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Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2005 May;42(5):396–401. doi: 10.1136/jmg.2004.026716

Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits

M Abdollahi 1, T Gaunt 1, H Syddall 1, C Cooper 1, D Phillips 1, S Ye 1, I Day 1
PMCID: PMC1736059  PMID: 15863668

Abstract

Background: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated.

Method: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits.

Results: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant.

Conclusions: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.

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Selected References

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  1. Alvarez R., Reguero J. R., Batalla A., Iglesias-Cubero G., Cortina A., Alvarez V., Coto E. Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res. 1998 Nov;40(2):375–379. doi: 10.1016/s0008-6363(98)00179-5. [DOI] [PubMed] [Google Scholar]
  2. Andreozzi Francesco, Laratta Emanuela, Sciacqua Angela, Perticone Francesco, Sesti Giorgio. Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res. 2004 Mar 25;94(9):1211–1218. doi: 10.1161/01.RES.0000126501.34994.96. [DOI] [PubMed] [Google Scholar]
  3. Antonellis Anthony, Rogus John J., Canani Luis H., Makita Yuchiro, Pezzolesi Marcus G., Nam MoonSuk, Ng Daniel, Moczulski Dariusz, Warram James H., Krolewski Andrzej S. A method for developing high-density SNP maps and its application at the type 1 angiotensin II receptor (AGTR1) locus. Genomics. 2002 Mar;79(3):326–332. doi: 10.1006/geno.2002.6713. [DOI] [PubMed] [Google Scholar]
  4. Barker D. J., Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986 May 10;1(8489):1077–1081. doi: 10.1016/s0140-6736(86)91340-1. [DOI] [PubMed] [Google Scholar]
  5. Benetos A., Gautier S., Ricard S., Topouchian J., Asmar R., Poirier O., Larosa E., Guize L., Safar M., Soubrier F. Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation. 1996 Aug 15;94(4):698–703. doi: 10.1161/01.cir.94.4.698. [DOI] [PubMed] [Google Scholar]
  6. Bonnardeaux A., Davies E., Jeunemaitre X., Féry I., Charru A., Clauser E., Tiret L., Cambien F., Corvol P., Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994 Jul;24(1):63–69. doi: 10.1161/01.hyp.24.1.63. [DOI] [PubMed] [Google Scholar]
  7. Cambien F., Léger J., Mallet C., Lévy-Marchal C., Collin D., Czernichow P. Angiotensin I-converting enzyme gene polymorphism modulates the consequences of in utero growth retardation on plasma insulin in young adults. Diabetes. 1998 Mar;47(3):470–475. doi: 10.2337/diabetes.47.3.470. [DOI] [PubMed] [Google Scholar]
  8. Carswell Christopher I., Goa Karen L. Losartan in diabetic nephropathy. Drugs. 2003;63(4):407–416. doi: 10.2165/00003495-200363040-00006. [DOI] [PubMed] [Google Scholar]
  9. Castellano M., Muiesan M. L., Beschi M., Rizzoni D., Cinelli A., Salvetti M., Pasini G., Porteri E., Bettoni G., Zulli R. Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Hypertension. 1996 Dec;28(6):1076–1080. doi: 10.1161/01.hyp.28.6.1076. [DOI] [PubMed] [Google Scholar]
  10. Chaves F. J., Corella D., Sorli J. V., Marin-Garcia P., Guillen M., Redon J. Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population. J Clin Endocrinol Metab. 2004 May;89(5):2301–2305. doi: 10.1210/jc.2003-031058. [DOI] [PubMed] [Google Scholar]
  11. Chistiakov D. A., Kobalova Zh D., Tereshchenko S. N., Moiseev S. V., Nosikov V. V. Polimorfizm gena sosudistogo retseptora angiotenzina II i serdechno-sosudistye zabolevaniia. Ter Arkh. 2000;72(4):27–30. [PubMed] [Google Scholar]
  12. Curnow K. M., Pascoe L., White P. C. Genetic analysis of the human type-1 angiotensin II receptor. Mol Endocrinol. 1992 Jul;6(7):1113–1118. doi: 10.1210/mend.6.7.1508224. [DOI] [PubMed] [Google Scholar]
  13. Duncan J. A., Scholey J. W., Miller J. A. Angiotensin II type 1 receptor gene polymorphisms in humans: physiology and pathophysiology of the genotypes. Curr Opin Nephrol Hypertens. 2001 Jan;10(1):111–116. doi: 10.1097/00041552-200101000-00017. [DOI] [PubMed] [Google Scholar]
  14. Fall C. H., Osmond C., Barker D. J., Clark P. M., Hales C. N., Stirling Y., Meade T. W. Fetal and infant growth and cardiovascular risk factors in women. BMJ. 1995 Feb 18;310(6977):428–432. doi: 10.1136/bmj.310.6977.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Folli F., Kahn C. R., Hansen H., Bouchie J. L., Feener E. P. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest. 1997 Nov 1;100(9):2158–2169. doi: 10.1172/JCI119752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gemmill R. M., Drabkin H. A. Report of the Second International Workshop on Human Chromosome 3 mapping. Cytogenet Cell Genet. 1991;57(4):162–166. [PubMed] [Google Scholar]
  17. Giacchetti Gilberta, Faloia Emanuela, Mariniello Barbara, Sardu Cipriana, Gatti Cristina, Camilloni Maria Angela, Guerrieri Mario, Mantero Franco. Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens. 2002 May;15(5):381–388. doi: 10.1016/s0895-7061(02)02257-4. [DOI] [PubMed] [Google Scholar]
  18. Guo D. F., Furuta H., Mizukoshi M., Inagami T. The genomic organization of human angiotensin II type 1 receptor. Biochem Biophys Res Commun. 1994 Apr 15;200(1):313–319. doi: 10.1006/bbrc.1994.1450. [DOI] [PubMed] [Google Scholar]
  19. Hales C. N., Barker D. J., Clark P. M., Cox L. J., Fall C., Osmond C., Winter P. D. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991 Oct 26;303(6809):1019–1022. doi: 10.1136/bmj.303.6809.1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kainulainen K., Perola M., Terwilliger J., Kaprio J., Koskenvuo M., Syvänen A. C., Vartiainen E., Peltonen L., Kontula K. Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension. 1999 Mar;33(3):844–849. doi: 10.1161/01.hyp.33.3.844. [DOI] [PubMed] [Google Scholar]
  21. Kislauskis E. H., Zhu X., Singer R. H. Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. J Cell Biol. 1994 Oct;127(2):441–451. doi: 10.1083/jcb.127.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lajemi M., Labat C., Gautier S., Lacolley P., Safar M., Asmar R., Cambien F., Benetos A. Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens. 2001 Mar;19(3):407–413. doi: 10.1097/00004872-200103000-00008. [DOI] [PubMed] [Google Scholar]
  23. Lee Yau-Jiunn, Tsai Jack C. R. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. Diabetes Care. 2002 Jun;25(6):1002–1008. doi: 10.2337/diacare.25.6.1002. [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. Moczulski D. K., Rogus J. J., Antonellis A., Warram J. H., Krolewski A. S. Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes. 1998 Jul;47(7):1164–1169. doi: 10.2337/diabetes.47.7.1164. [DOI] [PubMed] [Google Scholar]
  26. Montgomery H. E., Clarkson P., Dollery C. M., Prasad K., Losi M. A., Hemingway H., Statters D., Jubb M., Girvain M., Varnava A. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation. 1997 Aug 5;96(3):741–747. doi: 10.1161/01.cir.96.3.741. [DOI] [PubMed] [Google Scholar]
  27. Montgomery H. E., Marshall R., Hemingway H., Myerson S., Clarkson P., Dollery C., Hayward M., Holliman D. E., Jubb M., World M. Human gene for physical performance. Nature. 1998 May 21;393(6682):221–222. doi: 10.1038/30374. [DOI] [PubMed] [Google Scholar]
  28. Murphy T. J., Alexander R. W., Griendling K. K., Runge M. S., Bernstein K. E. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991 May 16;351(6323):233–236. doi: 10.1038/351233a0. [DOI] [PubMed] [Google Scholar]
  29. Nałogowska-Głośnicka K., Łacka B. I., Zychma M. J., Grzeszczak W., Zukowska-Szczechowska E., Poreba R., Michalski B., Kniazewski B., Rzempołuch J., PIH Study Group Angiotensin II type 1 receptor gene A1166C polymorphism is associated with the increased risk of pregnancy-induced hypertension. Med Sci Monit. 2000 May-Jun;6(3):523–529. [PubMed] [Google Scholar]
  30. O'Donnell C. J., Lindpaintner K., Larson M. G., Rao V. S., Ordovas J. M., Schaefer E. J., Myers R. H., Levy D. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation. 1998 May 12;97(18):1766–1772. doi: 10.1161/01.cir.97.18.1766. [DOI] [PubMed] [Google Scholar]
  31. Pepine Carl J., Cooper-Dehoff Rhonda M. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004 Aug 4;44(3):509–512. doi: 10.1016/j.jacc.2004.03.071. [DOI] [PubMed] [Google Scholar]
  32. Poirier O., Georges J. L., Ricard S., Arveiler D., Ruidavets J. B., Luc G., Evans A., Cambien F., Tiret L. New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde. J Hypertens. 1998 Oct;16(10):1443–1447. doi: 10.1097/00004872-199816100-00007. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Sayer A. A., Cooper C., Evans J. R., Rauf A., Wormald R. P., Osmond C., Barker D. J. Are rates of ageing determined in utero? Age Ageing. 1998 Sep;27(5):579–583. doi: 10.1093/ageing/27.5.579. [DOI] [PubMed] [Google Scholar]
  35. Schupp Michael, Janke Jürgen, Clasen Ronald, Unger Thomas, Kintscher Ulrich. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 2004 Apr 26;109(17):2054–2057. doi: 10.1161/01.CIR.0000127955.36250.65. [DOI] [PubMed] [Google Scholar]
  36. Song Jessica C., White C. Michael. Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207–224. doi: 10.2165/00003088-200241030-00005. [DOI] [PubMed] [Google Scholar]
  37. Strazzullo Pasquale, Iacone Roberto, Iacoviello Licia, Russo Ornella, Barba Gianvincenzo, Russo Paola, D'Orazio Andria, Barbato Antonio, Cappuccio Francesco Paolo, Farinaro Eduardo. Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti Prospective Heart Study. Ann Intern Med. 2003 Jan 7;138(1):17–23. doi: 10.7326/0003-4819-138-1-200301070-00007. [DOI] [PubMed] [Google Scholar]
  38. Szombathy T., Szalai C., Katalin B., Palicz T., Romics L., Császár A. Association of angiotensin II type 1 receptor polymorphism with resistant essential hypertension. Clin Chim Acta. 1998 Jan 12;269(1):91–100. doi: 10.1016/s0009-8981(97)00184-8. [DOI] [PubMed] [Google Scholar]
  39. Takami S., Imai Y., Katsuya T., Ohkubo T., Tsuji I., Nagai K., Satoh H., Hisamichi S., Higaki J., Ogihara T. Gene polymorphism of the renin-angiotensin system associates with risk for lacunar infarction. The Ohasama study. Am J Hypertens. 2000 Feb;13(2):121–127. doi: 10.1016/s0895-7061(99)00184-3. [DOI] [PubMed] [Google Scholar]
  40. Takayanagi R., Ohnaka K., Sakai Y., Nakao R., Yanase T., Haji M., Inagami T., Furuta H., Gou D. F., Nakamuta M. Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor. Biochem Biophys Res Commun. 1992 Mar 16;183(2):910–916. doi: 10.1016/0006-291x(92)90570-b. [DOI] [PubMed] [Google Scholar]
  41. Thekkumkara T. J., Thomas W. G., Motel T. J., Baker K. M. Functional role for the angiotensin II receptor (AT1A) 3'-untranslated region in determining cellular responses to agonist: evidence for recognition by RNA binding proteins. Biochem J. 1998 Jan 15;329(Pt 2):255–264. doi: 10.1042/bj3290255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tiret L., Blanc H., Ruidavets J. B., Arveiler D., Luc G., Jeunemaitre X., Tichet J., Mallet C., Poirier O., Plouin P. F. Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d'Etude des Gènes de l'Hypertension Artérielle Sévère à modérée Essentielle. J Hypertens. 1998 Jan;16(1):37–44. doi: 10.1097/00004872-199816010-00007. [DOI] [PubMed] [Google Scholar]
  43. Wang W. Y., Zee R. Y., Morris B. J. Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet. 1997 Jan;51(1):31–34. doi: 10.1111/j.1399-0004.1997.tb02410.x. [DOI] [PubMed] [Google Scholar]
  44. Wierzbicki A. S., Lambert-Hammill M., Lumb P. J., Crook M. A. Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia. Hypertension. 2000 Nov;36(5):808–812. doi: 10.1161/01.hyp.36.5.808. [DOI] [PubMed] [Google Scholar]
  45. Ye S., Dhillon S., Ke X., Collins A. R., Day I. N. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001 Sep 1;29(17):E88–E88. doi: 10.1093/nar/29.17.e88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ye S., Dhillon S., Seear R., Dunleavey L., Day L. B., Bannister W., Day I. N. M., Simpson I. Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis. Heart. 2003 Oct;89(10):1195–1199. doi: 10.1136/heart.89.10.1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zhang X., Erdmann J., Regitz-Zagrosek V., Kürzinger S., Hense H. W., Schunkert H. Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene. J Hypertens. 2000 Mar;18(3):267–272. doi: 10.1097/00004872-200018030-00005. [DOI] [PubMed] [Google Scholar]
  48. Zhu Xiaofeng, Yan Denise, Cooper Richard S., Luke Amy, Ikeda Morna A., Chang Yen-Pei C., Weder Alan, Chakravarti Aravinda. Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program. Genome Res. 2003 Feb;13(2):173–181. doi: 10.1101/gr.302003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. van Geel P. P., Pinto Y. M., Voors A. A., Buikema H., Oosterga M., Crijns H. J., van Gilst W. H. Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension. 2000 Mar;35(3):717–721. doi: 10.1161/01.hyp.35.3.717. [DOI] [PubMed] [Google Scholar]

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