately, the relative proximity of a QTL to the disease gene may mean up to 50 to 100 genes. Rapp has proposed a series of fixed rules (a paradigm) to test whether a given trait may be important in explaining a blood pressure difference between cases and controls: (1) the trait must be different in hypertensives and normotensives; (2) it must follow the Mendelian inheritance pattern; (3) the genes that affect the trait must cosegregate with significant blood pressure differences; and (4) it must be possible to show some logical biochemical or physiological link between the identified trait and blood pressure33.Rapp J.P. Genetics of experimental and human hypertension,.in: Genest J. Kuchel O. Hamet P. Cantin M. Hypertension: Physiopathology and Treatment. 2nd ed. Mc-Graw Hill, New York1983Google Scholar,34.Rapp J.P. A paradigm for identification primary genetic causes of hypertension in rats.Hypertension. 1983; 5: 198-203Crossref PubMed Google Scholar. A fifth corollary rule could be the con" @default.
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• W2029552785 title "A primer on the genetics of hypertension" @default.
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