Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study

Abstract

We examined the associations of single nucleotide polymorphisms (SNPs) in three candidate hypertension genes, α-adducin (ADD1/G460W), β2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein β3 subunit (GNB3/C825T), with retinal arteriolar calibre (an intermediate marker of chronic hypertension) and venular calibre. Data in 1842 participants (1554 whites and 288 African Americans) aged 69–96 years from the Cardiovascular Health Study with genotype and retinal vascular calibre data were included. A computer-assisted method was used to measure retinal vascular calibre. We analysed four SNPs and multilocus interaction for three genes. All SNPs were in Hardy–Weinberg equilibrium in whites and African Americans. The study had sufficient power to detect 0.5% of the total variance of retinal vascular calibre contributed by each SNP in the total population, except for the GNB3 gene variant. No significant associations between these SNPs in the genes studied and mean retinal arteriolar and venular calibre were found in single-gene or multilocus analysis (for example, age-, gender-, race-adjusted mean retinal arteriolar calibre was similar between participants who were ADD1/460W homozygotes and ADD1/G allele carriers, 166.2 vs 167.7 μm). In conclusion, this study found no evidence of an association of SNPs in candidate hypertension genes studied here with retinal vascular calibre.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Tanira MO, Al Balushi KA . Genetic variations related to hypertension: a review. J Hum Hypertens 2005; 19: 7–19.

    Article  CAS  PubMed  Google Scholar 

  2. Harrap SB . Where are all the blood-pressure genes? Lancet 2003; 361: 2149–2151.

    Article  CAS  PubMed  Google Scholar 

  3. Tabor HK, Risch NJ, Myers RM . Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002; 3: 391–397.

    Article  CAS  PubMed  Google Scholar 

  4. Agarwal A, Williams GH, Fisher ND . Genetics of human hypertension. Trends Endocrinol Metab 2005; 16: 127–133.

    Article  CAS  PubMed  Google Scholar 

  5. Wong TY, Mitchell P . The eye in hypertension. Lancet 2007; 369: 425–435.

    Article  PubMed  Google Scholar 

  6. Wong TY, Hubbard LD, Klein R, Marino EK, Kronmal R, Sharrett AR et al. Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. Br J Ophthalmol 2002; 86: 1007–1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wong TY, Kamineni A, Klein R, Sharrett AR, Klein BE, Siscovick DS et al. Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. Arch Intern Med 2006; 166: 2388–2394.

    Article  PubMed  Google Scholar 

  8. Taarnhoj NC, Larsen M, Sander B, Kyvik KO, Kessel L, Hougaard JL et al. Heritability of retinal vessel diameters and blood pressure: a twin study. Invest Ophthalmol Vis Sci 2006; 47: 3539–3544.

    Article  PubMed  Google Scholar 

  9. Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Klein BE et al. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med 2004; 140: 248–255.

    Article  PubMed  Google Scholar 

  10. Manunta P, Barlassina C, Bianchi G . Adducin in essential hypertension. FEBS Lett 1998; 430: 41–44.

    Article  CAS  PubMed  Google Scholar 

  11. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 1998; 18: 45–48.

    Article  CAS  PubMed  Google Scholar 

  12. Tang WH, Devereux RB, Kitzman DW, Province MA, Leppert M, Oberman A et al. The Arg16Gly polymorphism of the beta 2-adrenergic receptor and left ventricular systolic function. Am J Hypertens 2003; 16: 945–951.

    Article  CAS  PubMed  Google Scholar 

  13. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 1997; 349: 1353–1357.

    Article  CAS  PubMed  Google Scholar 

  14. Heckbert SR, Hindorff LA, Edwards KL, Psaty BM, Lumley T, Siscovick DS et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107: 2021–2024.

    Article  CAS  PubMed  Google Scholar 

  15. Kato N, Sugiyama T, Nabika T, Morita H, Kurihara H, Yazaki Y et al. Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population. Hypertension 1998; 31: 730–733.

    Article  CAS  PubMed  Google Scholar 

  16. Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991; 1: 263–276.

    Article  CAS  PubMed  Google Scholar 

  17. Tell GS, Fried LP, Hermanson B, Manolio TA, Newman AB, Borhani NO . Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. Ann Epidemiol 1993; 3: 358–366.

    Article  CAS  PubMed  Google Scholar 

  18. Wong TY, Klein R, Sharrett AR, Manolio TA, Hubbard LD, Marino EK et al. The prevalence and risk factors of retinal microvascular abnormalities in older persons: the Cardiovascular Health Study. Ophthalmology 2003; 110: 658–666.

    Article  PubMed  Google Scholar 

  19. Hubbard LD, Brothers RJ, King WN, Clegg LX, Klein R, Cooper LS et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999; 106: 2269–2280.

    Article  CAS  PubMed  Google Scholar 

  20. Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M et al. High-throughput genotyping with single nucleotide polymorphisms. Genome Res 2001; 11: 1262–1268.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Tell GS, Rutan GH, Kronmal RA, Bild DE, Polak JF, Wong ND et al. Correlates of blood pressure in community-dwelling older adults. The Cardiovascular Health Study. Cardiovascular Health Study (CHS) Collaborative Research Group. Hypertension 1994; 23: 59–67.

    Article  CAS  PubMed  Google Scholar 

  22. American Diabetes Association: clinical practice recommendations 1997. Diabetes Care 1997; 20 (Suppl 1): S1–S70.

  23. Robbins J, Wahl P, Savage P, Enright P, Powe N, Lyles M . Hematological and biochemical laboratory values in older Cardiovascular Health Study participants. J Am Geriatr Soc 1995; 43: 855–859.

    Article  CAS  PubMed  Google Scholar 

  24. Gauderman W, Morrison J . QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies. http://hydra.usc.edu/gxe, 2006.

  25. Carter KW, McCaskie PA, Palmer LJ . JLIN: a java based linkage disequilibrium plotter. BMC Bioinformatics 2006; 7: 60.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shioji K, Kokubo Y, Mannami T, Inamoto N, Morisaki H, Mino Y et al. Association between hypertension and the alpha-adducin, beta1-adrenoreceptor, and G-protein beta3 subunit genes in the Japanese population; the Suita study. Hypertens Res 2004; 27: 31–37.

    Article  CAS  PubMed  Google Scholar 

  27. Bagos PG, Elefsinioti AL, Nikolopoulos GK, Hamodrakas SJ . The GNB3 C825T polymorphism and essential hypertension: a meta-analysis of 34 studies including 14 094 cases and 17 760 controls. J Hypertens 2007; 25: 487–500.

    Article  CAS  PubMed  Google Scholar 

  28. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Article  PubMed  Google Scholar 

  29. Glorioso N, Filigheddu F, Cusi D, Troffa C, Conti M, Natalizio M et al. alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives. Hypertension 2002; 39: 357–362.

    Article  CAS  PubMed  Google Scholar 

  30. Beeks E, van der Klauw MM, Kroon AA, Spiering W, Fuss-Lejeune MJ, de Leeuw PW . Alpha-adducin Gly460Trp polymorphism and renal hemodynamics in essential hypertension. Hypertension 2004; 44: 419–423.

    Article  CAS  PubMed  Google Scholar 

  31. Guimaraes S, Moura D . Vascular adrenoceptors: an update. Pharmacol Rev 2001; 53: 319–356.

    CAS  PubMed  Google Scholar 

  32. Hein TW, Zhang C, Wang W, Kuo L . Heterogeneous beta2-adrenoceptor expression and dilation in coronary arterioles across the left ventricular wall. Circulation 2004; 110: 2708–2712.

    Article  CAS  PubMed  Google Scholar 

  33. Morrison AC, Doris PA, Folsom AR, Nieto FJ, Boerwinkle E . G-protein beta3 subunit and alpha-adducin polymorphisms and risk of subclinical and clinical stroke. Stroke 2001; 32: 822–829.

    Article  CAS  PubMed  Google Scholar 

  34. Siffert W . G protein beta 3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy. Nephrol Dial Transplant 2000; 15: 1298–1306.

    Article  CAS  PubMed  Google Scholar 

  35. van Rijn MJE, Bos MJ, Yazdanpanah M, Isaacs A, Arias-Vasquez A, Koudstaal PJ et al. alpha-Adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk. Stroke 2006; 37: 2930–2934.

    Article  CAS  PubMed  Google Scholar 

  36. Perticone F, Sciacqua A, Barlassina C, Del Vecchio L, Signorello MC, Dal Fiume C et al. Gly460Trp alpha-adducin gene polymorphism and endothelial function in untreated hypertensive patients. J Hypertens 2007; 25: 2234–2239.

    Article  CAS  PubMed  Google Scholar 

  37. Hindorff LA, Heckbert SR, Psaty BM, Lumley T, Siscovick DS, Herrington DM et al. beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study. Am J Hypertens 2005; 18: 392–397.

    Article  CAS  PubMed  Google Scholar 

  38. Mitchell A, Rushentsova U, Siffert W, Philipp T, Wenzel RR . The angiotensin II receptor antagonist valsartan inhibits endothelin 1-induced vasoconstriction in the skin microcirculation in humans in vivo: influence of the G-protein beta3 subunit (GNB3) C825T polymorphism. Clin Pharmacol Ther 2006; 79: 274–281.

    Article  CAS  PubMed  Google Scholar 

  39. Wong TY, Klein R, Nieto FJ, Klein BE, Sharrett AR, Meuer SM et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology 2003; 110: 933–940.

    Article  PubMed  Google Scholar 

  40. van Rijn MJE, Schut AFC, Aulchenko YS, Deinum J, Sayed-Tabatabaei FA, Yazdanpanah M et al. Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes. J Hypertens 2007; 25: 565–570.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The research reported in this paper was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and U01 HL080295 from the National Heart, Lung, and Blood Institute, and grant AG015366 from National Institute on Aging, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant R21-HL077166 from NHLBI, NIH and the Sylvia and Charles Viertel Clinical Investigator Award (TYW). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T Y Wong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, C., Wang, J., Islam, F. et al. Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study. J Hum Hypertens 23, 578–584 (2009). https://doi.org/10.1038/jhh.2008.168

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2008.168

Keywords

This article is cited by

Search

Quick links