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. 1997 Jun;60(6):1448–1460. doi: 10.1086/515452

Haplotypes of angiotensinogen in essential hypertension.

X Jeunemaitre 1, I Inoue 1, C Williams 1, A Charru 1, J Tichet 1, M Powers 1, A M Sharma 1, A P Gimenez-Roqueplo 1, A Hata 1, P Corvol 1, J M Lalouel 1
PMCID: PMC1716122  PMID: 9199566

Abstract

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

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Selected References

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  1. Arngrímsson R., Purandare S., Connor M., Walker J. J., Björnsson S., Soubrier F., Kotelevtsev Y. V., Geirsson R. T., Björnsson H. Angiotensinogen: a candidate gene involved in preeclampsia? Nat Genet. 1993 Jun;4(2):114–115. doi: 10.1038/ng0693-114. [DOI] [PubMed] [Google Scholar]
  2. Barley J., Blackwood A., Sagnella G., Markandu N., MacGregor G., Carter N. Angiotensinogen Met235-->Thr polymorphism in a London normotensive and hypertensive black and white population. J Hum Hypertens. 1994 Aug;8(8):639–640. [PubMed] [Google Scholar]
  3. Bennett C. L., Schrader A. P., Morris B. J. Cross-sectional analysis of Met235-->Thr variant of angiotensinogen gene in severe, familial hypertension. Biochem Biophys Res Commun. 1993 Dec 15;197(2):833–839. doi: 10.1006/bbrc.1993.2554. [DOI] [PubMed] [Google Scholar]
  4. Bloem L. J., Manatunga A. K., Tewksbury D. A., Pratt J. H. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest. 1995 Mar;95(3):948–953. doi: 10.1172/JCI117803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Caulfield M., Lavender P., Farrall M., Munroe P., Lawson M., Turner P., Clark A. J. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med. 1994 Jun 9;330(23):1629–1633. doi: 10.1056/NEJM199406093302301. [DOI] [PubMed] [Google Scholar]
  6. Caulfield M., Lavender P., Newell-Price J., Farrall M., Kamdar S., Daniel H., Lawson M., De Freitas P., Fogarty P., Clark A. J. Linkage of the angiotensinogen gene locus to human essential hypertension in African Caribbeans. J Clin Invest. 1995 Aug;96(2):687–692. doi: 10.1172/JCI118111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Charru A., Jeunemaitre X., Soubrier F., Corvol P., Chatellier G. Short report: HYPERGENE: a clinical and genetic database for genetic analysis of human hypertension. J Hypertens. 1994 Aug;12(8):981–985. [PubMed] [Google Scholar]
  8. Cohen P., Badouaille G., Gimenez-Roqueplo A. P., Mani J. C., Guyene T. T., Jeunemaitre X., Menard J., Corvol P., Pau B., Simon D. Selective recognition of M235T angiotensinogen variants and their determination in human plasma by monoclonal antibody-based immunoanalysis. J Clin Endocrinol Metab. 1996 Oct;81(10):3505–3512. doi: 10.1210/jcem.81.10.8855793. [DOI] [PubMed] [Google Scholar]
  9. Denton D., Weisinger R., Mundy N. I., Wickings E. J., Dixson A., Moisson P., Pingard A. M., Shade R., Carey D., Ardaillou R. The effect of increased salt intake on blood pressure of chimpanzees. Nat Med. 1995 Oct;1(10):1009–1016. doi: 10.1038/nm1095-1009. [DOI] [PubMed] [Google Scholar]
  10. Eaton S. B., Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985 Jan 31;312(5):283–289. doi: 10.1056/NEJM198501313120505. [DOI] [PubMed] [Google Scholar]
  11. Fornage M., Turner S. T., Sing C. F., Boerwinkle E. Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester, Minnesota. Hum Genet. 1995 Sep;96(3):295–300. doi: 10.1007/BF00210410. [DOI] [PubMed] [Google Scholar]
  12. Gaillard I., Clauser E., Corvol P. Structure of human angiotensinogen gene. DNA. 1989 Mar;8(2):87–99. doi: 10.1089/dna.1.1989.8.87. [DOI] [PubMed] [Google Scholar]
  13. Gardes J., Bouhnik J., Clauser E., Corvol P., Menard J. Role of angiotensinogen in blood pressure homeostasis. Hypertension. 1982 Mar-Apr;4(2):185–189. doi: 10.1161/01.hyp.4.2.185. [DOI] [PubMed] [Google Scholar]
  14. Gimenez-Roqueplo A. P., Leconte I., Cohen P., Simon D., Guyene T. T., Célerier J., Pau B., Corvol P., Clauser E., Jeunemaitre X. The natural mutation Y248C of human angiotensinogen leads to abnormal glycosylation and altered immunological recognition of the protein. J Biol Chem. 1996 Apr 19;271(16):9838–9844. doi: 10.1074/jbc.271.16.9838. [DOI] [PubMed] [Google Scholar]
  15. Gould A. B., Green D. Kinetics of the human renin and human substrate reaction. Cardiovasc Res. 1971 Jan;5(1):86–89. doi: 10.1093/cvr/5.1.86. [DOI] [PubMed] [Google Scholar]
  16. Hata A., Namikawa C., Sasaki M., Sato K., Nakamura T., Tamura K., Lalouel J. M. Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest. 1994 Mar;93(3):1285–1287. doi: 10.1172/JCI117083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hegele R. A., Brunt J. H., Connelly P. W. A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate. Circulation. 1994 Nov;90(5):2207–2212. doi: 10.1161/01.cir.90.5.2207. [DOI] [PubMed] [Google Scholar]
  18. Hixson J. E., Powers P. K. Detection and characterization of new mutations in the human angiotensinogen gene (AGT). Hum Genet. 1995 Jul;96(1):110–112. doi: 10.1007/BF00214197. [DOI] [PubMed] [Google Scholar]
  19. Hyer R. N., Julier C., Buckley J. D., Trucco M., Rotter J., Spielman R., Barnett A., Bain S., Boitard C., Deschamps I. High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q. Am J Hum Genet. 1991 Feb;48(2):243–257. [PMC free article] [PubMed] [Google Scholar]
  20. Inoue I., Nakajima T., Williams C. S., Quackenbush J., Puryear R., Powers M., Cheng T., Ludwig E. H., Sharma A. M., Hata A. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest. 1997 Apr 1;99(7):1786–1797. doi: 10.1172/JCI119343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Inoue I., Rohrwasser A., Helin C., Jeunemaitre X., Crain P., Bohlender J., Lifton R. P., Corvol P., Ward K., Lalouel J. M. A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. J Biol Chem. 1995 May 12;270(19):11430–11436. doi: 10.1074/jbc.270.19.11430. [DOI] [PubMed] [Google Scholar]
  22. Ishigami T., Umemura S., Iwamoto T., Tamura K., Hibi K., Yamaguchi S., Nyuui N., Kimura K., Miyazaki N., Ishii M. Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation. 1995 Feb 15;91(4):951–954. doi: 10.1161/01.cir.91.4.951. [DOI] [PubMed] [Google Scholar]
  23. Iwai N., Shimoike H., Ohmichi N., Kinoshita M. Angiotensinogen gene and blood pressure in the Japanese population. Hypertension. 1995 Apr;25(4 Pt 2):688–693. doi: 10.1161/01.hyp.25.4.688. [DOI] [PubMed] [Google Scholar]
  24. Jeunemaitre X., Charru A., Chatellier G., Dumont C., Sassano P., Soubrier F., Ménard J., Corvol P. M235T variant of the human angiotensinogen gene in unselected hypertensive patients. J Hypertens Suppl. 1993 Dec;11(5):S80–S81. [PubMed] [Google Scholar]
  25. Jeunemaitre X., Soubrier F., Kotelevtsev Y. V., Lifton R. P., Williams C. S., Charru A., Hunt S. C., Hopkins P. N., Williams R. R., Lalouel J. M. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. doi: 10.1016/0092-8674(92)90275-h. [DOI] [PubMed] [Google Scholar]
  26. Kamitani A., Rakugi H., Higaki J., Ohishi M., Shi S. J., Takami S., Nakata Y., Higashino Y., Fujii K., Mikami H. Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis. Hypertension. 1995 May;25(5):950–953. doi: 10.1161/01.hyp.25.5.950. [DOI] [PubMed] [Google Scholar]
  27. Kamitani A., Rakugi H., Higaki J., Yi Z., Mikami H., Miki T., Ogihara T. Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese. J Hum Hypertens. 1994 Jul;8(7):521–524. [PubMed] [Google Scholar]
  28. Katsuya T., Koike G., Yee T. W., Sharpe N., Jackson R., Norton R., Horiuchi M., Pratt R. E., Dzau V. J., MacMahon S. Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. Lancet. 1995 Jun 24;345(8965):1600–1603. doi: 10.1016/s0140-6736(95)90115-9. [DOI] [PubMed] [Google Scholar]
  29. Kim H. S., Krege J. H., Kluckman K. D., Hagaman J. R., Hodgin J. B., Best C. F., Jennette J. C., Coffman T. M., Maeda N., Smithies O. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2735–2739. doi: 10.1073/pnas.92.7.2735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kotelevtsev YuV, Clauser E., Corvol P., Soubrier F. Dinucleotide repeat polymorphism in the human angiotensinogen gene. Nucleic Acids Res. 1991 Dec 25;19(24):6978–6978. doi: 10.1093/nar/19.24.6978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. McCarron D. A., Stanton J., Henry H., Morris C. Assessment of nutritional correlates of blood pressure. Ann Intern Med. 1983 May;98(5 Pt 2):715–719. doi: 10.7326/0003-4819-98-5-715. [DOI] [PubMed] [Google Scholar]
  32. Ménard J., el Amrani A. I., Savoie F., Bouhnik J. Angiotensinogen: an attractive and underrated participant in hypertension and inflammation. Hypertension. 1991 Nov;18(5):705–707. doi: 10.1161/01.hyp.18.5.705. [DOI] [PubMed] [Google Scholar]
  33. Neel J. V. Lessons from a "primitive" people. Science. 1970 Nov 20;170(3960):815–822. doi: 10.1126/science.170.3960.815. [DOI] [PubMed] [Google Scholar]
  34. Nibu Y., Takahashi S., Tanimoto K., Murakami K., Fukamizu A. Identification of cell type-dependent enhancer core element located in the 3'-downstream region of the human angiotensinogen gene. J Biol Chem. 1994 Nov 18;269(46):28598–28605. [PubMed] [Google Scholar]
  35. Nibu Y., Tanimoto K., Takahashi S., Ono H., Murakami K., Fukamizu A. A cell type-dependent enhancer core element is located in exon 5 of the human angiotensinogen gene. Biochem Biophys Res Commun. 1994 Dec 15;205(2):1102–1108. doi: 10.1006/bbrc.1994.2779. [DOI] [PubMed] [Google Scholar]
  36. Nishiuma S., Kario K., Kayaba K., Nagio N., Shimada K., Matsuo T., Matsuo M. Effect of the angiotensinogen gene Met235-->Thr variant on blood pressure and other cardiovascular risk factors in two Japanese populations. J Hypertens. 1995 Jul;13(7):717–722. [PubMed] [Google Scholar]
  37. Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rotimi C., Morrison L., Cooper R., Oyejide C., Effiong E., Ladipo M., Osotemihen B., Ward R. Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans. Hypertension. 1994 Nov;24(5):591–594. doi: 10.1161/01.hyp.24.5.591. [DOI] [PubMed] [Google Scholar]
  39. Rust S., Funke H., Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res. 1993 Aug 11;21(16):3623–3629. doi: 10.1093/nar/21.16.3623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schmidt S., Sharma A. M., Zilch O., Beige J., Walla-Friedel M., Ganten D., Distler A., Ritz E. Association of M235T variant of the angiotensinogen gene with familial hypertension of early onset. Nephrol Dial Transplant. 1995;10(7):1145–1148. [PubMed] [Google Scholar]
  41. Stallings R. L., Ford A. F., Nelson D., Torney D. C., Hildebrand C. E., Moyzis R. K. Evolution and distribution of (GT)n repetitive sequences in mammalian genomes. Genomics. 1991 Jul;10(3):807–815. doi: 10.1016/0888-7543(91)90467-s. [DOI] [PubMed] [Google Scholar]
  42. Thompson E. A., Deeb S., Walker D., Motulsky A. G. The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet. 1988 Jan;42(1):113–124. [PMC free article] [PubMed] [Google Scholar]
  43. Tiret L., Ricard S., Poirier O., Arveiler D., Cambou J. P., Luc G., Evans A., Nicaud V., Cambien F. Genetic variation at the angiotensinogen locus in relation to high blood pressure and myocardial infarction: the ECTIM Study. J Hypertens. 1995 Mar;13(3):311–317. [PubMed] [Google Scholar]
  44. Walker W. G., Whelton P. K., Saito H., Russell R. P., Hermann J. Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects. Hypertension. 1979 May-Jun;1(3):287–291. doi: 10.1161/01.hyp.1.3.287. [DOI] [PubMed] [Google Scholar]
  45. Ward K., Hata A., Jeunemaitre X., Helin C., Nelson L., Namikawa C., Farrington P. F., Ogasawara M., Suzumori K., Tomoda S. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet. 1993 May;4(1):59–61. doi: 10.1038/ng0593-59. [DOI] [PubMed] [Google Scholar]
  46. Weatherall D. J. The molecular basis for phenotypic diversity of genetic disease. Ann N Y Acad Sci. 1995 Jun 30;758:245–260. doi: 10.1111/j.1749-6632.1995.tb24832.x. [DOI] [PubMed] [Google Scholar]
  47. Yanai K., Nibu Y., Murakami K., Fukamizu A. A cis-acting DNA element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene. J Biol Chem. 1996 Jul 5;271(27):15981–15986. doi: 10.1074/jbc.271.27.15981. [DOI] [PubMed] [Google Scholar]

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