- Renin-angiotensin system
While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana. Thirteen polymorphisms in eight candidate genes were studied. Each candidate gene has been shown to play a physiological role in blood pressure regulation and affects one of four pathways that modulate blood pressure: vasoconstriction (angiotensinogen, angiotensin converting enzyme – ACE, angiotensin II receptor), nitric oxide (NO) dependent and NO independent vasodilation pathways and sodium balance (G protein-coupled receptor kinase, GRK4). We evaluated single site allelic and genotypic associations, multilocus genotype equilibrium and multilocus genotype associations, using multifactor dimensionality reduction (MDR). For MDR, we performed systematic reanalysis of the data to address the role of various physiological pathways. We found no significant single site associations, but the hypertensive class deviated significantly from genotype equilibrium in more than 25% of all multilocus comparisons (2,162 of 8,178), whereas the normotensive class rarely did (11 of 8,178). The MDR analysis identified a two-locus model including ACE and GRK4 that successfully predicted blood pressure phenotype 70.5% of the time. Thus, our data indicate epistatic interactions play a major role in hypertension susceptibility. Our data also support a model where multiple pathways need to be affected in order to predispose to hypertension.
Copyright © 2004 S. Karger AG, Basel
- Kaplan NM: Kaplan’s Clinical Hypertension. 8th/ed. 2002, Philadelphia: Lippincott Williams & Wilkins, pp 550.
- Nijhout HF: The nature of robustness in development. Bioessays 2002;24(6):553–563.
- Halushka MK, et al: Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999;22(3):239–247.
- Moore JH, Williams SM: New strategies for identifying gene-gene interactions in hypertension. Ann Med 2002;34(2):88–95.
- Rotimi CN, et al: Maximum-likelihood generalized heritability estimate for blood pressure in Nigerian families. Hypertension 1999;33(3):874–878.
- Gu C, et al: Familial resemblance for resting blood pressure with particular reference to racial differences: Preliminary analyses from the HERITAGE Family Study. Hum Biol 1998;70(1):77–90.
- Caulfield M, et al: Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994;330(23):1629–1633.
- Jeunemaitre X, et al: Molecular basis of human hypertension: Role of angiotensinogen. Cell 1992;71(1):169–180.
- Chiang FT, et al: Molecular variant M235T of the angiotensinogen gene is associated with essential hypertension in Taiwanese. J Hypertens 1997;15(6):607–611.
- Hata A, et al: Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 1994;93(3):1285–1287.
- Brand E, et al: Evaluation of the angiotensinogen locus in human essential hypertension: A European study. Hypertension 1998;31(3):725–729.
- Rodriguez-Perez JC, et al: Effects of the angiotensinogen gene M235T and A(-6)G variants on blood pressure and other vascular risk factors in a Spanish population. J Hum Hypertens 2000;14(12):789–793.
- Niu T, et al: Angiotensinogen gene polymorphisms M235T/T174M: No excess transmission to hypertensive Chinese. Hypertension 1999;33(2):698–702.
- Kato N, et al: Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese. J Hypertens 2000;18(8):1025–1032.
- Templeton AR: Epistasis and complex traits; in Wolf JB, Brodie ED III, Wade MJ (eds): Epistasis and the Evolutionary Process. Oxford University Press: New York, NY, 2000, pp 41–57.
- Williams SM, Haines JL, Moore JH: The use of animal models in the study of complex disease: All else is never equal or why do so many human studies fail to replicate animal findings? BioEssays 2003, in press.
- Nakayama T, et al: Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese. Clin Genet 1997;51(1):26–30.
- Huang PL, et al: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995;377(6546):239–242.
- Takahashi Y, et al: Association analysis of TG repeat polymorphism of the neuronal nitric oxide synthase gene with essential hypertension. Clin Genet 1997;52(2):83–85.
- Rossi GP, et al: The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 2003;41(6):938–945.
- Fisslthaler B, et al: Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 1999;401(6752):493–497.
- Bauersachs J, et al: Cytochrome P450 2C expression and EDHF-mediated relaxation in porcine coronary arteries is increased by cortisol. Cardiovasc Res 2002;54(3):669–675.
- Jose PA, Eisner GM, Felder RA: Renal Dopamine Receptors in Health and Hypertension. Pharmacology & Therapeutics 1998;80(2):149–182.
- Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001;104(4):545–556.
- Williams SM, et al: Combinations of variations in multiple genes are associated with hypertension. Hypertension 2000;36(1):2–6.
- Felder RA, et al: G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci USA 2002;99(6):3872–3877.
- Pearson DL, et al: Neonatal pulmonary hypertension–urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 2001;344(24):1832–1838.
- Ritchie MD, et al: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001;69(1):138–147.
- Hahn LW, Ritchie MD, Moore JH: Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 2003;19(3):376–382.
- Dai D, et al: Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001;11(7):597–607.
- Sullivan KJ, et al: Low exhaled nitric oxide and a polymorphism in the NOS I gene is associated with acute chest syndrome. Am J Respir Crit Care Med 2001;164(12):2186–2190.
- Wang XL, et al: A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med 1996;2(1):41–45.
- Raymond M, Rousset F: An exact test for population differentiation. Evolution 1995;49(6):1280–1283.
- Lewis PO, Zaykin D: Genetic Data analysis, Version 1.0 (d16c). 1999.
- Weir BS: Genetic Data analysis II. 2 ed. 1996, Sunderland, MA: Sinauer. 445.
- Vasku A, et al: Angiotensin I-converting enzyme and angiotensinogen gene interaction and prediction of essential hypertension. Kidney Int 1998;53(6):1479–1482.
- Tsai CT, et al: Angiotensinogen gene haplotype and hypertension: interaction with ACE gene I allele. Hypertension 2003;41(1):9–15.
- Niu T, et al: Linkage analysis of candidate genes and gene-gene interactions in Chinese hypertensive sib pairs. Hypertension 1999;33(6):1332–1337.
- Wagner A: Robustness against mutations in genetic networks of yeast. Nat Genet 2000;24(4):355–361.
- Muoio DM, et al: Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol Chem 2002;277(29):26089–26097.
- Gilde AJ, et al: Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 2003;92(5):518–524.
- Lipkin SM, et al: MLH3: A DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet 2000;24(1):27–35.
- Vance JR, Wilson TE: Repair of DNA strand breaks by the overlapping functions of lesion-specific and non-lesion-specific DNA 3′ phosphatases. Mol Cell Biol 2001;21(21):7191–7198.
- Vance JR, Wilson TE: Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Proc Natl Acad Sci USA 2002;99(21):13669–13674.
- Amin NS, et al: exo1-dependent mutator mutations: model system for studying functional interactions in mismatch repair. Mol Cell Biol 2001;21(15):5142–5155.
- Luo J, et al: Mice lacking all isoforms of retinoic acid receptor beta develop normally and are susceptible to the teratogenic effects of retinoic acid. Mech Dev 1995;53(1):61–71.
- Solloway MJ, Robertson EJ: Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development 1999;126(8):1753–1768.
- Mendelsohn C, et al: Retinoic acid receptor beta 2 (RAR beta 2) null mutant mice appear normal. Dev Biol 1994;166(1):246–258.
- Anonymous: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.
Scott M. Williams, PhD
Division of Cardiovascular Medicine and Center for Human Genetics Research
519 Light Hall, Vanderbilt University Medical Center
Nashville, TN 37232 (USA)
Tel. +1 615 322 8036, Fax +1 615 343 8619, E-Mail firstname.lastname@example.org
Received: August 28, 2003
Accepted after revision: December 8, 2003
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 7, Number of References : 49
Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)
Vol. 57, No. 1, Year 2004 (Cover Date: Released April 2004)
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.ch/journals/hhe
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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.