Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors

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Angiotensin-converting enzyme 2 (ACE2), a newly discovered member of renin–angiotensin–aldosterone system, counterbalances the actions of angiotensin-converting enzyme. The objective of our study was to assess the association between rs2106809 polymorphism in ACE2 gene and the blood pressure response to ACE inhibitors in untreated hypertensive patients. After a 2-week, double-blind placebo run-in period, either benazepril or imidapril was administered for 6 weeks to 497 patients with mild to moderate essential hypertension. The achieved changes in BP were analyzed for their association with genotypes at ACE2 gene loci. In female hypertensive patients, the genotype frequency of ACE2 rs2106809 was 36.7%, 45.2% and 18.1% for CC, CT and TT genotypes, respectively. After 6 weeks of treatment, the reductions in diastolic blood pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (9.62±6.83 or 10.2±7.2 versus 6.81±6.31 mm Hg, respectively; P=0.045, analysis of variance (ANOVA)). Moreover, the reductions in mean arterial pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (12.1±7.5 or 12.0±7.9 versus 8.38±6.83 mm Hg, respectively; P=0.035, ANOVA). In male hypertensive patients, the genotype frequency of ACE2 rs2106809 was 58.1% and 41.9% for C and T genotypes, respectively. However, no association could be observed in males. We conclude that ACE2 rs2106809 is an important predictive factor of the response to antihypertensive treatment with ACE inhibitors in Chinese female hypertensive patients.

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  1. 1

    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J . Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: 217–223.

  2. 2

    Bidiville J, Nussberger J, Waeber G, Porchet M, Waeber B, Brunner HR . Individual responses to converting enzyme inhibitors and calcium antagonists. Hypertension 1988; 11: 166–173.

  3. 3

    Sciarrone MT, Stella P, Barlassina C, Manunta P, Lanzani C, Bianchi G et al. ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension 2003; 41: 398–403.

  4. 4

    Jiang S, Hsu YH, Venners SA, Zhang Y, Xing H, Wang X et al. Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients. J Hum Hypertens 2011; 25: 327–333.

  5. 5

    Kim S, Iwao H . Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol 2000; 52: 11–34.

  6. 6

    Mehta PK, Griendling KK . Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292: C82–C97.

  7. 7

    Probstfield JL, O'Brien KD . Progression of cardiovascular damage: the role of renin–angiotensin system blockade. Am J Cardiol 2010; 105: 10 A–20 A.

  8. 8

    le Tran Y, Forster C . Angiotensin-(1-7) and the rat aorta: modulation by the endothelium. J Cardiovasc Pharmacol 1997; 30: 676–682.

  9. 9

    Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 2003; 100: 8258–8263.

  10. 10

    Santos RA, Ferreira AJ, Nadu AP, Braga AN, de Almeida AP, Campagnole-Santos MJ et al. Expression of an angiotensin-(1–7)-producing fusion protein produces cardioprotective effects in rats. Physiol Genomics 2004; 17: 292–299.

  11. 11

    Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM et al. Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7). Am J Physiol Heart Circ Physiol 2007; 292: H736–H742.

  12. 12

    Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ et al. Angiotensin(1–7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res 2008; 103: 1319–1326.

  13. 13

    Nadu AP, Ferreira AJ, Reudelhuber TL, Bader M, Santos RA . Reduced isoproterenol-induced renin–angiotensin changes and extracellular matrix deposition in hearts of TGR(A1–7)3292 rats. J Am Soc Hypertens 2008; 2: 341–348.

  14. 14

    Savergnini SQ, Beiman M, Lautner RQ, de Paula-Carvalho V, Allahdadi K, Pessoa DC et al. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension 2010; 56: 112–120.

  15. 15

    Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002; 417: 822–828.

  16. 16

    Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML et al. Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension 2008; 52: 967–973.

  17. 17

    Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006; 116: 2218–2225.

  18. 18

    Fan X, Wang Y, Sun K, Zhang W, Yang X, Wang S et al. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women. Clin Pharmacol Ther 2007; 82: 187–196.

  19. 19

    Patnaik M, Pati P, Swain SN, Mohapatra MK, Dwibedi B, Kar SK et al. Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann Hum Biol 2014; 41: 145–152.

  20. 20

    Imidapril and Benazepril Clinical Study Cooperation Unit. Comparative study of hypotensive efficacy and the cough occurrence of imidapril versus benazepril. Chin J Cardiol 2004; 32: 304–307.

  21. 21

    Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C . Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67.

  22. 22

    Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM . Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 2006; 48: 914–920.

  23. 23

    Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005; 111: 2605–2610.

  24. 24

    Tikellis C, Bialkowski K, Pete J, Sheehy K, Su Q, Johnston C et al. ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes. Diabetes 2008; 57: 1018–1025.

  25. 25

    Sullivan JC, Rodriguez-Miguelez P, Zimmerman MA, Harris RA . Differences in angiotensin (1–7) between men and women. Am J Physiol Heart Circ Physiol 2015; 308: H1171–H1176.

  26. 26

    Zimmerman MA, Harris RA, Sullivan JC . Female spontaneously hypertensive rats are more dependent on ANG (1–7) to mediate effects of low-dose AT1 receptor blockade than males. Am J Physiol Renal Physiol 2014; 306: F1136–F1142.

  27. 27

    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: 1903–1913.

  28. 28

    Sesso HD, Stampfer MJ, Rosner B, Hennekens CH, Gaziano JM, Manson JE et al. Systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure as predictors of cardiovascular disease risk in men. Hypertension 2000; 36: 801–807.

  29. 29

    Dyer AR, Stamler J, Shekelle RB, Schoenberger JA, Stamler R, Shekelle S et al. Pulse pressure, III: prognostic significance in four Chicago epidemiologic studies. J Chron Dis 1982; 35: 283–294.

  30. 30

    Jiang L, Huang C, Sun Q, Guo H, Cheng T, Peng Z et al. The 5′-UTR intron of the midgut-specific BmAPN4 gene affects the level and location of expression in transgenic silkworms. Insect Biochem Mol Biol 2015; 63: 1–6.

  31. 31

    Le Hir H, Nott A, Moore MJ . How introns influence and enhance eukaryotic gene expression. Trends Biochem Sci 2003; 28: 215–220.

  32. 32

    Brinster RL, Allen JM, Behringer RR, Gelinas RE, Palmiter RD . Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci USA 1988; 85: 836–840.

  33. 33

    Oh VM, Chua BM, Heng CK, Yeo SB, Yim OS, Yap EP . Association of intronic single-nucleotide polymorphisms in the EMILIN1 gene with essential hypertension in a Chinese population. J Hum Hypertens 2012; 26: 553–561.

  34. 34

    Seo S, Takayama K, Uno K, Ohi K, Hashimoto R, Nishizawa D et al. Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene. PLoS ONE 2013; 8: e76960.

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We thank Xiangfeng Dou (Department of Epidemiology, Beijing Center for Disease Prevention and Control, Beijing, People's Republic of China) for his help in statistical analysis. This study was supported by National Natural Science Foundation of China (Nos 81273599 and 81370362); Guangdong Natural Science Foundation (No. 2015A030313661); Science and Technology Planning Project of Guangdong Province (No. 2014A020212404); National Major Research Plan Training Program (No. 91339108); and the National Basic Research Program of China (No. 2014CB542300).

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Correspondence to L J Jin or H M Yu.

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