A Genetic Predisposition to Hypertension?
2004; Lippincott Williams & Wilkins; Volume: 44; Issue: 1 Linguagem: Inglês
10.1161/01.hyp.0000134531.28796.32
ISSN1524-4563
Autores Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 44, No. 1A Genetic Predisposition to Hypertension? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Genetic Predisposition to Hypertension? David S. Geller David S. GellerDavid S. Geller From the Section of Nephrology, Yale University School of Medicine, New Haven, Conn. Originally published14 Jun 2004https://doi.org/10.1161/01.HYP.0000134531.28796.32Hypertension. 2004;44:27–28Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 14, 2004: Previous Version 1 Hypertension is a majorpublic health problem, and yet, the molecular mechanisms underlying hypertension are poorly understood in the majority of patients. A complex disorder, both environmental and genetic factors predispose individuals to hypertension. Whereas we know much about environmental factors, such as salt intake and exercise, that affect blood pressure, we know less about genetic factors that predispose individuals to hypertension. In recent years, there has been great progress in elucidating the molecular basis of monogenic disorders with primary effect on blood pressure, and this work has clarified many aspects of blood pressure regulation.1 Among the most significant findings from this work has been that all known single-gene disorders with primary effect on blood pressure act via a single final common pathway-alteration of renal sodium reabsorption. These studies mirror what has been observed in acquired forms of hypertension, which uniformly feature increased sodium reabsorption as well. The sum of these findings is consistent with a large body of physiological work and animal studies drawing on the pioneering work of Arthur Guyton, who proposed that sustained hypertension ultimately required the active participation of the kidney.2 The finding that all known inherited and acquired forms of hypertension ultimately operate via the same common pathway has led to the proposal that common forms of hypertension will feature perturbations in this pathway as well.1Although such work has greatly expanded our understanding of molecular mechanisms underlying hypertension, pathways determining this genetic predisposition to hypertension in the general population remain unknown. In recent years, there has been much effort expended in this area. One area of investigation has focused on association studies, in which various genomic polymorphisms are linked genetically to hypertensive phenotypes. Literally hundreds, if not thousands, of such studies have been reported, but, unfortunately, little real insight into underlying pathogenetic mechanisms has been gleaned from such studies.3 Frequent problems with such studies include, but are not restricted to, issues with population stratification, insufficient sample size, and a lack of replication in independent populations or in family based transmission disequilibrium studies. Genome-wide linkage studies have also been performed, and these have linked regions on chromosome 12p and 17q to hypertension in large cohort studies;4,5 these loci are intriguing because they have previously been linked to monogenic blood pressure disorders as well.6–8 Nevertheless, no precise genetic polymorphism affecting blood pressure has been identified at these sites to date, and so the link between genetic polymorphism and sustained rise in blood pressure remains elusive.In the June issue of Hypertension, Jeck et al assessed a possible association between essential hypertension and the common T481S variant in the ClC-Kb channel.9 In contrast to studies in which random single-nucleotide polymorphisms in genes thought relevant to hypertension are screened, this polymorphism was carefully chosen for its potential effect on renal sodium reabsorption. ClC-Kb is central to renal sodium reabsorption in the loop of Henle and distal-convoluted tubule, providing the route by which the transport partner of sodium, chloride, exits the cell through the basolateral membrane. The significance of this channel to renal sodium conservation is demonstrated by the finding that patients lacking this channel have Bartter syndrome type III, characterized by salt-wasting and hypotension.10 Intriguingly, the T481S substitution examined by Jeck et al is present in 20% to 40% of the population and induces a 7-fold increase in Cl− transport by this channel in Xenopus oocytes.11 The authors therefore ask whether the T481S variant might increase distal renal sodium reabsorption and thereby increase blood pressure in humans. Interestingly, they found that age-adjusted mean arterial pressure in a German study group is approximately 4 mm Hg higher in carriers of the T481S allele than in wild-type individuals (P=0.015); furthermore, they found that the prevalence of hypertension (defined as blood pressure >140/90) is significantly higher in T481S carriers than in wild-type individuals (P=0.0.011). They thus propose that the T481S variant leads to increased renal salt retention and consequent elevation of blood pressure.If this suggestion proves correct, it would be an important step forward in our understanding of blood pressure regulation in the general population. Physiologically, it would suggest that sodium transport in the loop of Henle and distal-convoluted tubule is rate-limited in part by basolateral chloride transport. Clinically, one might expect that hypertensive carriers of the T481S variant would derive particular benefit from thiazide or loop diuretics, which could override the effects of an overactive ClC-Kb channel.Before we can recommend genotyping all hypertensive patients for the T481S allele, however, it is important to remember the high rate of false-positive results in single-nucleotide polymorphism association studies.12 Although the study by Jeck et al does avoid 1 common pitfall of this type of association study, the problem of multiple associations testing, the authors have not effectively ruled out another common problem in this sort of analysis, the problem of population stratification. Population stratification occurs when unidentified ethnic subpopulations within the study group are responsible for the differences observed, providing a relatively trivial explanation for the study's findings.13 The authors have tried to limit the probability of population stratification within their study by noting that there is no evidence for stratification at the multidrug resistance 1 (MDR1) locus, but recent data suggest that ruling out population stratification is difficult even in well planned studies and requires much more thorough analysis.13 This is especially relevant in studies in which only borderline statistical significance is achieved, as is the case here. Methods exist to detect and correct for population stratification. For example, multilocus genotypes can be generated to identify individuals with different ancestries, providing a method to adjust for ancestry in the association analysis.13,14 Furthermore, genomic control methods use independent marker loci to quantitatively assess the degree of stratification and adjust test statistics accordingly.13,15 Unfortunately, for studies such as this report by Jeck et al,9 where only borderline significance is achieved, the number of independent loci that must be genotyped to effectively rule out population stratification is large.13The identification of genetic factors that predispose individuals to hypertension remains an important goal as we seek improved methods to diagnose and treat hypertension and its coincident morbidities. The demonstration by Jeck et al that the ClC-KbT481S polymorphism cosegregates with high blood pressure is an intriguing preliminary finding, but the use of the word "preliminary" is essential for now. It will be necessary to replicate this result in large independent populations to clarify the effect of the ClC-KbT481S variant on blood pressure.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This is an editorial commentary for Jeck N, Waldegger S, Lampert A, Boehmer C, Waldegger P, Lang PA, Wissinger B, Friedrich B, Risler T, Moehle R, Lang UE, Zill P, Bondy B, Schaeffeler E, Schwab M, Seyberth H, Lang F. Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. Hypertension. 2004;43:1175–1181.D.G. is supported by National Institutes of Health grants K08-DK02765 and P50-HL55007.FootnotesCorrespondence to David S. Geller, PO Box 208029, New Haven, CT 06520-8029. E-mail [email protected] References 1 Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001; 104: 545–556.CrossrefMedlineGoogle Scholar2 Guyton AC. Blood pressure control-special role of the kidneys and body fluids. Science. Jun 28. 1991; 252: 1813–1816.CrossrefMedlineGoogle Scholar3 Luft FC. Present status of genetic mechanisms in hypertension. Med Clin North Am. Jan 2004; 88: 1–18, vii.CrossrefMedlineGoogle Scholar4 Gong M, Zhang H, Schulz H, Lee YA, Sun K, Bahring S, Luft FC, Nurnberg P, Reis A, Rohde K, Ganten D, Hui R, Hubner N. Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum Mol Genet. 2003; 12: 1273–1277.CrossrefMedlineGoogle Scholar5 Levy D, DeStefano AL, Larson MG, O'Donnell CJ, Lifton RP, Gavras H, Cupples LA, Myers RH. 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: 477–483.CrossrefMedlineGoogle Scholar6 Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human hypertension caused by mutations in WNK kinases. Science. 2001; 293: 1107–1112.CrossrefMedlineGoogle Scholar7 Schuster H, Wienker TE, Bahring S, Bilginturan N, Toka HR, Neitzel H, Jeschke E, Toka O, Gilbert D, Lowe A, Ott J, Haller H, Luft FC. Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nat Genet. 1996; 13: 98–100.CrossrefMedlineGoogle Scholar8 Mansfield TA, Simon DB, Farfel Z, Bia M, Tucci JR, Lebel M, Gutkin M, Vialettes B, Christofilis MA, Kauppinen-Makelin R, Mayan H, Risch N, Lifton RP. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31–42 and 17p11–q21. Nature Genetics. 1997; 16: 202–205.CrossrefMedlineGoogle Scholar9 Jeck N, Waldegger S, Lampert A, Boehmer C, Waldegger P, Lang PA, Wissinger B, Friedrich B, Risler T, Moehle R, Lang UE, Zill P, Bondy B, Schaeffeler E, Schwab M, Seyberth H, Lang F. Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. Hypertension. 2004; 43: 1175–1181.LinkGoogle Scholar10 Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet. 1997; 17: 171–178.CrossrefMedlineGoogle Scholar11 Jeck N, Waldegger P, Doroszewicz J, Seyberth H, Waldegger S. A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Kidney Int. 2004; 65: 190–197.CrossrefMedlineGoogle Scholar12 Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003; 33: 177–182.CrossrefMedlineGoogle Scholar13 Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D. Assessing the impact of population stratification on genetic association studies. Nat Genet. 2004; 36: 388–393.CrossrefMedlineGoogle Scholar14 Pritchard JK, Stephens M, Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000; 155: 945–959.CrossrefMedlineGoogle Scholar15 Pritchard JK, Donnelly P. Case-control studies of association in structured or admixed populations. Theor Popul Biol. 2001; 60: 227–237.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Devuyst O, Zennaro M, Vargas-Poussou R and Satlin L (2021) Inherited Disorders of Sodium and Potassium Handling Pediatric Nephrology, 10.1007/978-3-642-27843-3_108-1, (1-45), . Devuyst O, Belge H, Konrad M, Jeunemaitre X and Zennaro M (2016) Renal Tubular Disorders of Electrolyte Regulation in Children Pediatric Nephrology, 10.1007/978-3-662-43596-0_34, (1201-1271), . Devuyst O, Belge H, Konrad M, Jeunemaitre X and Zennaro M (2015) Renal Tubular Disorders of Electrolyte Regulation in Children Pediatric Nephrology, 10.1007/978-3-642-27843-3_34-1, (1-80), . Mount D (2012) Transport of Sodium, Chloride, and Potassium Brenner and Rector's The Kidney, 10.1016/B978-1-4160-6193-9.10005-3, (158-201), . Yagil C and Yagil Y (2010) The Genomics of Hypertension Essentials of Genomic and Personalized Medicine, 10.1016/B978-0-12-374934-5.00022-2, (259-268), . Yagil C and Yagil Y (2009) The Genomics of Hypertension Genomic and Personalized Medicine, 10.1016/B978-0-12-369420-1.00054-8, (624-633), . Devuyst O, Konrad M, Jeunemaitre X and Zennaro M (2009) Tubular Disorders of Electrolyte Regulation Pediatric Nephrology, 10.1007/978-3-540-76341-3_38, (929-977), . Stover P (2016) Human Nutrition and Genetic Variation, Food and Nutrition Bulletin, 10.1177/15648265070281S109, 28:1_suppl1, (S101-S115), Online publication date: 1-Mar-2007. Flatman P (2007) Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation, Clinical Science, 10.1042/CS20060225, 112:4, (203-216), Online publication date: 1-Feb-2007. Jentsch T (2005) Chloride Transport in the Kidney: Lessons from Human Disease and Knockout Mice, Journal of the American Society of Nephrology, 10.1681/ASN.2005020207, 16:6, (1549-1561), Online publication date: 1-Jun-2005. Jentsch T, Neagoe I and Scheel O (2005) CLC chloride channels and transporters, Current Opinion in Neurobiology, 10.1016/j.conb.2005.05.002, 15:3, (319-325), Online publication date: 1-Jun-2005. Briet M, Vargas-Poussou R, Lourdel S, Houillier P and Blanchard A (2006) How Bartter's and Gitelman's Syndromes, and Dent's Disease Have Provided Important Insights into the Function of Three Renal Chloride Channels: ClC-Ka/b and ClC-5, Nephron Physiology, 10.1159/000090218, 103:1, (p7-p13) July 2004Vol 44, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/01.HYP.0000134531.28796.32PMID: 15197171 Originally publishedJune 14, 2004 PDF download Advertisement
Referência(s)