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:

The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13 940 cases and 16 364 controls

Journal of Human Hypertension volume 27, pages 245–255 (2013)Cite this article

Subjects

Abstract

The apolipoprotein E single-nucleotide polymorphisms are among the potential candidate genes that may serve as modulators in susceptibility to essential hypertension. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case–control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 45 studies, including 13 940 hypertensive cases and 16 364 controls. The contrast of E4 carriers versus non-carriers yielded an overall odds ratio (OR) of 1.16 (95% confidence interval (CI): 1.02, 1.31), whereas the contrast of E4 allele versus the others in a subtotal of 6617 cases and 7330 controls, yielded an OR of 1.39 (95% CI: 1.12, 1.72). There was moderate evidence of publication bias in both contrasts, which was eliminated after excluding studies not in Hardy–Weinberg equilibrium. Subgroup analyses revealed that significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, no evidence of publication bias was demonstrated in the comparisons within this subgroup. Our results are consistent with recent meta-analyses but show that the association is weaker than that has been previously demonstrated. Further studies are needed in order to fully address questions about the etiological mechanism of the particular association, as well as to study the effect in populations of African descent.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Ward R . Familial aggregation and genetic epidemiology of blood pressure. In: Laragh J, Brenner B, (eds). Hypertension-Pathophysiology, Diagnosis and Management. Raven Press: New York, 1990 pp 81.

    Google Scholar 

  2. Shore VG, Shore B . Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components. Biochemistry 1973; 12 (3): 502–507.

    Article  CAS  PubMed  Google Scholar 

  3. Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM et al. Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem 1995; 41 (8 Pt 1): 1068–1086.

    CAS  PubMed  Google Scholar 

  4. Schaeffner ES, Kurth T, Curhan GC, Glynn RJ, Rexrode KM, Baigent C et al. Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 2003; 14 (8): 2084–2091.

    CAS  PubMed  Google Scholar 

  5. Zak I, Niemiec P, Balcerzyk A, Krauze J . Combined ‘pro-atherosclerotic’ variants of the ACE and APOE genes increase the risk of the coronary artery disease associated with the presence of cigarette smoking. Acta Cardiol 2008; 63 (6): 741–747.

    Article  PubMed  Google Scholar 

  6. Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP . Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2005; 2 (12): e334.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283 (15): 2008–2012.

    Article  CAS  PubMed  Google Scholar 

  8. Bagos PG . A unification of multivariate methods for meta-analysis of genetic association studies. Stat Appl Genet Mol Biol 2008; 7 (1): Article31.

  9. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (3): 177–188.

    Article  CAS  PubMed  Google Scholar 

  10. Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557–560.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Thompson SG, Sharp SJ . Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18 (20): 2693–2708.

    Article  CAS  PubMed  Google Scholar 

  12. Begg CB, Mazumdar M . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50 (4): 1088–1101.

    Article  CAS  PubMed  Google Scholar 

  13. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315 (7109): 629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP . Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 2006; 163 (4): 300–309.

    Article  PubMed  Google Scholar 

  15. Guo SW, Thompson EA . Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992; 48 (2): 361–372.

    Article  CAS  PubMed  Google Scholar 

  16. Lau J, Schmid CH, Chalmers TC . Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. J Clin Epidemiol 1995; 48 (1): 45–57 discussion 59-60.

    Article  CAS  PubMed  Google Scholar 

  17. Ioannidis JP, Trikalinos TA . Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials. J Clin Epidemiol 2005; 58 (6): 543–549.

    Article  PubMed  Google Scholar 

  18. Bagos PG, Nikolopoulos GK . Generalized least squares for assessing trends in cumulative meta-analysis with applications in genetic epidemiology. J Clin Epidemiol 2009; 62 (10): 1037–1044.

    Article  PubMed  Google Scholar 

  19. Terry JG, Howard G, Mercuri M, Bond MG, Crouse JR . Apolipoprotein E polymorphism is associated with segment-specific extracranial carotid artery intima-media thickening. Stroke 1996; 27 (10): 1755–1759.

    Article  CAS  PubMed  Google Scholar 

  20. Djousse L, Myers RH, Province MA, Hunt SC, Eckfeldt JH, Evans G et al. Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis: National Heart, Lung, and Blood Institute Family Heart Study. Stroke 2002; 33 (5): 1357–1361.

    Article  PubMed  Google Scholar 

  21. Sachdev PS, Parslow R, Wen W, Anstey KJ, Easteal S . Sex differences in the causes and consequences of white matter hyperintensities. Neurobiol Aging 2009; 30 (6): 946–956.

    Article  CAS  PubMed  Google Scholar 

  22. Fuzikawa AK, Peixoto SV, Taufer M, Moriguchi EH, Lima-Costa MF . Association of ApoE polymorphisms with prevalent hypertension in 1406 older adults: the Bambui Health Aging Study (BHAS). Braz J Med Biol Res 2008; 41 (2): 89–94.

    Article  CAS  PubMed  Google Scholar 

  23. Resnick HE, Rodriguez B, Havlik R, Ferrucci L, Foley D, Curb JD et al. Apo E genotype, diabetes, and peripheral arterial disease in older men: the Honolulu Asia-aging study. Genet Epidemiol 2000; 19 (1): 52–63.

    Article  CAS  PubMed  Google Scholar 

  24. Profenno LA, Faraone SV . Diabetes and overweight associate with non-APOE4 genotype in an Alzheimer’s disease population. Am J Med Genet B Neuropsychiatr Genet 2008; 147B (6): 822–829.

    Article  PubMed  Google Scholar 

  25. Carmelli D, Swan GE, Reed T, Miller B, Wolf PA, Jarvik GP et al. Midlife cardiovascular risk factors, ApoE, and cognitive decline in elderly male twins. Neurology 1998; 50 (6): 1580–1585.

    Article  CAS  PubMed  Google Scholar 

  26. Bennouar N, Allami A, Laraqui A, Azeddoug H, El-Kadiri N, Benkouka F et al. [Apolipoprotein E and angiotensin-converting enzyme gene polymorphisms as risk factors of coronary disease]. Ann Biol Clin 2004; 62 (3): 295–304.

    CAS  Google Scholar 

  27. Carmo MM, Lima FL, Rodrigues MO, Albergaria I, Fonseca A . Influence of the APOE genotypes in some atherosclerotic risk factors. Acta Med Port 2008; 21 (5): 433–440.

    Google Scholar 

  28. Isbir T, Yilmaz H, Bihorac A, Akoglu E . Mild-to-moderate hypertension and apolipoprotein E gene polymorphism. Am J Hypertens 1997; 10 (7 Part 1): 827–828.

    CAS  PubMed  Google Scholar 

  29. Corbo RM, Vilardo T, Ruggeri M, Gemma AT, Scacchi R . Apolipoprotein E genotype and plasma levels in coronary artery disease. A case-control study in the Italian population. Clin Biochem 1999; 32 (3): 217–222.

    Article  CAS  PubMed  Google Scholar 

  30. Yilmaz H, Isbir T, Agachan B, Aydin M . Is epsilon4 allele of apolipoprotein E associated with more severe end-organ damage in essential hypertension? Cell Biochem Funct 2001; 19 (3): 191–195.

    Article  CAS  PubMed  Google Scholar 

  31. Li X, Du Y, Huang X . Association of apolipoprotein E gene polymorphism with essential hypertension and its complications. Clin Exp Med 2003; 2 (4): 175–179.

    Article  CAS  PubMed  Google Scholar 

  32. Niu W, Guo X, Su Y, Qiu C . Apolipoprotein E and low-density lipoprotein receptor gene polymorphisms in dyslipidemias-associated essential hypertension. J Hum Hypertens 2007; 21 (4): 337–339.

    Article  CAS  PubMed  Google Scholar 

  33. Dembinska-Kiec A, Kawecka-Jaszcz K, Kwasniak M, Guevara I, Pankiewicz J, Malczewska-Malec M et al. Apo E isoforms, insulin output and plasma lipid levels in essential hypertension. Eur J Clin Invest 1998; 28 (2): 95–99.

    Article  CAS  PubMed  Google Scholar 

  34. Eto M, Watanabe K, Chonan N, Ishii K . Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis 1988; 72 (2-3): 123–128.

    Article  CAS  PubMed  Google Scholar 

  35. Niu W, Qi Y, Qian Y, Gao P, Zhu D . The relationship between apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls. Hypertens Res 2009; 32 (12): 1060–1066.

    Article  CAS  PubMed  Google Scholar 

  36. Niu WQ, Qi Y . Meta-based evidence for apolipoprotein E varepsilon2/varepsilon3/varepsilon4 polymorphism in association with hypertension among Chinese. J Hum Hypertens 2011; 25 (12): 725–731.

    Article  CAS  PubMed  Google Scholar 

  37. Conn VS, Valentine JC, Cooper HM, Rantz MJ . Grey literature in meta-analyses. Nurs Res 2003; 52 (4): 256–261.

    Article  PubMed  Google Scholar 

  38. Young JH, Chang YP, Kim JD, Chretien JP, Klag MJ, Levine MA et al. Differential susceptibility to hypertension is due to selection during the out-of-Africa expansion. PLoS Genet 2005; 1 (6): e82.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Karvonen J, Kauma H, Kervinen K, Ukkola O, Rantala M, Paivansalo M et al. Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J Hypertens 2002; 20 (12): 2371–2378.

    Article  CAS  PubMed  Google Scholar 

  40. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D . Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men. Stroke 1996; 27 (12): 2230–2235.

    Article  CAS  PubMed  Google Scholar 

  41. Schmidt R, Schmidt H, Fazekas F, Schumacher M, Niederkorn K, Kapeller P et al. Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke 1997; 28 (5): 951–956.

    Article  CAS  PubMed  Google Scholar 

  42. Kessler C, Spitzer C, Stauske D, Mende S, Stadlmuller J, Walther R et al. The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol 1997; 17 (11): 2880–2884.

    Article  CAS  PubMed  Google Scholar 

  43. Kimura H, Suzuki Y, Gejyo F, Karasawa R, Miyazaki R, Suzuki S et al. Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM. Am J Kidney Dis 1998; 31 (4): 666–673.

    Article  CAS  PubMed  Google Scholar 

  44. Niemi M, Kervinen K, Rantala A, Kauma H, Paivansalo M, Savolainen MJ et al. The role of apolipoprotein E and glucose intolerance in gallstone disease in middle aged subjects. Gut 1999; 44 (4): 557–562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dzimiri N, Meyer BF, Hussain SS, Basco C, Afrane B, Halees Z . Relevance of apolipoprotein E polymorphism for coronary artery disease in the Saudi population. Arch Pathol Lab Med 1999; 123 (12): 1241–1245.

    CAS  PubMed  Google Scholar 

  46. Meigs JB, Ordovas JM, Cupples LA, Singer DE, Nathan DM, Schaefer EJ et al. Apolipoprotein E isoform polymorphisms are not associated with insulin resistance: the Framingham Offspring Study. Diabetes Care 2000; 23 (5): 669–674.

    Article  CAS  PubMed  Google Scholar 

  47. Gonzalez-Amieva A, Lopez-Miranda J, Fuentes F, Castro P, Marin C, Lopez-Granados A et al. Genetic variations of the apolipoprotein E gene determine the plasma triglyceride levels after heart transplantation. J Heart Lung Transplant 2000; 19 (8): 765–770.

    Article  CAS  PubMed  Google Scholar 

  48. Guz G, Nurhan Ozdemir F, Sezer S, Isiklar I, Arat Z, Turan M et al. Effect of apolipoprotein E polymorphism on serum lipid, lipoproteins, and atherosclerosis in hemodialysis patients. Am J Kidney Dis 2000; 36 (4): 826–836.

    Article  CAS  PubMed  Google Scholar 

  49. Imazu M, Yamamoto H, Toyofuku M, Watanabe T, Okubo M, Egusa G et al. Association of apolipoprotein E phenotype with hypertension in Japanese-Americans: data from the Hawaii-Los Angeles-Hiroshima Study. Hypertens Res 2001; 24 (5): 523–529.

    Article  CAS  PubMed  Google Scholar 

  50. Bednarska-Makaruk M, Broda G, Kurjata P, Rodo M, Roszczynko M, Rywik S et al. Apolipoprotein E genotype, lipid levels and coronary heart disease in a Polish population group. Eur J Epidemiol 2001; 17 (8): 789–792.

    Article  CAS  PubMed  Google Scholar 

  51. Schwanke CH, da Cruz IB, Leal NF, Scheibe R, Moriguchi Y, Moriguchi EH . Analysis of the association between apolipoprotein E polymorphism and cardiovascular risk factors in an elderly population with longevity. Arq Bras Cardiol 2002; 78 (6): 561–579.

    Article  CAS  PubMed  Google Scholar 

  52. Katsuya T, Baba S, Ishikawa K, Mannami T, Fu Y, Inamoto N et al. Epsilon 4 allele of apolipoprotein E gene associates with lower blood pressure in young Japanese subjects: the Suita Study. J Hypertens 2002; 20 (10): 2017–2021.

    Article  CAS  PubMed  Google Scholar 

  53. Mozas P, Castillo S, Reyes G, Tejedor D, Civeira F, Garcia-Alvarez I et al. Apolipoprotein E genotype is not associated with cardiovascular disease in heterozygous subjects with familial hypercholesterolemia. Am Heart J 2003; 145 (6): 999–1005.

    Article  CAS  PubMed  Google Scholar 

  54. Qiu C, Winblad B, Fastbom J, Fratiglioni L . Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD. Neurology 2003; 61 (5): 655–660.

    Article  PubMed  Google Scholar 

  55. Pezzini A, Grassi M, Del Zotto E, Bazzoli E, Archetti S, Assanelli D et al. Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults. Stroke 2004; 35 (2): 438–442.

    Article  CAS  PubMed  Google Scholar 

  56. de Leeuw FE, Richard F, de Groot JC, van Duijn CM, Hofman A, Van Gijn J et al. Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke 2004; 35 (5): 1057–1060.

    Article  CAS  PubMed  Google Scholar 

  57. Ranjith N, Pegoraro RJ, Rom L, Rajput MC, Naidoo DP . Lp(a) and apoE polymorphisms in young South African Indians with myocardial infarction. Cardiovasc J S Afr 2004; 15 (3): 111–117.

    CAS  PubMed  Google Scholar 

  58. Kang JH, Logroscino G, De Vivo I, Hunter D, Grodstein F . Apolipoprotein E cardiovascular disease and cognitive function in aging women. Neurobiol Aging 2005; 26 (4): 475–484.

    Article  CAS  PubMed  Google Scholar 

  59. Um JY, Hwang CY, Hwang WJ, Kang SD, Do KR, Cho JJ et al. Association between iris constitution and apolipoprotein e gene polymorphism in hypertensives. J Altern Complement Med 2004; 10 (6): 1101–1105.

    Article  PubMed  Google Scholar 

  60. Bhavani AB, Sastry KB, Reddy NK, Padma T . Lipid profile and apolipoprotein E polymorphism in essential hypertension. Indian Heart J 2005; 57 (2): 151–157.

    CAS  PubMed  Google Scholar 

  61. Rowan E, Morris CM, Stephens S, Ballard C, Dickinson H, Rao H et al. Impact of hypertension and apolipoprotein E4 on poststroke cognition in subjects >75 years of age. Stroke 2005; 369: 1864–1868.

    Article  Google Scholar 

  62. Pitsavos C, Choumerianou DM, Skoumas J, Maumus S, Stefanadis C, Dedoussis GV et al. Apolipoprotein E polymorphism is not associated with lipid levels and coronary artery disease in Greek patients with familial hypercholesterolaemia. Clin Exp Med 2005; 5 (4): 196–201.

    Article  CAS  PubMed  Google Scholar 

  63. Baum L, Lam LC, Kwok T, Lee J, Chiu HF, Mok VC et al. Apolipoprotein E epsilon4 allele is associated with vascular dementia. Dement Geriatr Cogn Disord 2006; 22 (4): 301–305.

    Article  CAS  PubMed  Google Scholar 

  64. Formiga F, Alia P, Navarro MA, Pujol R . Apolipoprotein e genotypes in nonagenarians. J Am Geriatr Soc 2006; 54 (9): 1471–1473.

    Article  PubMed  Google Scholar 

  65. Wohlin M, Sundstrom J, Lannfelt L, Axelsson T, Syvanen AC, Andren B et al. Apolipoprotein E epsilon4 genotype is independently associated with increased intima-media thickness in a recessive pattern. Lipids 2007; 42 (5): 451–456.

    Article  CAS  PubMed  Google Scholar 

  66. Wang B, Zhao H, Zhou L, Dai X, Wang D, Cao J et al. Association of genetic variation in apolipoprotein E and low density lipoprotein receptor with ischemic stroke in Northern Han Chinese. J Neurol Sci 2009; 276 (1-2): 118–122.

    Article  CAS  PubMed  Google Scholar 

  67. Ruixing Y, Jinzhen W, Weixiong L, Yuming C, Dezhai Y, Shangling P . The environmental and genetic evidence for the association of hyperlipidemia and hypertension. J Hypertens 2009; 27 (2): 251–258.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the two anonymous reviewers whose comments helped in improving the quality of the manuscript.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Biophysics, University of Athens, Athens, Greece

    S Stoumpos, S J Hamodrakas & P G Anthopoulos

  2. Department of Computer Science and Biomedical Informatics, University of Central Greece, Lamia, Greece

    P G Bagos

Authors
  1. S Stoumpos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S J Hamodrakas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P G Anthopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P G Bagos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P G Bagos.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stoumpos, S., Hamodrakas, S., Anthopoulos, P. et al. The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13 940 cases and 16 364 controls. J Hum Hypertens 27, 245–255 (2013). https://doi.org/10.1038/jhh.2012.37

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2012.37

Keywords

Search

Advanced search

Quick links