Objective: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). Methods: Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911–2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/ 90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values. Results: The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.
© 2011 S. Karger AG, Basel
- Antihypertensive medication
- Genetic location
- Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P: The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44:398–404.
- Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y, American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25–e146.
- Franklin SS: Hypertension in the metabolic syndrome. Metab Syndr Relat Disord 2006;4:287–298.
- Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J: Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–223.
- Bakris GL, Sowers JR: ASH Position Paper: treatment of hypertension in patients with diabetes – an update. J Clin Hypertens (Greenwich) 2008;10:707–713.
- Cutler JA, Sorlie PD, Wolz M, Thom T, Fields LE, Roccella EJ: Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988–1994 and 1999–2004. Hypertension 2008;52:818–827.
- Hypertension in America: a national reading. Am J Manag Care 2005;11:S383–S385.
- Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS: Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038–2047.
- Lifton RP: Molecular genetics of human blood pressure variation. Science 1996;272:676–680.
- Hamet P, Pausova Z, Adarichev V, Adaricheva K, Tremblay J: Hypertension: genes and environment. J Hypertens 1998;16:397–418.
- Hsueh WC, Mitchell BD, Schneider JL, Wagner MJ, Bell CJ, Nanthakumar E, Shuldiner AR: QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31–34 in Old Order Amish. Circulation 2000;101:2810–2816.
- Samani NJ: Genome scans for hypertension and blood pressure regulation. Am J Hypertens 2003;16:167–171.
- Adeyemo A, Luke A, Wu X, Cooper RS, Kan D, Omotade O, Zhu X: Genetic effects on blood pressure localized to chromosomes 6 and 7. J Hypertens 2005;23:1367–1373.
- Padmanabhan S, Melander O, Hastie C, Menni C, Delles C, Connell JM, Dominiczak AF: Hypertension and genome-wide association studies: combining high fidelity phenotyping and hypercontrols. J Hypertens 2008;26:1275–1281.
- Mullins LJ, Bailey MA, Mullins JJ: Hypertension, kidney, and transgenics: a fresh perspective. Physiol Rev 2006;86:709–746.
- Lifton RP: Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect 2004–2005;100:71–101.
- O’Shaughnessy KM: Dissecting complex traits: recent advances in hypertension genomics. Genome Med 200928;1:43.
- Mein CA, Caulfield MJ, Dobson RJ, Munroe PB: Genetics of essential hypertension. Hum Mol Genet 2004;13:R169–R175.
- Binder A: A review of the genetics of essential hypertension. Curr Opin Cardiol 2007;22:176–184.
- Caulfield M, Munroe P, Pembroke J, Samani N, 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 GM, Farrall M, Connell J; MRC British Genetics of Hypertension Study: Genome-wide mapping of human loci for essential hypertension. Lancet 2003;361:2118–2123.
- 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.
- Liu W, Zhao W, Chase GA: Genome scan meta-analysis for hypertension. Am J Hypertens 2004;17:1100–1106.
- Arora P, Newton-Cheh C: Blood pressure and human genetic variation in the general population. Curr Opin Cardiol 2010, Epub ahead of print.
- Hastie CE, Padmanabhan S, Dominiczak AE: Genome-wide association studies of hypertension: light at the end of the tunnel. Int J Hypertens 2010;2010:509581
- Rafiq S, Anand S, Roberts R: Genome-wide association studies of hypertension: have they been fruitful? J Cardiovasc Transl Res 2010;3:189–196.
- Ehret GB: Genome-wide association studies: contribution of genomics to understanding blood pressure and essential hypertension. Curr Hypertens Rep 2010;12:17–25.
- Newton-Cheh C, Cook NR, VanDenburgh M, Rimm EB, Ridker PM, Albert CM: A common variant at 9p21 is associated with sudden and arrhythmic cardiac death. Circulation 2009;120:2062–2068.
- Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, et al: Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677–687.
- Coletta DK, Schneider J, Hu SL, Dyer TD, Puppala S, Farook VS, Arya R, Lehman DM, Blangero J, Defronzo RA, Duggirala R, Jenkinson CP: Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study. Diabetes 2009;58:279–284.
- Dyke B: PEDSYS: a pedigree data management system. PGI. Tech rep no. 2, Population Genetics Laboratory, Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX (1999).
- McPeek MS, Sun L: Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 2000;66:1076–1094.
- Sobel E, Papp JC, Lange K: Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 2002;70:496–508.
- Heath SC: Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet 1997;61:748–760.
- Heath SC, Snow GL, Thompson EA, Tseng C, Wijsman EM: MCMC segregation and linkage analysis. Genet Epidemiol 1997;14:1011–1015.
- Amos CI: Robust variance components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 1994;54:535–543.
- Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198–1211.
- Hopper J, Matthews J: Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet 1982;46:373–383.
- Boehnke M, Lange K: Ascertainment and goodness of fit of variance component models for pedigree data. Prog Clin Biol Res 1984;147:173–192.
- Duggirala R, Almasy L, Blangero J, Jenkinson CP, Arya R, DeFronzo RA, Stern MP, O’Connell P, American Diabetes Association GENNID Study Group: Further evidence for type 2 diabetes susceptibility locus on chromosome 11q. Genet Epidemiol 2003;24:240–242.
- Comuzzie AG, Williams JT: Correcting for ascertainment bias in the COGA data set. Genet Epidemiol 1999;17(suppl 1):S109–S114.
- Tobin MD, Sheehan NA, Scurrah KJ, Burton PR: Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat Med 2005;24:2911–2935.
- Cui JS, Hopper JL, Harrap SB: Antihypertensive treatments obscure familial contributions to blood pressure variation. Hypertension 2003;41:207–210.
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572.
- Hunt SC, Ellison RC, Atwood LD, Pankow JS, Province MA, Leppert MF: Genome scans for blood pressure and hypertension: the National Heart, Lung, and Blood Institute Family Heart Study. Hypertension 2002;40:1–6.
- Allayee H, de Bruin TW, Michelle Dominguez K, Cheng LS, Ipp E, Cantor RM, Krass KL, Keulen ET, Aouizerat BE, Lusis AJ, Rotter JI: Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p. Hypertension 2001;38:773–778.
- Rutherford S, Cai G, Lopez-Alvarenga JC, Kent JW, Voruganti VS, Proffitt JM, Curran JE, Johnson MP, Dyer TD, Jowett JB, Bastarrachea RA, Atwood LD, Goring HH, Maccluer JW, Moses EK, Blangero J, Comuzzie AG, Cole SA: A chromosome 11q quantitative-trait locus influences change of blood-pressure measurements over time in Mexican Americans of the San Antonio Family Heart Study. Am J Hum Genet 2007;81:744–755.
- 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;99:1407–1410.
- 48 Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM: Finding the missing heritability of complex diseases. Nature 2009;461:747–753.
- Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS Biol 2010;8:e1000294.
- Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, Vasan RS, Mitchell GF: Framingham Heart Study 100K 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;447:661–678.
- Org E, Eyheramendy S, Juhanson P, Gieger C, Lichtner P, Klopp N, Veldre G, Döring A, Viigimaa M, Sõber S, Tomberg K, Eckstein G; KORA, Kelgo P, Rebane T, Shaw-Hawkins S, Howard P, Onipinla A, Dobson RJ, Newhouse SJ, Brown M, Dominiczak A, Connell J, Samani N, Farrall M; BRIGHT, Caulfield MJ, Munroe PB, Illig T, Wichmann HE, Meitinger T, Laan M: Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations. Hum Mol Genet 2009;18:2288–2296.
- Yang HC, Liang YJ, Wu YL, Chung CM, Chiang KM, Ho HY, Ting CT, Lin TH, Sheu SH, Tsai WC, Chen JH, Leu HB, Yin WH, Chiu TY, Chen CI, Fann CS, Wu JY, Lin TN, Lin SJ, Chen YT, Chen JW, Pan WH: Genome-wide association study of young-onset hypertension in the Han Chinese population of Taiwan. PLoS One 2009;4:e5459.
- Adeyemo A, Gerry N, Chen G, Herbert A, Doumatey A, Huang H, Zhou J, Lashley K, Chen Y, Christman M, Rotimi C: A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet 2009;5:e1000564.
- Hiura Y, Tabara Y, Kokubo Y, Okamura T, Miki T, Tomoike H, Iwai N: A genome-wide association study of hypertension-related phenotypes in a Japanese population. Circ J 2010;74:2353–2359.
Christopher P. Jenkinson, PhD
Division of Diabetes, Department of Medicine
The University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (USA)
Tel. +1 210 567 4755, Fax +1 210 567 6554, E-Mail email@example.com
Received: June 29, 2010
Accepted after revision: November 22, 2010
Published online: February 5, 2011
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 4, Number of References : 55
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 71, No. 1, Year 2011 (Cover Date: April 2011)
Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
Open Access License / Drug Dosage / Disclaimer
Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license
), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.