Dissecting Hypertension by Obesity Identifies a Locus at 1p36
2005; Lippincott Williams & Wilkins; Volume: 46; Issue: 6 Linguagem: Inglês
10.1161/01.hyp.0000188055.13764.dc
ISSN1524-4563
Autores Tópico(s)Diet, Metabolism, and Disease
ResumoHomeHypertensionVol. 46, No. 6Dissecting Hypertension by Obesity Identifies a Locus at 1p36 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDissecting Hypertension by Obesity Identifies a Locus at 1p36 Brian J. Morris Brian J. MorrisBrian J. Morris From the Basic & Clinical Genomics Laboratory, School of Medical Sciences and Institute for Biomedical Research, The University of Sydney, Australia. Originally published17 Oct 2005https://doi.org/10.1161/01.HYP.0000188055.13764.dcHypertension. 2005;46:1256–1258Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 17, 2005: Previous Version 1 The elevated arterial pressure that defines essential hypertension is regarded as the manifestation of a diverse array of interacting genetic and environmental causes. As such, hypertension is a heterogeneous disorder in which multiple contributing factors are responsible for the overarching phenotype of high blood pressure that is the primary clinical manifestation observed. Such heterogeneity has undoubtedly hampered efforts to elucidate the genetic basis of essential hypertension.Overweight and obesity are well known to increase the risk of essential hypertension. Yet, there are many hypertensive individuals whose weight is normal. So does obesity hypertension have a different underlying genetic cause than lean hypertension? In the current issue, Pausova et al report finding a locus with suggestive linkage to hypertension and then reanalyzed their data after dividing their families into lean and obese.1 Of considerable interest, the significance of the linkage peak increased for the obese families but disappeared in the case of the families with hypertension who were not obese. The striking contrast in results for each category of hypertension lends strong support to the idea that hypertension of obesity has a different genetic basis than other categories of hypertension. Not only is this finding important in discovery of the genetic basis of obesity hypertension, but it has obvious implications for approaches that might be used to identify the basis for other "intermediate phenotypes" of hypertension.The study by Pausova et al involved 55 extended families from the geographically remote French-Canadian Saguenay/Lac-St-Jean region of Quebec. This relatively small, isolated population has been spared the level of genetic "noise" present in populations elsewhere. As a result, the degree of genetic homogeneity should be elevated and likely contributed to the success obtained.The findings emanated from a whole-genome scan using microsatellite markers spread fairly uniformly across the genome. The 2 "best" loci were found on chromosomes 1 (at p36) and 11 (at p15). By changing affected status from "hypertension" to "obesity hypertension" the 1p36 locus became significant (logarithm of the odds for linkage [LOD] score=3.1), as indicated above. On the other hand, the 11p15 locus became less significant, showing that the latter was a locus for hypertension independent of obesity. Fine mapping of the 1p36 locus refined the region and increased the LOD score to 3.5. Such a score exceeds the genome-wide significance thresholds for linkage of ≥3.3 set down by Lander and Kruglyak.2Pausova et al use a definition of "obesity" as a body mass index of ≥27 kg/m2 and "nonobese" as <27 kg/m2. This definition differs from the World Health Organization (WHO) criteria of 35 kg/m2). Thus, although it might be acceptable to use the criteria described for allocating subjects to the "obese" and "nonobese" groups, the deviation from the internationally accepted definition could have implications for interpretation of data from other workers in the future who may wish to replicate the findings but by using the standard definition. Moreover, the number of "obese" families was only 15, whereas the number of "nonobese" families was 40.The study highlights the value that can be obtained by testing robust intermediate phenotypes in the search for hypertension genes.3 Here, despite a relatively small number of families being studied, a significant locus has emerged. This contrasts with the 2 largest genome scans for hypertension, the National Heart, Lung and Blood Institute Family Blood Pressure Program (NHLBI-FBP)4 and the British Investigation of the Genetics of Hypertension (BRIGHT)5 studies, which failed to find even a single locus that attained genome-wide significance (after discounting a false locus on chromosome 6 in the UK study).In viewing all of the various genome scans for essential hypertension,6,7 including the present one, what stands out is the remarkable inconsistency of the findings between different studies. Nevertheless, some loci do appear to show greater reproducibility than others for different cohorts. One of these is the 1p36 locus, which has shown suggestive linkage to hypertension in Australians,8,9 Taiwanese,10 and Sardinians,11 and to systolic blood pressure in hypertensive Hispanic families.12 It is thus possible that the suggestive linkage findings in these as well as other populations will turn out to be enhanced if obesity hypertension rather than general hypertension were to be examined.Importantly, in the context of the present obesity hypertension findings, a genome scan has previously identified 1p36 as containing a quantitative trait locus for the phenotypes of obesity itself.13 Genetic variation within a gene in the 1p36 region has also been implicated in familial combined hyperlipidemia.14 In addition, the chromosomal region 1p34–36 has been identified as being responsible for premature myocardial infarction.15 It remains to be seen whether the same gene, in conjunction with other genes elsewhere in the genome (or even within the same region), will prove to be contributing to these various, somewhat overlapping, conditions.So what could be the identity of the gene(s) responsible? Potential candidates in the 1p36 region include the chloride channel genes CLCNKA and CLCNKB, the tumor necrosis factor (TNF) receptor 2 gene TNFRSF1B, and the natriuretic peptide genes NPPA and NPPB. Association with hypertension has been reported for a T481S variant of CLCNKB16 and an intron 4 variant of TNFRSF1B,8 whereas CLCNKA17 and NPPA18 variants have proved negative. However, all genetic polymorphisms in the latter 2 have not been tested extensively, so before this is done, these remain as candidates. In the case of the initial TNFRSF1B and CLCNKB findings, more detailed follow-up studies in a cohort selected for enhanced biological power by having 2 affected parents, and that, not surprisingly, exhibited early onset moderate to severe hypertension, have proved negative.19 Moreover, no association of TNFRSF1B variants with obesity hypertension was observed.19 More extensive studies of these and other potential candidate genes in subjects with the phenotype of obesity hypertension are thus required to identify the gene(s) and causative variants responsible.The Figure shows 50 genes flanking the linkage peak at D1S2672. As well as those mentioned above, others that stand out as being of possible interest include the angiotensin II receptor-associated protein AGTRAP, the methylenetetrahydrofolate reductase gene MTHFR, which has been implicated in myocardial infarction20 and systemic inflammation,21 and the mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein implicated in obesity.22 The 1p34–36 region has shown significant genome-wide linkage to premature myocardial infarction,15 and variation in the gene GJA4 for the gap–junction protein expressed in arterial endothelium, connexin 37, located in this region has shown strong association with myocardial infarction.15,23Download figureDownload PowerPointGenes flanking the linkage peak for obesity hypertension at D1S2672 identified within the p36 region of chromosome 1 and location (derived from information at http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?TAXID=9606&CHR= 1%7CCelera&MAPS=ugHs%2Cgenes% 2Csts-r&QSTR=D1S2672&QUERY= uid%2849898%29&BEG=11 M&END=16 M&thmb=o). The region shown spans base pairs 11 million to 16 million from the distal end of the p arm of chromosome 1. On the right is an ordered list of 50 genes in this region, showing symbol and description of each, and on the left, are the positions of many of these (those not shown because of space limitations can be inferred from the list on the right).Hypertensive subjects exhibit dyslipidemia, and genetic variation in TNFRSF1B is associated with plasma total, low-density and high-density lipoprotein cholesterol in hypertensive subjects,8 as well as with elevated cholesterol in familial combined hyperlipidemia.14Not only does the work of Pausova et al provide an important insight into the cause of obesity hypertension, it also gives hope to those of us who have been frustrated by attempts to identify the genetic basis of hypertension by way of genome-wide linkage scans and other genetic approaches. The use of intermediate phenotypes has been long touted for facilitating an understanding of the genetic basis of essential hypertension. The new finding appears to offer the strongest support yet for this being the way of the future in the genetic dissection of the phenotype of elevated blood pressure that we call "essential hypertension." The findings are thus very encouraging in more ways than one.The opinions expressed in this editorial commentary do not necessarily reflect those of the editors or of the American Heart Association.FootnotesCorrespondence to Brian J. Morris, PhD, DSc, School of Medical Sciences, Anderson Stuart Building, F13, The University of Sydney, NSW 2006, Australia. E-mail [email protected] References 1 Pausova Z, Gaudet D, Gossard F, Bernard M, Kaldunski M, Jomphe M, Tremblay J, Hudson TJ, Bouchard G, Kotchen T, Cowley AW, Hamet P. Genome-wide scan for linkage to obesity associated hypertension in French Canadians. Hypertension. 2005; 46: 1280–1285.LinkGoogle Scholar2 Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995; 11: 241–247.CrossrefMedlineGoogle Scholar3 Timberlake DS, O'Connor DT, Parmer RJ. Molecular genetics of essential hypertension: recent results and emerging strategies. Curr Opin Nephrol Hypertens. 2001; 10: 71–79.CrossrefMedlineGoogle Scholar4 Province MA, Kardia SL, Ranade K, Rao DC, Thiel BA, Cooper RS, Risch N, Turner ST, Cox DR, Hunt SC, Weder AB, Boerwinkle E. 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: 144–147.CrossrefMedlineGoogle Scholar5 Caulfield M, Munroe P, Samani N, Pembroke J, Dominiczak A, Brown M, Benjamin N, Webster J, Ratcliffe P, O'Shea S, Papp J, Taylor E, Dobson R, Knight J, Newhouse S, Hooper J, Lee W, Brain N, Clayton D, Lathrop M, Farrall M, Connell J. Genome-wide mapping for human loci for essential hypertension. Lancet. 2003; 361: 2118–2123.CrossrefMedlineGoogle Scholar6 Morris BJ, Benjafield AV, Lin RCY. Essential hypertension: genes and dreams. Clin Chem Lab Med. 2003; 41: 834–844.CrossrefMedlineGoogle Scholar7 Mein CA, Caulfield MJ, Dobson RJ, Munroe PB. Genetics of essential hypertension. Hum Mol Genet. 2004; 13: R169–R175.CrossrefMedlineGoogle Scholar8 Glenn CL, Wang WYS, Benjafield AV, Morris BJ. Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. Hum Mol Genet. 2000; 9: 1943–1949.CrossrefMedlineGoogle Scholar9 Benjafield AV, Speirs HJ, Wang WYS, Morris BJ. Genome-wide scan for hypertension in Sydney sibships: the GENIHUSS Study. Am J Hypertens. 2005; 18: 828–832.CrossrefMedlineGoogle Scholar10 Pan TH, Chen JW, Fann C, Jou YS, Wu SY. Linkage analysis with candidate genes: the Taiwan young-onset hypertension genetic study. 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J Clin Endocrinol Metab. 2004; 89: 875–882.CrossrefMedlineGoogle Scholar14 Geurts JMW, Janssen RGJH, van Greenenbroek MMJ, van der Kallen CJH, Cantor RM, Bu X-d, Aouizerat BE, Allayee H, Rotter JI, de Bruin TWA. Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. Hum Mol Genet. 2000; 9: 2067–2074.CrossrefMedlineGoogle Scholar15 Wang Q, Rao S, Shen GQ, Li L, Moliterno DJ, Newby LK, Rogers WJ, Cannata R, Zirzow E, Elston RC, Topol EJ. Premature myocardial infarction novel susceptibility locus on chromosome 1P34–36 identified by genomewide linkage analysis. Am J Hum Genet. 2004; 74: 262–271.CrossrefMedlineGoogle Scholar16 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, Asante-Poku S, Seyberth H, Schwab M, Lang F. Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. Hypertension. 2004; 43: 1175–1181.LinkGoogle Scholar17 Lin RCY, Morris BJ. Polymorphism (1339G>A; A447T) in exon 13 of human kidney chloride channel gene CLCNKA. Hum Mutat. 2000; 16: 96(online report no. 139, http://humu.edoc.com/1059–7794/pdf/mutation/mpr139.pdf).Google Scholar18 Zee RYL, Lou Y-k, Griffiths LR, Morris BJ. Molecular genetic analyses of RFLPs for PCR-amplified growth hormone gene, renal kallikrein gene and atrial natriuretic factor gene in essential hypertension. Hypertens Res. 1993; 16: 113–120.CrossrefGoogle Scholar19 Speirs HJ, Wang WYS, Benjafield AV, Morris BJ. No association with hypertension of CLCNKB and TNFRSF1B polymorphisms at a hypertension locus on chromosome 1p36. J Hypertens. 2005; 23: 1491–1496.CrossrefMedlineGoogle Scholar20 Helfenstein T, Fonseca FA, Relvas WG, Santos AO, Dabela ML, Matheus SC, D'Almeida V, Tufik S, Souza FG, Rodrigues PR, Taglieri R, Sousa EF, Izar MC. 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