Polymorphism in angiotensin II receptor genes and hypertension

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1 Exp Physiol 90.3 pp Experimental Physiology Themed Issue Cardiovascular Genomics Paper Polymorphism in angiotensin II receptor genes and hypertension Bruno Baudin 1,2 1 Service de Biochimie A, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, Paris, Cedex 12, France 2 UFR des Sciences Pharmaceutiques, Boulevard Bequerel, 14032, Caen (UniversitédeBasse-Normandie), Cedex, France Molecular variants of individual components of the renin angiotensin system (RAS) have been thought to contribute to an inherited predisposition towards essential hypertension. The angiotensin II type 1 receptor (AT-1) mediates the major pressor and trophic actions of angiotensin II (Ang II) and at least 50 different polymorphisms have been described in the AT-1 gene (AT 1 R gene); in particular, the C allele of the +1166A/C polymorphism has been associated with the severe form of essential hypertension, but the role of this polymorphism is still ambiguous in pathologies related to high Ang II levels, such as deterioration of renal function, arterial stiffness and hypertrophic cardiomyopathy. A relationship was suggested between AT 1 R A1166C polymorphism and the humoral and renal haemodynamic responses to losartan, an AT-1 blocker, as well as with enhanced Ang II vascular reactivity or sensitivity. Polymorphism has also been described in angiotensin II type 2 receptor (AT-2) gene, AT-2 being the mediator for vasodilatation, natriuresis and apoptosis of smooth muscle cells; associations were found between some of these polymorphisms and both hypertension and left ventricular structure. Further evaluation in adequately powered studies is necessary for full assessment of the allelic markers in genes for RAS components, as well as to allow determination of a predisposition to hypertension or related diseases and selection of an appropriate antihypertensive drug for an individual. (Received 10 September 2004; accepted after revision 4 January 2005; first published online 7 January 2005) Corresponding author B. Baudin: Service de Biochimie A, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, Paris, Cedex 12, France. bruno.baudin@sat.ap-hop-paris.fr High blood pressure (BP) is an important risk factor for cardiovascular diseases, kidney failure and stroke. It is recognized as a multifactorial trait resulting from the effect of a combination of environmental and genetic factors. Efforts to date have identified several candidate genes involved in high BP or primary hypertension. Special attention has been paid to the study of genes implicated in the renin angiotensin system (RAS) because its activation and the subsequent generation of angiotensin II (Ang II) both play important roles in normal physiology and in the progression of cardiac and renal diseases. Most of the known actions of Ang II are mediated by the Ang II type 1 receptor (AT-1), including vascular contraction, pressor responses, renal tubular sodium transport and aldosterone secretion (Fig. 1). Antagonists of AT-1 have been developed and are now widely used in the treatment of hypertension, either alone (Burnier & Brunner, 2000) or in combination with angiotensin converting enzyme (ACE) inhibitors for complete RAS blockade (Azizi & Ménard, 2004). Over the past few decades, several polymorphisms in the AT-1 gene (AT 1 R gene) have been studied in relation to arterial hypertension and related cardiovascular impairments, but often with confusing results. More recently, polymorphism was also shown in the AT 2 R gene, and sometimes in relation to cardiovascular events. This article will try to improve our comprehension of this genetic variability related to parameters of blood pressure, ventricular structure and reactivity. AT 1 R gene polymorphism in hypertension and related diseases The human AT 1 R gene has a length of >55 kb, is composed of five exons and four introns, and has been found to be highly polymorphic. In particular, a single nucleotide polymorphism (SNP) has been described in which there is either an adenine (A) or a cytosine (C) base (A/C transversion) in position 1166 in the 3 untranslated DOI: /expphysiol

2 278 B. Baudin Exp Physiol 90.3 pp region of the gene (Bonnardeaux et al. 1994); at present this +1166A/C polymorphism is the best evaluated. The Aallele that lacks the enzyme-restriction site is designated as the larger fragment, whereas the C allele, which has an enzyme-restriction site at nucleotide position 1166, is designated as the smaller fragment. The physiological significance of this polymorphism is uncertain because of its location in an untranslated region. Another SNP at nucleotide position +573 was investigated inhypertension and diabetes (Doria et al. 1997; Chaves et al. 2001). Erdmann et al. (1999) characterized nine other SNPs, which may have the potential to influence AT 1 R gene expression given their location in the functional promoter region of the gene. Poirier et al. (1998) detected seven other SNPs in the 5 -flanking region of the gene, not in linkage equilibrium with +1166A/C polymorphism and Takahashi et al. (2000) found seven other polymorphisms; recently, Zhu et al. (2003) described five more SNPs at both 5 - and 3 -flanking regions. Finally, at least 50 SNPs have been described; however, not all of them are associated with hypertension and they are not unique, since they can be linked together defining haplotypes. Moreover, in some studies a linkage disequilibrium was shown between these new SNPs and the +1166A/C polymorphism, in particular the 153A/G polymorphism (Lajemi et al. 2001). The silent +1166A/C SNP in the AT 1 R gene has been associated with the severe form of essential hypertension, and in particular in drug-resistant hypertensive patients taking two or more antihypertensive drugs (Bonnardeaux et al. 1994; Kainulainen et al. 1999). The Callele was others angiotensins and aldosterone secretion AT-1 vasoconstriction glomerular filtration tubular reabsorption cell growth and proliferation angiotensinogen angiotensin I active renin ACE angiotensin II alternative pathways for ang II formation others AT-R AT-2 vasodilatation natriuresis cognitive functions cell growth arrest and apoptosis Figure 1. The RAS and the main functions of the angiotensin II receptors (AT-1 and AT-2) ACE, angiotensin I converting enzyme. particularly over-represented in Caucasian hypertensive subjects with a strong family history (Wang et al. 1997), and it was also significantly more frequent in women with pregnancy-induced hypertension, whereas polymorphisms in genes of other components of the RAS, i.e. ACE I/D and angiotensinogen (AG) M235T polymorphisms, were not associated with a predisposition for development of hypertension in pregnant women (Nalogowska-Glosnicka et al. 2000), or independently associated (Kobashi et al. 2004). However, a significant interaction between the ACE I/D and AT 1 R +1166A/C polymorphisms in terms of influence on BP variation has been reported (Wang & Staessen, 2000), although their linkage mechanism remains unclear. Henskens et al. (2003) recently confirmed an association of both these polymorphisms with BP in healthy normotensive subjects, although synergistic effects did not seem to be present. But large interethnic differences in the frequencies of genotype polymorphisms of the RAS exist; for example, a higher prevalence of the AT 1 R CC genotype was found in Chinese hypertensive patients than in a control population (Jiang et al. 2001), whereas the +1166A/C genotype distribution did not differ between hypertensive and normotensive subjects from Japan (Ono et al. 2003). In a sample of Swedish twins, Iliadou et al. (2002) did not find any significant linkage between ACE I/D polymorphism or AT 1 R +1166A/C polymorphism and high BP. In Caucasoid subjects from Germany, Schmidt et al. (1997) did not detect any association of +1166A/C polymorphism with hypertension, but a trend was observed towards a decreased prevalence of the C allele among hypertensive patients with a late age at diagnosis (>50 years). Tiret et al. (1998) showed a higher prevalence of C allele among female hypertensive patients than in control subjects but no such difference was observed in men. Szombathy et al. (1998) did not find any difference for this polymorphism in the AT 1 R gene between normotensive control subjects and subjects with resistant essential hypertension, but high values of systolic BP were associated with the C allele in older and overweight patients. Thus, the data on +1166A/C AT 1 R gene polymorphism must be interpreted as a function of age, sex and ethnic origin. Hypertension is a major risk factor for stroke, renal failure and cardiovascular diseases. Sierra et al. (2002) showed that the presence of the ACE Dallele may be a predisposing factor for developing white matter lesions in essential hypertensive patients, whereas no significant association for the AG M235T and AT 1 R +1166A/C polymorphisms was found. Moreover, no association was shown between AT 1 R gene polymorphisms and stroke (Tiret et al. 1998); on the contrary, the presence of the C allele in the AT 1 R gene might be associated with faster deterioration of renal function (Buraczynska et al. 2002; Coll et al. 2003). Originally a synergistic effect was

3 Exp Physiol 90.3 pp Angiotensin II receptor genes and hypertension 279 suggested for AT 1 R +1166A/C polymorphism and poor glycaemic control on the risk of diabetic nephropathy in insulin-dependent diabetic patients (Doria et al. 1997); but this association was not confirmed in subsequent studies (Chowdhury et al. 1997; Savage et al. 1999; Tarnow et al. 2000). RAS gene polymorphism was also investigated in obesity, and particularly in obesityassociated hypertension. No association was detected between AG M235T or AT 1 R +1166A/C polymorphism and anthropometric indexes or BP, whereas the ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity (Strazzullo et al. 2003). Finally, among hypertension-related diseases, only impairment of renal function was clearly related to AT 1 R +1166A/C polymorphism. Arterial stiffness is associated with excess morbidity and mortality, independently of other cardiovascular risk factors. Lajemi et al. (2001) found that the 1166C allele in the AT 1 R gene influences the relationship between age and arterial pulse valve velocity in an additive effect with the 153A/G SNP in the AT 1 R gene. The C allele was also associated with aortic stiffness in both normotensive and hypertensive subjects (Benetos et al. 1996a,b), but Girerd et al. (1998) did not find such a correlation with vascular hypertrophy in subjects with no evidence of cardiovascular disease. Epistatic interactions with ACE I/D polymorphism were shown in relation to the extent of coronary heart disease (Tiret et al. 1994; Benetos et al. 1996a,b; Yeet al. 2003). Hypertrophic cardiomyopathy occurs as a familial disorder with at least six genes clearly identified; but other factors, genetic as well as environmental, may modify the phenotypic expression of the mutated gene. Angiotensin II is an important modulator of cardiac hypertrophy, and ACE inhibition induces regression of cardiac hypertrophy and prevents dilatation and remodelling of the ventricle after myocardial infarction. Diez et al. (2003) suggested that the +1166A/C polymorphism in the AT 1 R gene is associated with collagen type I synthesis and myocardial stiffness in patients with hypertensive heart disease. Osterop et al. (1998) investigated whether the ACE I/D and AT 1 R +1166A/C polymorphisms influence left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy and concluded that the C allele in the AT 1 R gene modulates the phenotype of hypertrophy. Takami et al. (1998) also reported an association between the C allele and left ventricular mass index, but in normotensive subjects without hypertrophic cardiomyopathy. These results are not in accordance with the studies of Hamon et al. (1997) and Ishanov et al. 1998), but Andersson et al. (1999) found that patients with ACE DD and AT 1 R CC or AC genotypes tented to have a lower ejection fraction and increased left ventricular mass. Hamon et al. (1997) also observed that the subjects homozygous for the AT 1 R CC genotype had a significantly lower ejection fraction than those with the A allele. Thus, when AT 1 R +1166A/C polymorphism is not clearly associated with arterial stiffness and cardiac hypertrophy, the C allele remains a candidate for the association of vascular and cardiac phenotypes with genetic variation in genes of the RAS components. Among the other polymorphisms in the AT 1 R gene, at the 5 -flanking region a higher frequency of the Tallele ( 535C/T SNP) was observed in hypertensive patients (Takahashi et al. 2000), whereas Zhang et al. (2000), evaluating nine newly characterized SNPs, did not show any association with arterial hypertension. Poirier et al. (1998) also noticed that among seven new polymorphisms none was associated with pressor levels in control subjects, whereas Chaves et al. (2001) found that the +573C/T polymorphism might be a genetic protective factor for urinary albumin excretion in a population of essential hypertensive patients. Investigating 25 new polymorphisms in RAS genes, Zhu et al. (2003) particularly described an association between two AT 1 R gene polymorphisms and hypertension in African but not European Americans. Moreover, among six SNPs discovered in the promoter region of the AT 1 R gene, Jin et al. (2003) found that the 810A/T polymorphism is a genetic risk factor for coronary heart disease complicated with essential hypertension. More adequately funded investigations will be necessary for the assessment of these allelic markers in hypertension and related diseases, in particular for comparison with SNPs in genes of other RAS components. AT 2 R gene polymorphism Polymorphism in the AT 2 R gene, which is located on the X-chromosome, was also investigated (Fig. 1); in particular, the +3123A/C polymorphism may contribute to cardiac hypertrophy in cardiomyopathy (Deinum et al. 2001). Delles et al. (2000) tested another SNP in the AT 2 R gene, namely the +1675G/A polymorphism, and in parallel the 2228G/A polymorphism in the AT 1 R gene; the response to Ang II infusion did not differ between the AT 1 R and AT 2 R genotypes. More recently, identifying nine new SNPs in the AT 2 R gene, Zhang et al. (2003) suggested a relationship between the 1334T/C polymorphism and the development of hypertension in a Chinese population, whereas Alfakih et al. (2004) showed an identical relation but in the UK population and for the 1332G/A polymorphism, and Plummer et al. (2004) showed a similar relationship for preeclampsia in women involving other haplotypes in the AT 2 R gene. Pharmacogenomic considerations regarding Ang II receptors The response of patients to antihypertensive therapy is variable; individuals may respond differently to different

4 280 B. Baudin Exp Physiol 90.3 pp medications, suggesting that treatment should be matched to individual responsiveness. The two main targets in the RAS for an antihypertensive therapy are ACE and AT-1, with ACE inhibitors and AT-1 antagonists (or blockers), respectively. For ACE I/D polymorphism, the first conclusions from pharmacogenomic studies have been analysed (Baudin, 2000), but few data are available for polymorphisms in the AT 1 R gene (Baudin, 2002). Miller et al. (1999) hypothesized that renal and systemic AngIIactivity would be augmented in subjects with the Callele of the AT 1 R gene +1116A/C polymorphism, and tested this hypothesis by comparing haemodynamic and humoral responses to AT-1 blockade with losartan (the first AT-1 antagonist) and with low-dose suppressor infusions of Ang II. In this study, losartan increased the glomerular filtration rate and decreased mean arterial blood pressure in subjects with the C allele. Kurland et al. (2001b) showed that the C allele is associated with a reduction in both endothelium-dependent and -independent vasodilatations in normotensive individuals, whereas the Dallele in the ACE gene was only reduced in endothelium-dependent vasodilatation. Several studies have examined relationships between the ACE and AT 1 R genes during antihypertensive therapy but without AT-1 receptor antagonists. Dieguez-Lucena et al. (1996) showed that the AT-1 messenger level in peripheral blood mononuclear cells varies in relation to ACE I/D genotype after treatment with an ACE inhibitor, but not other antihypertensive drugs. Moreover, Benetos et al. (1996a,b) found that, according to the +1166A/C genotype of the AT 1 R gene, an ACE inhibitor and a calcium channel antagonist affect pulse wave velocity but in opposite ways. In another study, Kurland et al. (2001a) did not show relationships between AG M235T or AT 1 R +1116A/C polymorphism and response to treatment for 3 months with irbesartan (an AT-1 antagonist) or atenolol, whereas ACE I/D genotype predicted the blood-lowering response to these antihypertensive therapies. Moreover, the variability in the individual response to AT-1 antagonists could also result from variations in the pharmacokinetics of the drugs. The pharmacogenomic studies on the AT 1 R gene are as yet too poor and disseminated for assessment of the influence of +1166A/C genotype in determination of antihypertensive treatment, but the C allele always appears as a candidate. References Alfakih K, Maqbool A, Sivanthan M et al. (2004). Left ventricle mass index and the common, functional, X-linked angiotensin II type-2 receptor gene polymorphism ( 1332 G/A) in patients with systemic hypertension. Hypertension 43, Andersson B, Blange I & Sylven C (1999). Angiotensin-II type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure. Eur J Heart Fail 1, Azizi M & Ménard J (2004). Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 109, Baudin B (2000). Angiotensin I-converting enzyme gene polymorphism and drug response. Clin Chem Laboratory Med 38, Baudin B (2002). Angiotensin II receptor polymorphisms in hypertension. Pharmacogenomic considerations. Pharmacogenomics 3, 1 9. Benetos A, Cambien F, Gautier S et al. (1996a). Influence of the angiotensin II, type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive patients. Hypertension 28, Benetos A, Gautier S, Ricard S et al. (1996b). Influence of angiotensin-converting enzyme and angiotensin II, type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 94, Bonnardeaux A, Davies E, Jeunemaître X et al. (1994). Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 24, Buraczynska M, Ksiazek P, Zaluska W, Spasiewicz D, Nowicka T&Ksiazek A (2002). Angiotensin II type 1 receptor gene polymorphism in end-stage renal disease. Nephron 92, Burnier M & Brunner HR (2000). Angiotensin II receptor antagonists. Lancet 335, Chaves FJ, Pascual JM, Rovira E, Armengod ME & Redon J (2001). Angiotensin II AT1 receptor gene polymorphism and microalbuminuria in essential hypertension. AmJHypertens 14, Chowdhury TA, Dyer PH, Kumar S et al. (1997). Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependant diabetes mellitus. Diabet Med 14, Coll E, Campos B, Gonzalez-Nunez D, Botey A & Poch E (2003). Association between the A1166C polymorphism of the angiotensin II receptor type 1 and progression of chronic renal insufficiency. JNephrol 16, Deinum J, Van Gool J, Kofflard M, Ten Kate F & Jan Danser AH (2001). Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension 38, Delles C, Erdmann J, Jacobi J, Fleck E, Regitz-Zagrosek V & Schmieder RE (2000). Lack of association between polymorphisms of angiotensin II receptor genes and response to short-term angiotensin II infusion. JHypertens 18, Dieguez-Lucena JL, Aranda-Lara P, Ruiz-Galdon M, Garcia-Villanova J, Morell-Ocana M & Reyes-Engel A (1996). Angiotensin I-converting enzyme genotypes and angiotensin II receptors. Response to therapy. Hypertension 28,

5 Exp Physiol 90.3 pp Angiotensin II receptor genes and hypertension 281 Diez J, Laviades C, Orbe J et al. (2003). The A1166C polymorphism of the AT 1 receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives. JHypertens21, Doria A, Onuma T, Warram JH & Krolewski AS (1997). Synergistic effect of angiotensin II type 1 receptor genotype poor glycaemic control on risk of nephropathy in IDDM. Diabetologia 40, Erdmann J, Riedel K, Rohde K et al. (1999). Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene. Ann Hum Genet 63, Girerd X, Hanon O, Mourad JJ, Boutouyrie P, Laurent S & Jeunemaître X (1998). Lack of association between reninangiotensin system, gene polymorphisms, and wall thickness of the radial and carotid arteries. Hypertension 32, Hamon M, Amant C, Bauters C et al. (1997). Association of angiotensin-converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries. Heart 77, Henskens LH, Spiering W, Stoffers E et al. (2003). Effects of ACE I/D and AT 1 R-A 1666 Cpolymorphisms on blood pressure in a healthy normotensive primary care population: first results of the Hippocrates study. JHypertens21, Iliadou A, Lichtenstein P, Morgenstern R et al. (2002). Repeated blood pressure measurements in a sample of Swedish twins: heritabilities and associations with polymorphisms in the renin-angiotensin-aldosterone system. JHypertens20, Ishanov A, Okamoto H, Watanabe M et al. (1998). Angiotensin II type 1 receptor gene polymorphisms in patients with cardiac hypertrophy. Jap Heart J 39, Jiang Z, Zhao W, Yu F & Xu G (2001). Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Chin Med J 114, Jin W,LiuY,Sheng HH et al. (2003). Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 24, Kainulainen K, Perola M, Terwilliger J et al. (1999). Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 33, Kobashi G, Hata A, Ohta K et al. (2004). A1166C variant of angiotensin II type 1 receptor gene is associated with severe hypertension in pregnancy independently of T235 variant of angiotensinogen gene. JHuman Genet 49, Kurland L, Melhus H, Karlsson J et al. (2001a). Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II, receptor type 1 antagonist treatment in hypertensive patients. JHypertens 19, Kurland L, Melhus H, Sarabi M, Millgard J, LjunghallS&Lind L (2001b). Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects. Clin Physiol 21, Lajemi M, Labat C, Gautier S et al. (2001). Angiotensin II type 1 receptor 153 A/G and 1166 A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. JHypertens19, Miller JA, Thai K & Scholey JW (1999). Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II. Kidney Inter 56, Nalogowska-Glosnicka K, Lacka BI, Zychma MJ et al. (2000). Angiotensin II type 1 receptor gene A166C polymorphism associated with the increased risk of pregnancy-induced hypertension. MedSci Monitor 6, Ono K, Mannami T, Baba S, Yasui N, OgiharaT&IwaiN (2003). Lack of association between angiotensin II type 1 receptor gene polymorphism and essential hypertension in Japanese. Hypertens Res 26, Osterop A, Kofflard M, Sandkuijl L et al. (1998). AT 1 receptor A/C 1166 polymorphism contributes to cardiac hypertrophic cardiomyopathy. Hypertension 32, Plummer S, Tower C, Alonso P et al. (2004). Haplotypes of the angiotensin II receptor genes AGTR1 and AGTR2 in women with normotensive pregnancy and women with preeclampsia. Human Mut 24, Poirier O, Georges JL, Ricard S et al. (1998). 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. JHypertens16, Savage DA, Feeney SA, Fogarty DG & Maxwell AP (1999). Risk of developing diabetic nephropathy is not associated with synergism between the angiotensin II (type 1) receptor C1166 allele and poor glycaemic control. Nephrol Dial Transplant 14, Schmidt S, Beige S, Walla-Friedel M, Michel MC, Sharma AM &Ritz E (1997). A polymorphism in the gene for the angiotensin II type 1 receptor is not associated with hypertension. JHypertens15, Sierra C, Coca A, Gomez-Angelats E, Poch E, Sobrino J & De La Sierra A (2002). Renin-angiotensin system genetic polymorphisms and cerebral white matter lesions in essential hypertension. Hypertension 39, Strazzullo P, Iacone R, Iacoviello L et al. (2003). Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti prospective heart study. Ann Intern Med 138, Szombathy T, Szalai C, Katalin B, Palicz T, Romics L & Csaszar A (1998). Association of angiotensin II type 1 receptor polymorphism in resistant hypertension. Clin Chim Acta 269, Takahashi N, Murakami H, Kodama K et al. (2000). Association of a polymorphism at the 5 -region of the angiotensin II type 1 receptor with hypertension. Ann Hum Genet 64, Takami S, Katsuya T, Rakugi H et al. (1998). Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am J Hypertens 11, Tarnow L, Kjeld T, Knudsen E, Major-Pedersen A & Parving HH (2000). Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin-angiotensin system on risk of developing diabetic nephropathy in type I diabetic patients. Diabetologia 43,

6 282 B. Baudin Exp Physiol 90.3 pp Tiret L,Blanc H, Ruidavets JB et al. (1998). Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. JHypertens16, Tiret L,Bonnardeaux A, Poirier O et al. (1994). Synergistic effects of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 344, Wang JG & Staessen JA (2000). Genetic polymorphisms in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease. EurJPharmacol 410, Wang WY, Zee RY & Morris BJ (1997). Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 51, Ye S, Dhillon S, Seear R et al. (2003). 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 89, Zhang X, Erdmann J, Regitz-Zagrosek V, Kurzinger S, Hense HW & Schunkert H (2000). Evaluation of three polymorphisms in the promoter region of the angiotensin II type 1 receptor gene. JHypertens18, Zhang Y, Zhang KX, Wang GL, HuangW&ZhuDL(2003). Angiotensin II type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin 24, Zhu X, Chang YPC, Yan D et al. (2003). Associations between hypertension and genes in the renin-angiotensin system. Hypertension 41,