Gene polymorphisms of the renin‐angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study

Objective To investigate a possible involvement of polymorphisms of the renin-angiotensin system in predisposition to moderate and severe hypertension and their relationship to parental histories of myocardial infarction and stroke. Methods Hypertensive cases (453 men, 326 women) were patients followed up by general practitioners for established hypertension. Inclusion criteria were an age of onset of hypertension < 60 years and a diastolic blood pressure > 105 mmHg without antihypertensive medication or > 100 mmHg under treatment. Normotensive controls were selected from population-based samples (362 men) and during a preventative medicine visit (170 women). Polymorphisms of the angiotensinogen gene (AGT M235T and T174M), the angiotensin I converting enzyme gene (ACE I/D), and the angiotensin II type 1 receptor gene (AGT1R A1166C) were investigated. Results The AGTT235 allele prevalence was higher among male hypertensive cases than it was among controls (0.46 versus 0.40, P = 0.01) and a similar trend was observed with female cases whose hypertension had been diagnosed before they were aged 45 years (0.44 versus 0.38, P = 0.20). The AGT1R C1166 allele prevalence was higher among female hypertensives than it was among controls (0.30 versus 0.23, P = 0.03) but no such difference was observed for men. The AGT T174M and ACE I/D polymorphisms were not associated with hypertension. Hypertensive patients reporting a parental history of myocardial infarction before age 60 years had a higher prevalence of the ACE D allele than did those without such a parental history (0.68 versus 0.56, P = 0.01). The ACE D allele prevalence was also greater among patients reporting a parental history of stroke incidence before age 65 years (0.66 versus 0.57, P = 0.05). Conclusions These results support the hypothesis that the AGT gene plays a role in predisposition to hypertension and that the ACE gene plays a role in predisposition to acute ischemic events.

[1]  N. Iwai,et al.  Human SA gene locus as a candidate locus for essential hypertension. , 1994, Hypertension.

[2]  R. Lifton.  Genetic determinants of human hypertension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Philippe Amouyel,et al.  Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction , 1992, Nature.

[4]  M. Caulfield,et al.  Linkage of the angiotensinogen gene locus to human essential hypertension in African Caribbeans. , 1995, The Journal of clinical investigation.

[5]  M. Margaglione,et al.  Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[6]  G. Murray,et al.  Lack of association between angiotensin converting enzyme gene insertion/deletion polymorphism and stroke , 1995, Journal of hypertension.

[7]  A. Evans,et al.  A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease. The ECTIM Study. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[8]  G. Watt,et al.  Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. , 1992, Journal of hypertension.

[9]  N. Iwai,et al.  Angiotensinogen gene and blood pressure in the Japanese population. , 1995, Hypertension.

[10]  T. Ogihara,et al.  Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese. , 1994, Journal of human hypertension.

[11]  Y. Friedlander,et al.  M235→ T polymorphism of the angiotensinogen gene predicts hypertension in the elderly , 1996, Journal of hypertension.

[12]  B. Morris,et al.  Cross-sectional analysis of Met235-->Thr variant of angiotensinogen gene in severe, familial hypertension. , 1993, Biochemical and biophysical research communications.

[13]  J. Lalouel,et al.  A molecular variant of angiotensinogen associated with preeclampsia , 1993, Nature Genetics.

[14]  Steven C. Hunt,et al.  Molecular basis of human hypertension: Role of angiotensinogen , 1992, Cell.

[15]  P. Whelton,et al.  Relation Between Blood Pressure and Renin, Renin Substrate, Angiotensin II, Aldosterone and Urinary Sodium and Potassium in 574 Ambulatory Subjects , 1979, Hypertension.

[16]  K. Kario,et al.  Effect of the angiotensinogen gene Met235$Thr variant on blood pressure and other cardiovascular risk factors in two Japanese populations , 1995, Journal of hypertension.

[17]  N. Carter,et al.  Molecular approach to assessing the genetic risk of cerebral infarction: deletion polymorphism in the gene encoding angiotensin 1-converting enzyme. , 1994, Journal of human hypertension.

[18]  A. Hingorani,et al.  Blood pressure and the M235T polymorphism of the angiotensinogen gene. , 1996, Hypertension.

[19]  H. S. Kim,et al.  Genetic control of blood pressure and the angiotensinogen locus. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Hegele,et al.  A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate. , 1994, Circulation.

[21]  U. Ikeda,et al.  Angiotensin-converting enzyme gene polymorphism in hypertensive individuals with parental history of stroke. , 1996, Stroke.

[22]  C. Rotimi,et al.  Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans. , 1994, Hypertension.

[23]  D. Wilcken,et al.  Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. , 1995, Circulation.

[24]  O. Costerousse,et al.  Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. , 1993, The Biochemical journal.

[25]  J. Staessen,et al.  The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular‐renal risk , 1997, Journal of hypertension.

[26]  P Corvol,et al.  An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. , 1990, The Journal of clinical investigation.

[27]  J. Lalouel,et al.  Haplotypes of angiotensinogen in essential hypertension. , 1997, American journal of human genetics.

[28]  L. Tiret,et al.  Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. , 1992, American journal of human genetics.

[29]  R. Zulli,et al.  Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. , 1996, Hypertension.

[30]  D. Arveiler,et al.  Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction , 1993, The Lancet.

[31]  J. Lalouel,et al.  Angiotensinogen as a risk factor for essential hypertension in Japan. , 1994, The Journal of clinical investigation.

[32]  A. Manatunga,et al.  The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. , 1995, The Journal of clinical investigation.

[33]  D. Arveiler,et al.  Genetic variation at the angiotensinogen locus in relation to high blood pressure and myocardial infarction: the ECTIM study , 1994, Journal of hypertension.

[34]  F. Cambien,et al.  Angiotensin I converting enzyme gene polymorphism and coronary heart disease. , 1995, European heart journal.

[35]  S. Purandare,et al.  Angiotensinogen: a candidate gene involved in preeclampsia? , 1993, Nature Genetics.

[36]  X. Jeunemaître,et al.  Role of the renin-angiotensin system in blood pressure regulation and in human hypertension: new insights from molecular genetics. , 1995, Recent progress in hormone research.

[37]  F. Cambien,et al.  Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. , 1996, Circulation.

[38]  D. Clayton,et al.  Linkage of the angiotensinogen gene to essential hypertension. , 1994, The New England journal of medicine.

[39]  B. Morris,et al.  Different frequencies of angiotensin-converting enzyme genotypes in older hypertensive individuals. , 1994, The Journal of clinical investigation.

[40]  C. Rotimi,et al.  Angiotensinogen and blood pressure among blacks: findings from a community survey in Jamaica , 1996, Journal of hypertension.

[41]  L. Tiret,et al.  Testing for association between disease and linked marker loci: a log-linear-model analysis. , 1991, American journal of human genetics.

[42]  L. Tiret,et al.  Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. , 1994, Hypertension.

[43]  A. Rantala,et al.  Variation at the angiotensin-converting enzyme gene and angiotensinogen gene loci in relation to blood pressure. , 1996, Hypertension.

[44]  J. Erikssen,et al.  Insertion /deletion (I/D) polymorphism at the locus for angiotensin I‐converting enzyme and parental history of myocardial infarction , 1993, Clinical genetics.

[45]  H. Markus,et al.  Angiotensin-converting enzyme gene deletion polymorphism. A new risk factor for lacunar stroke but not carotid atheroma. , 1995, Stroke.

[46]  J. Barrett,et al.  Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. , 1996, Stroke.

[47]  P Ducimetière,et al.  Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction , 1994, The Lancet.

[48]  K. Kario,et al.  Ischemic stroke and the gene for angiotensin-converting enzyme in Japanese hypertensives. , 1996, Circulation.

[49]  H. Schunkert,et al.  The angiotensinogen T235 variant and the use of antihypertensive drugs in a population-based cohort. , 1997, Hypertension.

[50]  John Quackenbush,et al.  A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. , 1997, The Journal of clinical investigation.

[51]  J. Ménard,et al.  M235T variant of the human angiotensinogen gene in unselected hypertensive patients , 1993, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.