Skip to main content
Log in

Context-dependent genetic effects in hypertension

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

There is a growing frustration with the limitations and inconsistencies of single locus candidate gene association and linkage studies. This frustration is exacerbated by the knowledge that a large influx of genotypic and gene expression data is expected to emerge over the next 5 years, and we are not prepared for the type of multigenic conceptual framework that will be necessary to analyze that data. A review of the hypertension genetic literature reveals substantial evidence for the importance of both genetic and environmental contexts on the mapping between single locus polymorphisms and risk of disease. These trends indicate that the current reliance on simple single gene studies to elucidate the complex etiology of hypertension needs to undergo some kind of transformation. It is suggested that even a minor shift to a more systematic investigation of context-dependent effects will increase our understanding of the multidimensional genetic and environmental realities underneath current studies. This shift is also necessary if we are to gain a deeper understanding of the specific ways in which an individual’s risk of hypertension is a consequence of the interactions among genes and environments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Garrod AE: Inborn errors of metabolism. Lancet 1908, 2:1–7.

    Article  CAS  Google Scholar 

  2. McKusick VA: Mendelian inheritance in man: a catalog of human genes and genetic disorders. Baltimore: Johns Hopkins University Press; 1998.

    Google Scholar 

  3. Luft FC: Molecular genetics of human hypertension. J Hypertens 1998, 16:1871–1878.

    Article  PubMed  CAS  Google Scholar 

  4. Kunz R, Kreutz R, Beige J, et al.: Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension 1996, 30:1331–1337. A good review of the methodological limitations of hypertension candidate gene studies and implications for meta-analyses.

    Google Scholar 

  5. Human Genome Project. National Human Genome Research Institute Web site. Available at: http://www.nhgri.nih.gov/HGP.

  6. Affymetrix Gene Chip Web site. Available at: http:// www.affymerix.com/.

  7. Halushka MK, Fan JB, Bentley K, et al.: Patterns of singlenucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999, 22:239–247. A harbinger of the kind of high dimensional genetic information that will soon become a part of hypertension genetic research efforts.

    Article  PubMed  CAS  Google Scholar 

  8. Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995, 59:97–105.

    PubMed  CAS  Google Scholar 

  9. Cheverud JM, Routman EJ: Epistasis and its contribution to genetic variance components. Genetics 1995, 139:1455–1461. An important reparameterization of epistasis that gives new meaning to the study of genotype-by-genotype interaction.

    PubMed  CAS  Google Scholar 

  10. Tiret L, Bonnardeaux A, Poirier O, et al.: Synergistic effects of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on risk of myocardial infraction. Lancet 1994, 344:910–913.

    Article  PubMed  CAS  Google Scholar 

  11. Alvarez R, Regurero JR, Batalla A, et al.: Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res 1998, 40:375–379.

    Article  PubMed  CAS  Google Scholar 

  12. Vasku A, Soucek M, Znojil V, et al.: Angiotensin I-converting enzyme and angiotensinogen gene interaction and prediction of essential hypertension. Kidney Int 1998, 53:1479–1482.

    Article  PubMed  CAS  Google Scholar 

  13. Berge KE, Berg K: Polymorphism at the angiotensinogen (AGT) and angiotensin II type 1 receptor (ATIR) loci and normal blood pressure. Clin Genet 1998, 53:214–219.

    Article  PubMed  CAS  Google Scholar 

  14. Phillips PC: From complex traits to complex alleles. Trends Genet 1999, 15:6–8.

    Article  PubMed  CAS  Google Scholar 

  15. Butler R, Morris AD, Burchell B, Struthers AD: DD angiotensinconverting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans. Hypertension 1999, 33:1164–1168.

    PubMed  CAS  Google Scholar 

  16. Kornitzer M, Dramaix M, Backer GD: Epidemiology of risk factors for hypertension: implications for prevention and therapy. Drugs 1999, 57:695–712.

    Article  PubMed  CAS  Google Scholar 

  17. Arroll N, Beaglehole R: Does physical activity lower blood pressure: a critical review of the clinical trials. J Clin Epidemiol 1992, 45:439–447.

    Article  PubMed  CAS  Google Scholar 

  18. Ascherio A, Rimm EB, Giovannucci EL, et al.: A prospective study of nutritional factors and hypertension among US men. Circulation 1992, 86:1475–1485.

    PubMed  CAS  Google Scholar 

  19. The Trials of Hypertension Prevention Collaborative Research Group: Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The Trials of Hypertension Prevention, phase II. Arch Intern Med 1997, 157:657–667.

    Article  Google Scholar 

  20. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al.: Molecular basis of human hypertension: role of angiotensinogen. Cell 1992, 71:7–20.

    Article  Google Scholar 

  21. Fornage M, Amos CI, Kardia S, et al.: Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels among young white males. Circulation 1998, 97:1773–1779.

    PubMed  CAS  Google Scholar 

  22. O’Donnell CJ, Lindpaintner K, Larson MG, et al.: Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 1998, 97:1763–1765.

    Google Scholar 

  23. Kainulainen K, Perola M, Terwilliger J, et al.: Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 1999, 33:844–849.

    PubMed  CAS  Google Scholar 

  24. Turner ST, Boerwinkle E, Sing CF: Context dependent associations of the ACE I/D polymorphism with blood pressure. Hypertension 1999, 34(part 2):773–778. One of the most systematic investigations and demonstrations of the influence of gender, age, and body size on the relationship between variation in a candidate gene and variation in blood pressure and risk of hypertension.

    PubMed  CAS  Google Scholar 

  25. Benjafield AV, Jeyasingam CL, Nyholt DR, et al.: G-protein beta 3 subunit gene (GNB#) variant in causation of essential hypertension. Hypertension 1998, 32:1094–1097.

    PubMed  CAS  Google Scholar 

  26. Glenn CL, Wang WYS, Morris BJ: Different frequencies o inducible nitric oxide synthase genotypes in older hypertensives. Hypertension 1999, 33:927–932.

    PubMed  CAS  Google Scholar 

  27. Tiret L, Poirier O, Hallet V, et al.: The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999, 33:1169–1174.

    PubMed  CAS  Google Scholar 

  28. Mark AL, Correia M, Morgan DA, et al.: State-of-the-art lecture: obesity-induced hypertension: new concepts from the emerging biology of obesity Hypertension 1999, 33(suppl):537–541.

    PubMed  CAS  Google Scholar 

  29. Giner V, Poch E, Bragulat E, et al.: Angiotensin converting enzyme (ACE) and angiotensinogen (AG) gene polymorphism in relation to salt-sensitivity in essential hypertension. Hypertension 1999, 34:354.

    Google Scholar 

  30. Hunt SC, Geleijinse JM, Wu LL, et al.: Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Am J Hypertens 1999, 12:460–466.

    Article  PubMed  CAS  Google Scholar 

  31. Schorr U, Blaschke K, Beige J, et al.: Angiotensinogen M235T variant and salt sensitivity in young normotensive Caucasians. J Hypertens 1999, 17:475–479.

    Article  PubMed  CAS  Google Scholar 

  32. Svetkey LP, Chen Y-T, McKeown SP, et al.: Preliminary evidence of linkage of salt sensitivity in black Americans at the beta2 -andrenergic receptor locus. Hypertension 1997, 29:918–922.

    PubMed  CAS  Google Scholar 

  33. Hunt SC, Cook NR, Oberman A, et al.: Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention phase II. Hypertension 1998, 32:393–401. An excellent example of the type of genotype-environment studies that are needed in hypertension genetic research.

    PubMed  CAS  Google Scholar 

  34. O’Byrne S, Caufield M: Genetics of hypertension. Drugs 1998, 56:203–214.

    Article  PubMed  CAS  Google Scholar 

  35. Schunkert H, Hense HW, Gimenez-Roqueplo AP, et al.: The angiotensinogen T235 variant and the use of antihypertensive drugs in a population-based cohort. Hypertension 1997, 29:628–633.

    PubMed  CAS  Google Scholar 

  36. Hingorani AD, Jia H, Stevens PA, et al.: Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin-converting enzyme inhibition. J Hypertens 1995, 13(part 2):1602–1609.

    PubMed  CAS  Google Scholar 

  37. Feldman RD: Beta-andrenergic receptor alterations in hypertension: physiological and molecular correlates. Can J Physiol Pharmacol 1987, 65:1666–1672.

    PubMed  CAS  Google Scholar 

  38. Krushkal J, Xiong M, Ferrell R, et al.: Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum Mol Genet 1998, 7:1379–1383.

    Article  PubMed  CAS  Google Scholar 

  39. Kotanko P, Binder A, Tasker J, et al.: Essential hypertension in African Caribbeans associates with a variant of the beta2-adrenoceptor. Hypertension 1997, 30:773–776.

    PubMed  CAS  Google Scholar 

  40. Timmermann B, Mo R, Luft FC, et al.: Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study. Kidney Int 1998, 53:1455–1460.

    Article  PubMed  CAS  Google Scholar 

  41. Gratze G, Fortin J, Labugger R, et al.: Beta-2 adrenergic receptor variants affect resting blood pressure and agonistinduced vasodilation in young adult Caucasians. Hypertension 1999, 33:1425–1430.

    PubMed  CAS  Google Scholar 

  42. Ellsworth DL, Sholinsky P, Jaquish C, et al.: Coronary heart disease: at the interface of molecular genetics and preventive medicine. Am J Prev Med 1999, 16:122–133.

    Article  PubMed  CAS  Google Scholar 

  43. Kardia SLR, Haviland MB, Sing CF: Correlates of family history of coronary artery disease in children. J Clin Epidemiol 1998, 51:473–486.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kardia, S.L.R. Context-dependent genetic effects in hypertension. Current Science Inc 2, 32–38 (2000). https://doi.org/10.1007/s11906-000-0055-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-000-0055-6

Keywords

Navigation