M235t Polymorphism Of Agt Gene And Hypertension

The AGT gene contains five exons and four introns, which span 13 kb (18). An extensive study of the potential role of the AGT gene in human essential hypertension was performed on two large series of hypertensive siblingships yielding 379 sibling pairs. The highly polymorphic CA dinucleotide repeat marker located in the 3'-region of the AGT gene and the powerful affected sibling pair methodology were used to obtain evidence of a genetic linkage between the AGT gene and hypertension in this study (19). A 17% excess of AGT allele sharing was found in severely hypertensive sibling pairs. Whereas significant linkage was obtained in male pairs in both the Utah and Paris groups, no excess of shared AGT alleles was observed in female subjects, suggesting the influence of an epistatic hormonal phenomenon. These studies also showed that variants 235T and 174M of the AGT gene are associated with hypertension. From these studies, it was estimated that mutations at the AGT locus might be a predisposing factor in at least 3-6% of hypertensive individuals younger than 60 yr of age in the Caucasian population. When the same methodology was used to analyze the same hypertensive sibling pairs from Utah or Paris, it showed no linkage with other genes of the renin system: namely renin (20), ACE (21), or Ang II type I receptor (22).

Two other linkage studies also indicate a relationship between the AGT locus and hypertension. This linkage was observed in the subgroup of patients with diastolic pressure above 100 mmHg, but there was no difference among female-female pairs. However, there was no association between hypertension and the 235T AGT variant in this population (23). The same group also found linkage and association of the AGT locus with high BP in 63 affected sibling pairs of African-Caribbean origin, suggesting some similarity in the genetic basis of essential hypertension in populations of different ethnicity (24). The corroboration of these linkage studies indicate that molecular variants of the AGT gene, such as M235T, or those in linkage disequilibrium with this variant are inherited predispositions to essential hypertension in humans.

However, results of these studies must be interpreted with caution for several reasons. First, the frequency of the 235T AGT allele varies in different ethnic groups. The 235T allele is more frequent in the Asian than in the Caucasian population and is by far the predominant allele in the African population. As a consequence, positive results may arise from population admixture, and negative results in populations in which this allele is predominant may result from the constraint of limited statistical power. Second, differences in the design of each study and the choice of the control group make any overall comparison difficult. Finally, most of the results reported to date have been obtained with relatively small numbers of patients, which can also generate false negative or false positive results.

There are divergent results on the association between variants in AGT at position 235 (235T) or 174 (174M) and hypertension in Caucasians. In their original study, Jeunemaitre et al. found that the M235T variant was more frequent in hypertensive probands from Utah and Paris, especially in the more severe index cases (19). A subsequent study by the same group on 136 mild to moderate hypertensive subjects also found that the frequency of the 235T allele was increased, although the increase was significant only for patients with a family history of hypertension. Schmidt also found a higher frequency of the 235T allele in subjects with hypertension, a family history of the disease, and early onset of hypertension (25).

However, other studies have not found any association between the 235T variant and hypertension. Hingorani et al. found no difference in the frequency of M235T in 223 hypertensive subjects and 187 normotensive individuals in Anglia in the United Kingdom (26). A more powerful study performed in Finland by Kiema gave negative results with 508 mild hypertensives and 523 population-based controls (27). On the other hand, four large studies recently showed a positive association between the M235T allele and essential hypertension. An association with severe hypertension with stronger relation ship for men than for women was found in a sample from the Framingham Heart study and from the Atherosclerosis Risk in Community (ARIC) study, when the effect of body mass index and triglycerides were taken into account (28). The proportions of cases attributable to the 235 allele were 8% in the ARIC population and 20% in the Framingham population. In a study testing a large number of AGT alleles, the frequency of the 235T allele was 0.47 in the 477 probands of hypertensive families and 0.38 in the 364 Caucasian controls (29). In a cross-section sample of634 middle-aged subjects from the MONIC Angsburg cohort, Schunkert found that individuals carrying at least one copy of the T235 allele had high SBP and diastolic BP(DBP)s and were more likely to use antihypertensive drugs (30). Finally, another case-control study involving 802 hypertensive subjects and 658 Caucasian controls has shown a significant increase in the frequency of the T235 allele in men and in women whose hypertension was diagnosed before they were 45 yr of age (31). These studies emphasize the importance of sample size testing for susceptibility locus in a complex disease such as hypertension (32).

The frequency of the T235 allele is invariably high in the Japanese population, ranging from 0.65 to 0.75. An association between hypertension and molecular variants of AGT in the Japanese population has been found in several independent studies (33-35). All of the studies reported so far indicate that frequency of the 235T variant is higher in Japanese hypertensive subjects. A more homogeneous genetic and environmental background may explain why the results reported for Japanese populations are more uniform. However, Ishigami et al. (36) showed that the -20C variant of the human AGT gene plays an important role in hypertension in Japanese population.

Walker et al. showed a remarkably high correlation between plasma AGT concentration and elevated BP (p < 0.0001) in a large study involving 574 black subjects (4). Bloem et al. (37) showed that (1) plasma AGT level is about 19% higher in black children as compared with white children; and (2) BP is normally higher and increases faster over time in black children as compared with white children. Caulfield et al. (24) found an association between the AGT gene locus and high BP in 63 affected sibling pairs of African-Carribean origin using CA dinucleotide marker. However, these workers could not find an association between variants M235T and hypertension in the African-American population. Various recent studies have suggested that although the frequency of 235T allele is increased in the African-American population (0.8-0.9), there is no association between 235T allele and hypertension in this population (38).

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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