Skip to main content
Log in

Genetics, Ancestry, and Hypertension: Implications for Targeted Antihypertensive Therapies

  • Antihypertensive Agents: Mechanisms of Drug Action (ME Ernst, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Hypertension is the most common chronic condition seen by physicians in ambulatory care and a condition for which life-long medications are commonly prescribed. There is evidence for genetic factors influencing blood pressure variation in populations and response to medications. This review summarizes recent genetic discoveries that surround blood pressure, hypertension, and antihypertensive drug response from genome-wide association studies, while highlighting ancestry-specific findings and any potential implication for drug therapy targets. Genome-wide association studies have identified several novel loci for inter-individual variation of blood pressure and hypertension risk in the general population. Evidence from pharmacogenetic studies suggests that genes influence the blood pressure response to antihypertensive drugs, although results are somewhat inconsistent across studies. There is still much work that remains to be done to identify genes both for efficacy and adverse events of antihypertensive medications.

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.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ashman JJ, Beresovsky V. Multiple chronic conditions among us adults who visited physician offices: data from the national ambulatory medical care survey, 2009. Prev Chronic Dis. 2013;10:E64.

    PubMed  PubMed Central  Google Scholar 

  2. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the us adult population. Results from the third national health and nutrition examination survey, 1988-1991. Hypertension. 1995;25:305–13.

    CAS  PubMed  Google Scholar 

  3. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129:399–410.

    PubMed  Google Scholar 

  4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13.

    PubMed  Google Scholar 

  5. Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165:923–8.

    PubMed  Google Scholar 

  6. Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513–8.

    PubMed  Google Scholar 

  7. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). Shep Cooperative Research group. JAMA. 1991;265:3255–64.

  8. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension detection and follow-up program cooperative group. JAMA. 1979;242:2562–71.

  9. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213:1143–52.

  10. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (syst-eur) Trial Investigators. Lancet. 1997;350:757–64.

    CAS  PubMed  Google Scholar 

  11. MRC trial of treatment of mild hypertension: principal results. Medical research council working party. Br Med J (Clin Res Ed). 1985;291:97–104.

  12. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. J Hypertens. 1985;3:379–92.

  13. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2005;67:2089–100.

    PubMed  Google Scholar 

  14. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health and Nutrition Examination Survey, 2001 to 2010. Circulation. 2012;126:2105–14.

    CAS  PubMed  Google Scholar 

  15. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA. 2003;290:199–206.

    PubMed  Google Scholar 

  16. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103–9. This is the largest GWAS of BP published. It identified 29 SNPs in 28 loci for BP traits and hypertension. The study comprised of 69,395 individuals of European ancestry for discovery and approximately 200,000 individuals were included in the discovery and replication samples.

  17. Hopkins PN, Hunt SC. Genetics of hypertension. Genet Med. 2003;5:413–29.

    PubMed  Google Scholar 

  18. Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. Human hypertension caused by mutations in wnk kinases. Science. 2001;293:1107–12.

    CAS  PubMed  Google Scholar 

  19. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009.

  20. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009.

  21. Wain LV, Verwoert GC, O'Reilly PF, Shi G, Johnson T, Johnson AD, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43:1005–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, Kuznetsova T, et al. Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial no synthase. Hypertension. 2012;59:248–55.

    CAS  PubMed  Google Scholar 

  23. Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D, et al. Genome-wide association study of blood pressure extremes identifies variant near umod associated with hypertension. PLoS Genet. 2010;6:e1001177.

    PubMed  PubMed Central  Google Scholar 

  24. Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet. 2014;94:349–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN, et al. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013;22:1663–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Johnson T, Gaunt TR, Newhouse SJ, Padmanabhan S, Tomaszewski M, Kumari M, et al. Blood pressure loci identified with a gene-centric array. Am J Hum Genet. 2011;89:688–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Johnson AD, Newton-Cheh C, Chasman DI, Ehret GB, Johnson T, Rose L, et al. Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. Hypertension. 2011;57:903–10.

    CAS  PubMed  Google Scholar 

  28. Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in East Asians. Nat Genet. 2011;43:531–8. A large GWAS of East Asians. It identified four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. The paper compares the effect estimates for the ICBP SNPs between European and East Asian studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527–34.

    CAS  PubMed  Google Scholar 

  30. Zhu X, Young JH, Fox E, Keating BJ, Franceschini N, Kang S, et al. Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium. Hum Mol Genet. 2011;20(11):2285–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Franceschini N, Fox E, Zhang Z, Edwards TL, Nalls MA, Sung YJ, et al. Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. Am J Hum Genet. 2013;93:545–54. This is the largest GWAS of BP in African ancestry individuals. The study identified three novel loci for blood pressure traits and allelic heterogeneity in one known locus.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Parra EJ, Marcini A, Akey J, Martinson J, Batzer MA, Cooper R, et al. Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet. 1998;63:1839–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F, et al. Meta-analysis identifies multiple loci associated with kidney function-related traits in East Asian populations. Nat Genet. 2012;44:904–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Marth GT, Yu F, Indap AR, Garimella K, Gravel S, Leong WF, et al. The functional spectrum of low-frequency coding variation. Genome Biol. 2011;12:R84.

    PubMed  PubMed Central  Google Scholar 

  35. Sanna S, Li B, Mulas A, Sidore C, Kang HM, Jackson AU, et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet. 2011;7:e1002198.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bustamante CD, Burchard EG, De la Vega FM. Genomics for the world. Nature. 2011;475:163–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Scaroni C, Biason A, Carpene G, Opocher G, Mantero F. 17-alpha-hydroxylase deficiency in three siblings: short- and long-term studies. J Endocrinol Invest. 1991;14:99–108.

    CAS  PubMed  Google Scholar 

  39. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. 1993. Biochem Biophys Res Commun. 2012;425:548–55.

    CAS  PubMed  Google Scholar 

  40. Stein PP, Black HR. A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Med (Baltimore). 1991;70:46–66.

    CAS  Google Scholar 

  41. Wang H, Liu J, Liu K, Liu Y, Wang Z, Lou Y, et al. Beta1-adrenoceptor gene arg389gly polymorphism and essential hypertension risk in general population: a meta-analysis. Mol Biol Rep. 2013;40:4055–63.

    CAS  PubMed  Google Scholar 

  42. Hunt SC, Geleijnse JM, Wu LL, Witteman JC, Williams RR, Grobbee DE. Enhanced blood pressure response to mild sodium reduction in subjects with the 235t variant of the angiotensinogen gene. Am J Hypertens. 1999;12:460–6.

    CAS  PubMed  Google Scholar 

  43. Svetkey LP, Moore TJ, Simons-Morton DG, Appel LJ, Bray GA, Sacks FM, et al. Angiotensinogen genotype and blood pressure response in the Dietary Approaches to Stop Hypertension (DASH) study. J Hypertens. 2001;19:1949–56.

    CAS  PubMed  Google Scholar 

  44. Wolf MB, Baynes JW. Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction. Biometals. 2007;20:73–81.

    CAS  PubMed  Google Scholar 

  45. Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B, et al. Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. Arterioscler Thromb Vasc Biol. 2009;29:1392–8.

    CAS  PubMed  Google Scholar 

  46. Staessen JA, Kuznetsova T, Roels HA, Emelianov D, Fagard R. Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public Health and Environmental Exposure to Cadmium Study Group. Am J Hypertens. 2000;13(2):146–156.

    CAS  PubMed  Google Scholar 

  47. Tellez-Plaza M, Navas-Acien A, Crainiceanu CM, Guallar E. Cadmium exposure and hypertension in the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Environ Health Perspect. 2008;116(1):51–56.

    CAS  PubMed  Google Scholar 

  48. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet. 2009;41:712–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, et al. Common noncoding umod gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 2013;19:1655–60.

    CAS  PubMed  Google Scholar 

  50. Freedman BI, Murea M. Target organ damage in African American hypertension: role of APOL1. Curr Hypertens Rep. 2012;14:21–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic apol1 variants with kidney disease in African Americans. Science. 2010;329:841–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet. 2008;40:1185–92.

    CAS  PubMed  Google Scholar 

  53. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 2008;40:1175–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sanseau P, Agarwal P, Barnes MR, Pastinen T, Richards JB, Cardon LR, et al. Use of genome-wide association studies for drug repositioning. Nat Biotechnol. 2012;30:317–20.

    CAS  PubMed  Google Scholar 

  55. Lynch AI, Boerwinkle E, Davis BR, Ford CE, Eckfeldt JH, Leiendecker-Foster C, et al. Pharmacogenetic association of the NPPA t2238c genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA. 2008;299:296–307.

    CAS  PubMed  Google Scholar 

  56. Luo F, Wang Y, Wang X, Sun K, Zhou X, Hui R. A functional variant of nedd4l is associated with hypertension, antihypertensive response, and orthostatic hypotension. Hypertension. 2009;54:796–801.

    CAS  PubMed  Google Scholar 

  57. Manunta P, Lavery G, Lanzani C, Braund PS, Simonini M, Bodycote C, et al. Physiological interaction between alpha-adducin and wnk1-nedd4l pathways on sodium-related blood pressure regulation. Hypertension. 2008;52:366–72.

    CAS  PubMed  Google Scholar 

  58. Svensson-Farbom P, Wahlstrand B, Almgren P, Dahlberg J, Fava C, Kjeldsen S, et al. A functional variant of the NEDD4L gene is associated with beneficial treatment response with beta-blockers and diuretics in hypertensive patients. J Hypertens. 2011;29:388–95.

    PubMed  Google Scholar 

  59. Turner ST, Boerwinkle E, O'Connell JR, Bailey KR, Gong Y, Chapman AB, et al. Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension. 2013;62:391–7. Two recent GWAS of blood response to antihypertensive drugs.

    CAS  PubMed  Google Scholar 

  60. Arnett DK, Claas SA. Pharmacogenetics of antihypertensive treatment: detailing disciplinary dissonance. Pharmacogenomics. 2009;10:1295–307.

    CAS  PubMed  Google Scholar 

  61. Johnson JA. Advancing management of hypertension through pharmacogenomics. Ann Med. 2012;44 Suppl 1:S17–22.

    CAS  PubMed  Google Scholar 

  62. Gong Y, McDonough CW, Wang Z, Hou W, Cooper-DeHoff RM, Langaee TY, et al. Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study. Circ Cardiovasc Genet. 2012;5:686–91. Two recent GWAS of blood response to antihypertensive drugs.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. He J, Kelly TN, Zhao Q, Li H, Huang J, Wang L, et al. Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese. Circ Cardiovasc Genet. 2013;6:598–607.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Del-Aguila JL, Beitelshees AL, Cooper-Dehoff RM, Chapman AB, Gums JG, Bailey K, et al. Genome-wide association analyses suggest nell1 influences adverse metabolic response to hctz in African Americans. Pharmacogenomics J. 2014;14:35–40.

    CAS  PubMed  Google Scholar 

  65. Gong Y, McDonough CW, Beitelshees AL, Karnes JH, O'Connell JR, Turner ST, et al. PROX1 gene variant is associated with fasting glucose change after antihypertensive treatment. Pharmacotherapy. 2014;34:123–30.

    CAS  PubMed  Google Scholar 

  66. McDonough CW, Gillis NK, Alsultan A, Chang SW, Kawaguchi-Suzuki M, Lang JE, et al. Atenolol induced HDL-C change in the pharmacogenomic evaluation of antihypertensive responses (PEAR) Study. PLoS ONE 2013;8(10): e76984. doi:10.1371/journal.pone.0076984

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pare G, Kubo M, Byrd JB, McCarty CA, Woodard-Grice A, Teo KK, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2013;23:470–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Karnes JH, Gong Y, Pacanowski MA, McDonough CW, Arwood MJ, Langaee TY, et al. Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes. Pharmacogenet Genomics. 2013;23:697–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (jnc 8). JAMA. 2014;311:507–20.

    CAS  PubMed  Google Scholar 

  70. 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;288:2981–97.

  71. Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, et al. Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses. Hypertension. 1991;17:I102–8.

    CAS  PubMed  Google Scholar 

  72. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481–90

    CAS  PubMed  Google Scholar 

  73. Tu W, Eckert GJ, Hannon TS, Liu H, Pratt LM, Wagner MA, et al. Racial differences in sensitivity of blood pressure to aldosterone. Hypertension. 2014.

Download references

Acknowledgments

Funding NIH U01- GM074492 (to RKCD)

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nora Franceschini.

Ethics declarations

Conflict of Interest Nora Franceschini and Daniel I. Chasman declare that they have no conflicts of interest.

Rhonda M. Cooper-DeHoff has received research grants from NIH and Abbott Laboratories. She also has received a patent for clinical trial software and royalties from the University of Florida Foundation.

Donna K. Arnett has received a grant from the NIH.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Franceschini, N., Chasman, D.I., Cooper-DeHoff, R.M. et al. Genetics, Ancestry, and Hypertension: Implications for Targeted Antihypertensive Therapies. Curr Hypertens Rep 16, 461 (2014). https://doi.org/10.1007/s11906-014-0461-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-014-0461-9

Keywords

Navigation