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. 2004 Feb;41(2):99–103. doi: 10.1136/jmg.2003.013441

A study of gene–environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach

F Sayed-Tabatabaei 1, A Schut 1, A Hofman 1, A Bertoli-Avella 1, J Vergeer 1, J Witteman 1, C M van Duijn 1
PMCID: PMC1735668  PMID: 14757856

Abstract

Introduction: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene–environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness.

Methods: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products.

Results: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r2 = 0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers.

Discussion: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis.

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Selected References

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  1. Barua R. S., Ambrose J. A., Eales-Reynolds L. J., DeVoe M. C., Zervas J. G., Saha D. C. Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. Circulation. 2001 Oct 16;104(16):1905–1910. doi: 10.1161/hc4101.097525. [DOI] [PubMed] [Google Scholar]
  2. Bots M. L., Hofman A., De Jong P. T., Grobbee D. E. Common carotid intima-media thickness as an indicator of atherosclerosis at other sites of the carotid artery. The Rotterdam Study. Ann Epidemiol. 1996 Mar;6(2):147–153. doi: 10.1016/1047-2797(96)00001-4. [DOI] [PubMed] [Google Scholar]
  3. Bots M. L., Mulder P. G., Hofman A., van Es G. A., Grobbee D. E. Reproducibility of carotid vessel wall thickness measurements. The Rotterdam Study. J Clin Epidemiol. 1994 Aug;47(8):921–930. doi: 10.1016/0895-4356(94)90196-1. [DOI] [PubMed] [Google Scholar]
  4. Butler R., Morris A. D., Burchell B., Struthers A. D. DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans. Hypertension. 1999 May;33(5):1164–1168. doi: 10.1161/01.hyp.33.5.1164. [DOI] [PubMed] [Google Scholar]
  5. Castellano M., Muiesan M. L., Rizzoni D., Beschi M., Pasini G., Cinelli A., Salvetti M., Porteri E., Bettoni G., Kreutz R. Angiotensin-converting enzyme I/D polymorphism and arterial wall thickness in a general population. The Vobarno Study. Circulation. 1995 Jun 1;91(11):2721–2724. doi: 10.1161/01.cir.91.11.2721. [DOI] [PubMed] [Google Scholar]
  6. Celermajer D. S., Sorensen K. E., Georgakopoulos D., Bull C., Thomas O., Robinson J., Deanfield J. E. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993 Nov;88(5 Pt 1):2149–2155. doi: 10.1161/01.cir.88.5.2149. [DOI] [PubMed] [Google Scholar]
  7. Clara J. G., Coelho C., Breitenfeld L., Siqueira C., Bicho M., de Pádua F. Acçes agudas do tabaco e risco vascular modulado por factores genéticos. Rev Port Cardiol. 2000 Dec;19(12):1279–1283. [PubMed] [Google Scholar]
  8. Danser A. H., Schalekamp M. A., Bax W. A., van den Brink A. M., Saxena P. R., Riegger G. A., Schunkert H. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995 Sep 15;92(6):1387–1388. doi: 10.1161/01.cir.92.6.1387. [DOI] [PubMed] [Google Scholar]
  9. Dessi-Fulgheri P., Catalini R., Sarzani R., Sturbini S., Siragusa N., Guazzarotti F., Offidani M., Tamburrini P., Zingaretti O., Rappelli A. Angiotensin converting enzyme gene polymorphism and carotid atherosclerosis in a low-risk population. J Hypertens. 1995 Dec;13(12 Pt 2):1593–1596. [PubMed] [Google Scholar]
  10. Diamantopoulos E. J., Andreadis E., Kakou M., Vlachonikolis I., Vassilopoulos C., Giannakopoulos N., Tarassi K., Papasteriades C., Nicolaides A., Raptis S. Atherosclerosis of carotid arteries and the ace insertion/deletion polymorphism in subjects with diabetes mellitus type 2. Int Angiol. 2002 Mar;21(1):63–69. [PubMed] [Google Scholar]
  11. Erdös E. G., Skidgel R. A. The angiotensin I-converting enzyme. Lab Invest. 1987 Apr;56(4):345–348. [PubMed] [Google Scholar]
  12. Friedland J., Silverstein E. A sensitive fluorimetric assay for serum angiotensin-converting enzyme. Am J Clin Pathol. 1976 Aug;66(2):416–424. doi: 10.1093/ajcp/66.2.416. [DOI] [PubMed] [Google Scholar]
  13. Hibi K., Ishigami T., Kimura K., Nakao M., Iwamoto T., Tamura K., Nemoto T., Shimizu T., Mochida Y., Ochiai H. Angiotensin-converting enzyme gene polymorphism adds risk for the severity of coronary atherosclerosis in smokers. Hypertension. 1997 Sep;30(3 Pt 2):574–579. doi: 10.1161/01.hyp.30.3.574. [DOI] [PubMed] [Google Scholar]
  14. Hofman A., Grobbee D. E., de Jong P. T., van den Ouweland F. A. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol. 1991 Jul;7(4):403–422. doi: 10.1007/BF00145007. [DOI] [PubMed] [Google Scholar]
  15. Hosoi M., Nishizawa Y., Kogawa K., Kawagishi T., Konishi T., Maekawa K., Emoto M., Fukumoto S., Shioi A., Shoji T. Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients. Circulation. 1996 Aug 15;94(4):704–707. doi: 10.1161/01.cir.94.4.704. [DOI] [PubMed] [Google Scholar]
  16. Hung J., McQuillan B. M., Nidorf M., Thompson P. L., Beilby J. P. Angiotensin-converting enzyme gene polymorphism and carotid wall thickening in a community population. Arterioscler Thromb Vasc Biol. 1999 Aug;19(8):1969–1974. doi: 10.1161/01.atv.19.8.1969. [DOI] [PubMed] [Google Scholar]
  17. Jeerooburkhan N., Jones L. C., Bujac S., Cooper J. A., Miller G. J., Vallance P., Humphries S. E., Hingorani A. D. Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease. Hypertension. 2001 Nov;38(5):1054–1061. doi: 10.1161/hy1101.092967. [DOI] [PubMed] [Google Scholar]
  18. Kasahara Y., Ashihara Y. Colorimetry of angiotensin-I converting enzyme activity in serum. Clin Chem. 1981 Nov;27(11):1922–1925. [PubMed] [Google Scholar]
  19. Kauma H., Päivänsalo M., Savolainen M. J., Rantala A. O., Kiema T. R., Lilja M., Reunanen A., Kesäniemi Y. A. Association between angiotensin converting enzyme gene polymorphism and carotid atherosclerosis. J Hypertens. 1996 Oct;14(10):1183–1187. doi: 10.1097/00004872-199610000-00005. [DOI] [PubMed] [Google Scholar]
  20. Keavney B., McKenzie C. A., Connell J. M., Julier C., Ratcliffe P. J., Sobel E., Lathrop M., Farrall M. Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum Mol Genet. 1998 Oct;7(11):1745–1751. doi: 10.1093/hmg/7.11.1745. [DOI] [PubMed] [Google Scholar]
  21. Lindpaintner K., Pfeffer M. A., Kreutz R., Stampfer M. J., Grodstein F., LaMotte F., Buring J., Hennekens C. H. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med. 1995 Mar 16;332(11):706–711. doi: 10.1056/NEJM199503163321103. [DOI] [PubMed] [Google Scholar]
  22. Lohmueller Kirk E., Pearce Celeste L., Pike Malcolm, Lander Eric S., Hirschhorn Joel N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003 Jan 13;33(2):177–182. doi: 10.1038/ng1071. [DOI] [PubMed] [Google Scholar]
  23. Mannami T., Katsuya T., Baba S., Inamoto N., Ishikawa K., Higaki J., Ogihara T., Ogata J. Low potentiality of angiotensin-converting enzyme gene insertion/deletion polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a Japanese city: the Suita study. Stroke. 2001 Jun;32(6):1250–1256. doi: 10.1161/01.str.32.6.1250. [DOI] [PubMed] [Google Scholar]
  24. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nergizoğlu G., Keven K., Gürses M. A., Aras O., Ertürk S., Duman N., Ateş K., Akar H., Akar N., Karatan O. Carotid intima-media thickness and ACE-gene polymorphism in hemodialysis patients. J Nephrol. 1999 Jul-Aug;12(4):261–265. [PubMed] [Google Scholar]
  26. Piquilloud Y., Reinharz A., Roth M. Studies on the angiotensin converting enzyme with different substrates. Biochim Biophys Acta. 1970 Apr 22;206(1):136–142. doi: 10.1016/0005-2744(70)90090-2. [DOI] [PubMed] [Google Scholar]
  27. Pujia A., Motti C., Irace C., Cortese C., Biagiotti L., Mattioli P. L., Federici G., Gnasso A. Deletion polymorphism in angiotensin converting enzyme gene associated with carotid wall thickening in a healthy male population. Coron Artery Dis. 1996 Jan;7(1):51–55. [PubMed] [Google Scholar]
  28. Ramchandran R., Sen G. C., Misono K., Sen I. Regulated cleavage-secretion of the membrane-bound angiotensin-converting enzyme. J Biol Chem. 1994 Jan 21;269(3):2125–2130. [PubMed] [Google Scholar]
  29. Rieder M. J., Taylor S. L., Clark A. G., Nickerson D. A. Sequence variation in the human angiotensin converting enzyme. Nat Genet. 1999 May;22(1):59–62. doi: 10.1038/8760. [DOI] [PubMed] [Google Scholar]
  30. Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990 Oct;86(4):1343–1346. doi: 10.1172/JCI114844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sass C., Zannad F., Herbeth B., Salah D., Chapet O., Siest G., Visvikis S. Apolipoprotein E4, lipoprotein lipase C447 and angiotensin-I converting enzyme deletion alleles were not associated with increased wall thickness of carotid and femoral arteries in healthy subjects from the Stanislas cohort. Atherosclerosis. 1998 Sep;140(1):89–95. doi: 10.1016/s0021-9150(98)00120-8. [DOI] [PubMed] [Google Scholar]
  32. Sayed-Tabatabaei Fakhredin A., Houwing-Duistermaat Jeanine J., van Duijn Cornelia M., Witteman Jacqueline C. M. Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis. Stroke. 2003 Jun 12;34(7):1634–1639. doi: 10.1161/01.STR.0000077926.49330.64. [DOI] [PubMed] [Google Scholar]
  33. Soubrier Florent, Martin Sabrina, Alonso Amalia, Visvikis Sophie, Tiret Laurence, Matsuda Fumihiko, Lathrop G. Mark, Farrall Martin. High-resolution genetic mapping of the ACE-linked QTL influencing circulating ACE activity. Eur J Hum Genet. 2002 Sep;10(9):553–561. doi: 10.1038/sj.ejhg.5200847. [DOI] [PubMed] [Google Scholar]
  34. Tabara Y., Kohara K., Nakura J., Miki T. Risk factor-gene interaction in carotid atherosclerosis: effect of gene polymorphisms of renin-angiotensin system. J Hum Genet. 2001;46(5):278–284. doi: 10.1007/s100380170079. [DOI] [PubMed] [Google Scholar]
  35. Tiret L., Rigat B., Visvikis S., Breda C., Corvol P., Cambien F., Soubrier F. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992 Jul;51(1):197–205. [PMC free article] [PubMed] [Google Scholar]
  36. Tsuchiya Masahiko, Asada Akira, Kasahara Emiko, Sato Eisuke F., Shindo Mitsuo, Inoue Masayasu. Smoking a single cigarette rapidly reduces combined concentrations of nitrate and nitrite and concentrations of antioxidants in plasma. Circulation. 2002 Mar 12;105(10):1155–1157. doi: 10.1161/hc1002.105935. [DOI] [PubMed] [Google Scholar]
  37. Uçar G., Yildirim Z., Ataol E., Erdoğan Y., Biber C. Serum angiotensin converting enzyme activity in pulmonary diseases: correlation with lung function parameters. Life Sci. 1997;61(11):1075–1082. doi: 10.1016/s0024-3205(97)00616-4. [DOI] [PubMed] [Google Scholar]
  38. Watanabe Y., Ishigami T., Kawano Y., Umahara T., Nakamori A., Mizushima S., Hibi K., Kobayashi I., Tamura K., Ochiai H. Angiotensin-converting enzyme gene I/D polymorphism and carotid plaques in Japanese. Hypertension. 1997 Sep;30(3 Pt 2):569–573. doi: 10.1161/01.hyp.30.3.569. [DOI] [PubMed] [Google Scholar]
  39. Zhang S., Day I., Ye S. Nicotine induced changes in gene expression by human coronary artery endothelial cells. Atherosclerosis. 2001 Feb 1;154(2):277–283. doi: 10.1016/s0021-9150(00)00475-5. [DOI] [PubMed] [Google Scholar]
  40. Zhu X., McKenzie C. A., Forrester T., Nickerson D. A., Broeckel U., Schunkert H., Doering A., Jacob H. J., Cooper R. S., Rieder M. J. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet. 2000 Sep 19;67(5):1144–1153. doi: 10.1016/s0002-9297(07)62945-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

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