Skip to main content
SpringerLink
Log in

Angiotensin-converting enzyme gene deletion allele increases the risk of left ventricular hypertrophy: evidence from a meta-analysis

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Large panels of studies have examined the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk for left ventricular hypertrophy (LVH), yet with inconclusive results. We therefore sought to evaluate this association via a comprehensive meta-analysis. A random-effects model was applied irrespective of between-study heterogeneity. Data and study quality were independently assessed by two investigators. Total 52 studies encompassing 3,663 case-patients and 8,953 controls were meta-analyzed. Overall results indicated that carriers homozygous for DD genotype conferred 1.59 times (95 % confidence interval [95 % CI]: 1.31–1.92; P < 0.0005) more likely to develop LVH compared with those with II genotype, accompanying moderate evidence of heterogeneity (I 2 = 49.0 %). In subgroup analyses by ethnicity, DD homozygotes had a 90 % (95 % CI: 1.42–2.53; P < 0.0005) increased risk in East Asians, but merely a 33 % (95 % CI: 1.03–1.73; P = 0.032) increased risk in Caucasians. Moreover, differences in source of controls, cutoff for the definition of hypertension, and diagnostic method of LVH were also regarded as potential sources of heterogeneity. Further, the risk estimate associated with D allele was more pronounced in studies involving males (odds ratio [OR] = 1.47; 95 % CI: 1.2–1.8; P < 0.0005) and untreated subjects (OR = 1.39; 95 % CI: 1.2–1.62; P < 0.0005). The magnitude of publication bias was greatly improved in homozygous subgroups. Taken together, our results demonstrated significant association of ACE gene I/D polymorphism with LVH risk, especially in East Asians, and this association was more pronounced in studies involving males and untreated subjects.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Schunkert H, Hense HW, Holmer SR, Stender M, Perz S et al (1994) Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 330:1634–1638

    Article  PubMed  CAS  Google Scholar 

  2. Nogueira JB (2005) Genetics of left ventricular hypertrophy and its regression. Rev Port Cardiol 24:105–117

    PubMed  Google Scholar 

  3. Arnett DK, de las Fuentes L, Broeckel U (2004) Genes for left ventricular hypertrophy. Curr Hypertens Rep 6:36–41

    Article  PubMed  Google Scholar 

  4. Sasaki M, Oki T, Iuchi A, Tabata T, Yamada H et al (1996) Relationship between the angiotensin converting enzyme gene polymorphism and the effects of enalapril on left ventricular hypertrophy and impaired diastolic filling in essential hypertension: M-mode and pulsed Doppler echocardiographic studies. J Hypertens 14:1403–1408

    Article  PubMed  CAS  Google Scholar 

  5. Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley SC Jr et al (2004) Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol 165:1019–1032

    Article  PubMed  CAS  Google Scholar 

  6. Rigat B, Hubert C, Corvol P, Soubrier F (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 20:1433

    Article  PubMed  CAS  Google Scholar 

  7. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P et al (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Investig 86:1343–1346

    Article  PubMed  CAS  Google Scholar 

  8. Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR et al (1995) Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 92:1387–1388

    Article  PubMed  CAS  Google Scholar 

  9. Niu W, Qi Y (2011) Association of alpha-adducin and G-protein beta3 genetic polymorphisms with hypertension: a meta-analysis of Chinese populations. PLoS ONE 6:e17052

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Bowden J, Tierney JF, Copas AJ, Burdett S (2011) Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics. BMC Med Res Methodol 11:41

    Article  PubMed  Google Scholar 

  12. Celentano A, Mancini FP, Crivaro M, Palmieri V, Ferrara LA et al (1999) Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension. Am J Cardiol 83:1196–1200

    Article  PubMed  CAS  Google Scholar 

  13. Clarkson PB, Prasad N, MacLeod C, Burchell B, MacDonald TM (1997) Influence of the angiotensin converting enzyme I/D gene polymorphisms on left ventricular diastolic filling in patients with essential hypertension. J Hypertens 15:995–1000

    Article  PubMed  CAS  Google Scholar 

  14. Coto E, Palacin M, Martin M, Castro MG, Reguero JR et al (2010) Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier. J Transl Med 8:64

    Article  PubMed  Google Scholar 

  15. Di Mauro M, Izzicupo P, Santarelli F, Falone S, Pennelli A et al (2010) ACE and AGTR1 polymorphisms and left ventricular hypertrophy in endurance athletes. Med Sci Sports Exerc 42:915–921

    Article  PubMed  Google Scholar 

  16. Fernandez-Llama P, Poch E, Oriola J, Botey A, Rivera F et al (1998) Angiotensinogen gene M235T and T174M polymorphisms in essential hypertension: relation with target organ damage. Am J Hypertens 11:439–444

    Article  PubMed  CAS  Google Scholar 

  17. Frossard PM, Hill SH, Elshahat YI, Obineche EN, Bokhari AM et al (1998) Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a Gulf population. Clin Genet 54:285–293

    Article  PubMed  CAS  Google Scholar 

  18. Gharavi AG, Lipkowitz MS, Diamond JA, Jhang JS, Phillips RA (1996) Deletion polymorphism of the angiotensin-converting enzyme gene is independently associated with left ventricular mass and geometric remodeling in systemic hypertension. Am J Cardiol 77:1315–1319

    Article  PubMed  CAS  Google Scholar 

  19. Gomez-Angelats E, de la Sierra A, Enjuto M, Sierra C, Oriola J et al (2000) Lack of association between ACE gene polymorphism and left ventricular hypertrophy in essential hypertension. J Hum Hypertens 14:47–49

    Article  PubMed  CAS  Google Scholar 

  20. Hernandez D, de la Rosa A, Barragan A, Barrios Y, Salido E et al (2003) The ACE/DD genotype is associated with the extent of exercise-induced left ventricular growth in endurance athletes. J Am Coll Cardiol 42:527–532

    Article  PubMed  CAS  Google Scholar 

  21. Iwai N, Ohmichi N, Nakamura Y, Kinoshita M (1994) DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy. Circulation 90:2622–2628

    Article  PubMed  CAS  Google Scholar 

  22. Jeng JR (2000) Carotid thickening, cardiac hypertrophy, and angiotensin converting enzyme gene polymorphism in patients with hypertension. Am J Hypertens 13:111–119

    Article  PubMed  CAS  Google Scholar 

  23. Kasikcioglu E, Kayserilioglu A, Ciloglu F, Akhan H, Oflaz H et al (2004) Angiotensin-converting enzyme gene polymorphism, left ventricular remodeling, and exercise capacity in strength-trained athletes. Heart Vessels 19:287–293

    Article  PubMed  Google Scholar 

  24. Kato N, Tatara Y, Ohishi M, Takeya Y, Onishi M et al (2011) Angiotensin-converting enzyme single nucleotide polymorphism is a genetic risk factor for cardiovascular disease: a cohort study of hypertensive patients. Hypertens Res 34:728–734

    Article  PubMed  CAS  Google Scholar 

  25. Kauma H, Ikaheimo M, Savolainen MJ, Kiema TR, Rantala AO et al (1998) Variants of renin-angiotensin system genes and echocardiographic left ventricular mass. Eur Heart J 19:1109–1117

    Article  PubMed  CAS  Google Scholar 

  26. Kim HS, Lee MM, Oh BH, Kim KI, Han KH et al (2000) Synergistic effect of angiotensin-converting enzyme and angiotensinogen gene on cardiac hypertrophy. Int J Cardiol 72:151–161

    Article  PubMed  CAS  Google Scholar 

  27. Kupari M, Perola M, Koskinen P, Virolainen J, Karhunen PJ (1994) Left ventricular size, mass, and function in relation to angiotensin-converting enzyme gene polymorphism in humans. Am J Physiol 267:H1107–H1111

    PubMed  CAS  Google Scholar 

  28. Lindpaintner K, Lee M, Larson MG, Rao VS, Pfeffer MA et al (1996) Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass. N Engl J Med 334:1023–1028

    Article  PubMed  CAS  Google Scholar 

  29. Makeeva OA, Puzyrev KV, Pavliukova EN, Koshel’skaia OA, Golubenko MV et al (2004) ACE and AGTR1 genes polymorphisms in left ventricular hypertrophy pathogenesis in humans. Mol Biol (Mosk) 38:990–996

    Article  CAS  Google Scholar 

  30. Montgomery HE, Clarkson P, Dollery CM, Prasad K, Losi MA et al (1997) Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation 96:741–747

    Article  PubMed  CAS  Google Scholar 

  31. Obineche EN, Frossard PM, Bokhari AM (2001) An association study of five genetic loci and left ventricular hypertrophy amongst Gulf Arabs. Hypertens Res 24:635–639

    Article  PubMed  CAS  Google Scholar 

  32. Obineche EN, Frossard PM, Bokhari AM (2002) Association between an ANF Gene I/D dimorphism and left ventricular hypertrophy in a Gulf Arab population. Ann Saudi Med 22:22–25

    PubMed  Google Scholar 

  33. Olcay A, Nisanci Y, Ekmekci CG, Umman B, Bugra Z et al (2006) Aldosterone synthase −344C/T and angiotensin-converting enzyme I/D polymorphisms in Turkish hypertensive patients with normal coronary arteries. Acta Cardiol 61:29–34

    Article  PubMed  Google Scholar 

  34. Osono E, Kurihara S, Hayama N, Sakurai Y, Ohwada K et al (1998) Insertion/deletion polymorphism in intron 16 of the ACE gene and left ventricular hypertrophy in patients with end-stage renal disease. Am J Kidney Dis 32:725–730

    Article  PubMed  CAS  Google Scholar 

  35. Pan M, Zhu JH, Liu ZH, Jiang WP, Cui ZC et al (2007) Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left ventricular hypertrophy but not essential hypertension. Hypertens Res 30:31–37

    Article  PubMed  CAS  Google Scholar 

  36. Perticone F, Ceravolo R, Cosco C, Trapasso M, Zingone A et al (1997) Deletion polymorphism of angiotensin-converting enzyme gene and left ventricular hypertrophy in southern Italian patients. J Am Coll Cardiol 29:365–369

    Article  PubMed  CAS  Google Scholar 

  37. Perticone F, Maio R, Cosco C, Ceravolo R, Iacopino S et al (1999) Hypertensive left ventricular remodeling and ACE-gene polymorphism. Cardiovasc Res 43:192–199

    Article  PubMed  CAS  Google Scholar 

  38. Rizzo M, Gensini F, Fatini C, Manetti P, Pucci N et al (2003) ACE I/D polymorphism and cardiac adaptations in adolescent athletes. Med Sci Sports Exerc 35:1986–1990

    Article  PubMed  Google Scholar 

  39. Saeed M, Saleheen D, Siddiqui S, Khan A, Butt ZA et al (2005) Association of angiotensin converting enzyme gene polymorphisms with left ventricular hypertrophy. Hypertens Res 28:345–349

    Article  PubMed  CAS  Google Scholar 

  40. Ueno H, Takata M, Yasumoto K, Tomita S, Inoue H (1999) Angiotensin-converting enzyme gene polymorphism and geometric patterns of hypertensive left ventricular hypertrophy. Jpn Heart J 40:589–598

    Article  PubMed  CAS  Google Scholar 

  41. West MJ, Summers KM, Burstow DJ, Wong KK, Huggard PR (1994) Renin and angiotensin-converting enzyme genotypes in patients with essential hypertension and left ventricular hypertrophy. Clin Exp Pharmacol Physiol 21:207–210

    Article  PubMed  CAS  Google Scholar 

  42. Wong KK, Summers KM, Burstow DJ, West MJ (1995) Angiotensin-converting enzyme and angiotensinogen genes in patterns of left ventricular hypertrophy and in diastolic dysfunction. Clin Exp Pharmacol Physiol 22:438–440

    Article  PubMed  CAS  Google Scholar 

  43. Shen D, Ha D (1998) The relationship between angiotensin converting enzyme genotypes and hypertension complicated with left ventricular hypertrophy. Chin J Med Genet 15:364–366

    CAS  Google Scholar 

  44. Shen D, Ha D, Bai C (2001) Investigation of angiotensin converting enzyme genetic polymorphism and hypertension complicated with left ventricular hypertrophy in older subjects. Chin J Gerontol 21:186–188

    Google Scholar 

  45. Xiang G, Wang Y (2002) The relationship between angiotensin converting enzyme gene and hypertension complicated with left ventricular hypertrophy in patients with type 2 diabetes mellitus. Chin J Diabetes 10:180–181

    Google Scholar 

  46. Zhao D, Zhang R, Song W (2003) ACE gene polymorphism relating to essential hypertension and left ventricular hypertrophy. Mod Med Health 19:1526–1527

    Google Scholar 

  47. Wang J, Jiang M, Wang X, Wu X (2005) A study on the relationship between essential hypertension and the polymorphism of angiotensin-converting enzyme receptor gene. Acta Acad Med Xuzhou 25:520–522

    CAS  Google Scholar 

  48. Yu D, Qiao W, Xu Z, Zuo L, Ren X et al (2010) The relationship between angiotensin II type 1 receptor genetic polymorphism and left ventricular hypertrophy. Shandong Med J 50:55–56

    CAS  Google Scholar 

  49. Lin Y, Yin Y, Yang M, Tao J, Yin L et al (2003) Renin-angiotensin system gene polymorphisms and left ventricular hypertrophy in essential hypertension: an association study. Chin J Geriatr Cardiovasc Cerebrovasc Dis 5:86–89

    Google Scholar 

  50. Liao X, Zhang R, Hu Y, Wang S, Dong S (2005) A study on angiotensin converting enzyme gene polymorphisms in essential hypertension patients with left ventricular hypertrophy. J Chin Physician 7:462–464

    Google Scholar 

  51. Liang R (2008) The relationship between AGT, ACE and eNOS gene polymorphisms and hypertension and left ventricular hypertrophy. Dissertation for Master Degree, Guangdong Medical College

  52. Li X, Gao C (1999) A study on angiotensin converting enzyme gene polymorphism and hypertension with left ventricular hypertrophy. Chin Hypertens J 7:311–313

    Google Scholar 

  53. Gao D, Gao L, Zhao S, Li C, Dai Y et al (2010) The association between hypertension with left ventricular hypertrophy and ACE/ID polymorphisms. Mol Cardiol China 6:328–331

    Google Scholar 

  54. He H, Li L, Cao W, Sun N, Liu M et al (2004) Association between the I/D polymorphism of the ACE gene, A/B polymorphism of the chymase gene and left ventricular hypertrophy in essential hypertension. Chin J Hypertens 12:39–43

    Google Scholar 

  55. Deng Y, Huang D, Cheng Y (1999) A study on angiotensin converting enzyme gene polymorphism and left ventricular hypertrophy in essential hypertension. Chin J Cardiol 27:127–134

    Google Scholar 

  56. Kuznetsova T, Staessen JA, Wang JG, Gasowski J, Nikitin Y et al (2000) Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis. J Hum Hypertens 14:447–454

    Article  PubMed  CAS  Google Scholar 

  57. Yu J, Kuznetsova T, Thijs L, Richart T, Stolarz-Skrzypek K et al (2011) Association of echocardiographic left ventricular structure with the ACE D/I polymorphism: a meta-analysis. J Renin Angiotensin Aldosterone Syst 12:243–253

    Article  Google Scholar 

  58. Hemminki K, Lorenzo Bermejo J, Forsti A (2006) The balance between heritable and environmental aetiology of human disease. Nat Rev Genet 7:958–965

    Article  PubMed  CAS  Google Scholar 

  59. Yu K, Zhang J, Dou C, Gu S, Xie Y et al (2010) Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis. Eur J Hum Genet 18:370–378

    Article  PubMed  CAS  Google Scholar 

  60. Baessler A, Kwitek AE, Fischer M, Koehler M, Reinhard W et al (2006) Association of the Ghrelin receptor gene region with left ventricular hypertrophy in the general population: results of the MONICA/KORA Augsburg Echocardiographic Substudy. Hypertension 47:920–927

    Article  PubMed  CAS  Google Scholar 

  61. Zhu H, Wang X, Dong Y, Treiber FA, Snieder H (2005) Influence of the eNOS gene on development of blood pressure and left ventricular mass: longitudinal findings in multiethnic youth. Pharmacogenet Genomics 15:669–675

    Article  PubMed  CAS  Google Scholar 

  62. Burrell LM, Burchill L, Dean RG, Griggs K, Patel SK, et al. (2011) Chronic kidney disease: cardiac and renal angiotensin converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition. Exp Physiol 97:477–485

    Google Scholar 

  63. Barton M, Meyer MR (2009) Postmenopausal hypertension: mechanisms and therapy. Hypertension 54:11–18

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Shanghai Rising Star Program (11QA1405500), the Natural Science Foundation of Shanghai (11ZR1430500), and the National Natural Science Foundation of China (30900808).

Conflict of interest

The authors have declared that no completing interests exist.

Author information

Authors and Affiliations

  1. State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiaobo Li, Yuqiong Li, Shujie Guo & Wenquan Niu

  2. Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Second Road 197, Shanghai, 200025, China

    Xiaobo Li, Yuqiong Li, Nan Jia & Shaoli Chu

  3. Shanghai Institute of Hypertension, Shanghai, China

    Xiaobo Li, Yuqiong Li, Nan Jia, Shujie Guo, Shaoli Chu & Wenquan Niu

Authors
  1. Xiaobo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuqiong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shujie Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shaoli Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenquan Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nan Jia or Wenquan Niu.

Additional information

Xiaobo Li, Yuqiong Li are the authors have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 64 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, X., Li, Y., Jia, N. et al. Angiotensin-converting enzyme gene deletion allele increases the risk of left ventricular hypertrophy: evidence from a meta-analysis. Mol Biol Rep 39, 10063–10075 (2012). https://doi.org/10.1007/s11033-012-1875-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-1875-6

Keywords

Search

Navigation