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Themed Issue papers |
1 Service de Biochimie A, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, 75571 Paris, Cedex 12, France2 UFR des Sciences Pharmaceutiques, Boulevard Bequerel, 14032, Caen (Université de Basse-Normandie), Cedex, France
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Abstract |
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 Top Abstract IntroductionReferences |
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(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, 75571 Paris, Cedex 12, France. Email: bruno.baudin{at}sat.ap-hop-paris.fr
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Introduction |
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TopAbstractIntroductionReferences |
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The human AT1R 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 region of the gene (Bonnardeaux et al. 1994); at present this +1166A/C polymorphism is the best evaluated. The A allele 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 in hypertension 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 AT1R 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 AT1R 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 C allele was 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 AT1R+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 AT1R 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 AT1R+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 AT1R 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 AT1R 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 D allele may be a predisposing factor for developing white matter lesions in essential hypertensive patients, whereas no significant association for the AG M235T and AT1R+1166A/C polymorphisms was found. Moreover, no association was shown between AT1R gene polymorphisms and stroke (Tiret et al. 1998); on the contrary, the presence of the C allele in the AT1R gene might be associated with faster deterioration of renal function (Buraczynska et al. 2002; Coll et al. 2003). Originally a synergistic effect was suggested for AT1R+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 obesity-associated hypertension. No association was detected between AG M235T or AT1R+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 AT1R+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 AT1R gene influences the relationship between age and arterial pulse valve velocity in an additive effect with the –153A/G SNP in the AT1R 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; Ye et 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 AT1R 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 AT1R+1166A/C polymorphisms influence left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy and concluded that the C allele in the AT1R 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 AT1R 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 AT1R CC genotype had a significantly lower ejection fraction than those with the A allele. Thus, when AT1R+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 AT1R gene, at the 5'-flanking region a higher frequency of the T allele (–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 AT1R gene polymorphisms and hypertension in African but not European Americans. Moreover, among six SNPs discovered in the promoter region of the AT1R 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.
AT2R gene polymorphism
Polymorphism in the AT2R 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 AT2R gene, namely the +1675G/A polymorphism, and in parallel the –2228G/A polymorphism in the AT1R gene; the response to Ang II infusion did not differ between the AT1R and AT2R genotypes. More recently, identifying nine new SNPs in the AT2R 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 AT2R gene.
Pharmacogenomic considerations regarding Ang II receptors
The response of patients to antihypertensive therapy is variable; individuals may respond differently to different 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 AT1R gene (Baudin, 2002). Miller et al. (1999) hypothesized that renal and systemic Ang II activity would be augmented in subjects with the C allele of the AT1R 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 D allele in the ACE gene was only reduced in endothelium-dependent vasodilatation. Several studies have examined relationships between the ACE and AT1R 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 AT1R 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 AT1R+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 AT1R 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.
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