Atr Gene Polymorphisms And Hypertension

Hypertension has a multifactorial etiology with a strong genetic component. Of many human candidate gene loci examined, those encoding components of the RAS are considered to be among the most plausible candidates. The association of renin gene polymorphism with essential hypertension has been scarcely reported (16). On the contrary, several studies have demonstrated a link between the angiotensinogen (AG) gene and hypertension (17-19), particularly the M235T variant which correlates with both plasma angiotensinogen concentration and elevated BP variation; nevertheless, large ethnic discrepancies make this genotyping difficult to use.

The cloning of ACE gene enabled the detection of many polymorphisms (20,21), one of which consists of the presence (insertion allele I) or absence (deletion allele D) of a 287-bp DNA fragment in intron 16 of the ACE gene. A strong association was detected between the alleles of this polymorphism and the level of serum ACE, individuals ho-mozygous for the D allele (genotype DD) displaying serum ACE levels almost twice as high as those in individuals homozygous for the I allele (genotype II) but without clear correlation to BP (20,22,23). In particular, no association was found between this I/D polymorphism in the ACE gene and essential hypertension in young, middle-aged, or elderly populations, even when interindividual variation in BP could be dependent on contexts that are indexed by gender, age, and measures at body size. One possible explanation is that this polymorphism is in linkage disequilibrium with functional variants elsewhere in the ACE gene that are responsible for the BP.

For AT1R gene, the silent A1166C SNP has been associated with the severe form of essential hypertension, and in particular in resistant hypertensive patients taking two or more antihypertensive drugs (9,24). The C allele was particularly overrepresented in Caucasian hypertensive subjects with a strong family history (25), and it was also significantly more frequent in women with pregnancy-induced hypertension, whereas ACE I/ D and AG M235T polymorphisms were not associated with predisposition to development of hypertension in pregnant women (26). However, a significant interaction between the ACE I/D and AT1R A1166C polymorphisms in terms of influence on BP variation has been reported (27), but their linkage mechanism remains unclear. Henskens et al. (28) recently confirmed an association of both these polymorphisms with BP in healthy nor-motensive subjects, although synergistic effects did not seem to be present; in these studies ACE D allele and AT1R C allele were associated with highest pressures, either systolic, diastolic, or both. Berge et al. (29) also found an association of AT1R C allele with systolic BP in normotensive subjects. But large interethnic differences in the frequencies of genotype polymorphisms of the RAS exist; for example, the ACE DD and the AT1R CC genotypes have low prevalence in Chinese subjects compared with whites, whereas the AG M235T variant is much higher in Asian populations compared with white populations. Moreover, a higher prevalence of the AT1R CC genotype was found in Chinese hypertensive patients than in controls (30), whereas the A1166C genotype distribution did not differ between hypertensive and normotensive subjects from Japan (31) or Taiwan (32). In a sample of Swedish twins, Iliadou et al. (33) did not find any significant linkage and association between ACE I/D polymorphism or AT1R A1166C polymorphism and BP. In Caucasoid subjects from Germany, Schmidt et al. (34) did not detect any association of A1166C polymorphism with hypertension, but a trend towards a decreased prevalence of the C allele among hypertensive patients with a late age at diagnosis (>50 yr) was observed. Tiret et al. (35) showed a higher prevalence of C allele among female hypertensives than in controls but no such difference was observed for men. Szombathy et al. (36) did not find any difference for this polymorphism in AT1R gene between normotensive controls and subjects with resistant essential hypertension, but high values of systolic BP were associated with the C allele in older and overweight patients. Moreover, Castellano et al. (37) found that BP values were lower in CC homozygotes in an Italian population; these homozygotes also presented a lower incidence of family history of hypertension.

The molecular basis of salt sensitivity in human hypertension was explored by De la Sierra's team, and in particular by the evaluation of RAS gene polymorphisms; patients with ACE II or ID genotype had significantly higher prevalence of salt sensitivity than DD hypertensives, whereas AT1R A1166C polymorphism had no effect (38,39). Moreover, Tabara et al. (40) did not find any significant associations between orthostatic hypotension and gene polymorphisms of ACE I/D, AG M235T, and AT1R A1166C, orthostatic hypotension being an important risk factor for future cardiovascular morbidity and mortality. Several studies explored the sensitivity to Ang II in relation to AT1R A1166C polymorphism; for example, in normotensive subjects, Paillard et al. (41) did not find any genotype effect of this polymorphism on the Bmax and KD values of AT-1 on platelets. Testing for the response to short term infusion of Ang II in normotensive and moderately hypertensive subjects, Hilgers et al. (42) also concluded that the A1166C polymorphism does not have a major effect on the action of Ang II, i.e., increases in BP, plasma aldosterone, glomerular filtration rate, and decrease in renal blood flow.

Hypertension is a major risk factor for stroke, renal failure, and cardiovascular diseases. RAS gene polymorphism was studied in patients with cerebral white matter lesions assessed by brain magnetic resonance imaging; these lesions represent a subclinical form of ischemic brain damage and hypertension is one of the most important factors for their development. Sierra et al. (43) 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 A1166C polymorphisms was found. Moreover, no association was shown between AT1R gene polymorphisms and stroke (35). On the contrary, the presence of the C allele in AT1R gene might be associated with faster deterioration of renal function, i.e., progression to end-stage renal disease, and whatever the aetiology of the renal failure (44,45). Originally, a synergistic effect was suggested for AT1R A1166C polymorphism and poor glycemic control on the risk of diabetic nephropathy in insulin-dependent diabetic patients (11). But the subsequent studies performed failed to find any association between this polymorphism in AT1R gene and diabetic nephropathy (46-50). RAS gene polymorphism was also investigated in obesity, and particularly in obesity-associated hypertension. No association was detected between AG M235T or AT1R A1166C polymorphism and anthropometric indexes or BP, whereas the ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity in man, the DD homozygosity being associated with larger increases in body weight and BP in aging persons, as well as with higher incidence of overweight (51).

Arterial stiffness is associated with excess morbidity and mortality, independently of other cardiovascular risk factors. Age is the main determinant responsible for arterial wall changes leading to arterial stiffening. However, arterial stiffness is also influenced by vasoactive systems, and particularly the RAS. When AG M235T, ACE I/D, and aldosterone synthase gene polymorphisms were not associated with aortic stiffness as assessed by carotid-femoral pulse valve velocity, the 1166C allele in AT1R gene influenced the relationship between age and arterial pulse valve velocity and in an additive effect with another SNP in AT1R gene, the -153 A/G (52). The C allele was also associated with aortic stiffness in both normotensive and hypertensive subjects (53), and moreover in correlation with the ratio of total cholesterol on high-density lipoprotein cholesterol (54). Conversely, Girerd et al. (55) did not find such a correlation with vascular hypertrophy as assessed by high resolution echography in subjects with no evidence of cardiovascular disease.

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. Ang 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. Osterop et al. (56) investigated whether the ACE I/D and ATR A1166C polymorphisms influence left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy and concluded that the C allele in ATR gene modulates the phenotype of hypertrophy as determined by two-dimensional echocardiography, and independently of ACE I/D polymorphism. Takami et al. (57) also reported an association between C allele and left ventricular mass index, but in normotensive subjects without hypertrophic cardiomyopathy. These results are not in accordance with the study of Hamon et al. (58), which does not find any association of the ATR A1166C polymorphism with left ventricular hypertrophy in subjects with normal coronary arteries; however, a strong association was observed between left ventricular mass and systemic hypertension. Ishanov et al. (59) also concluded that this polymorphism does not contribute to the development of cardiac hypertrophy in patients with hypertensive left ventricular hypertrophy or hypertrophic cardiomyopathy. Moreover, no kind of relationship between AT-1 density and/or function and ATR gene C allele has yet been observed (60). Investigating patients by echocardiography for idiopathic heart failure diagnosis, Andersson et al. (61) found that patients with ACE DD and ATR CC or AC genotypes tented to have lower ejection fraction and increased left ventricular mass, suggesting an interaction of these two genetic traits on disease severity. Hamon et al. (58) also observed that the subjects homozygous for the ATR CC genotype had a significantly lower ejection fraction than those with A allele. These studies appear to suggest that in severe forms of hypertension, the ATR A1116C SNP is potentially involved in the regulation of BP; even when contrasted with other components of RAS, no direct effect of this polymorphism on the gene product has been demonstrated until now. Moreover, results from one ethnic group cannot be extrapolated to another.

Among the other polymorphisms in ATR gene, at 5'-flanking region a higher frequency of the T allele (-535C/T SNP) was observed in hypertensive patients (14), whereas Zhang et al. (62), evaluating nine newly characterized SNPs, did not show any association with arterial hypertension. Poirier et al. (13) also noticed that among seven new polymorphisms, all different from those formerly described, none was associated with pressor levels in control subjects, whereas Chaves et al. (10) found that the +573C/T polymorphism might be a genetic protective factor for urinary albumin excretion in a population of essential hypertensives. Investigating 25 new polymorphisms in RAS genes, Zhu et al. (15) particularly described an association between two ATR gene polymorphisms, located at the 3'-flanking region, and hypertension in African Americans but not in European Americans.

Recently, polymorphism in Ang II type 2 receptor (AT2R) gene was also shown and investigated, in particular the A3123C located in the 3' untranslated region of exon 3 in a study showing that this polymorphism may contribute to cardiac hypertrophy in women with hypertrophic cardiomyopathy (63). Conversely, no association was detected between

AT2R polymorphism and hypertension (57). Delles et al. (64) tested another SNP in AT2R gene, namely +1675 G/A polymorphism, and in parallel of a SNP in AT1R gene, i.e., -2228 G/A polymorphism; the response to Ang II infusion did not differ across the AT1R and AT2R genotypes. Conversely, this latter polymorphism in AT2R gene was associated with left ventricular structure in young adults with normal or mildly elevated BP; in particular, as stated by echocardiography, hypertensive subjects with the A allele had greater left ventricular thickness and mass index than those with the G allele, suggesting early structural changes of the heart owing to hypertension in association with a genetic trait in RAS (65). Research on AT-2 has unveiled hitherto unknown functions of the RAS extending beyond the classical role of this hormonal system in cardiovascular control, providing a solid basis for further research variation (66), and in particular using AT-1 antagonists.

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