Haplotypes of Angiotensinogen in Essential Hypertension

Abstract

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

The 460Trp polymorphism of the human α-adducin gene is not associated with isolated systolic hypertension in elderly Australian Caucasians

“…In Japanese and other ethnic populations, further studies, including the generation of haplotypes and family-based tests for linkage disequilibrium, would be required to reveal whether or not the molecular variants of the ␣-adducin gene are responsible for hypertension. [28][29][30] The variation among frequences of ␣-adducin genetic variants, the presence of hypertension and ethnicity in various studies has been demonstrated not only for the ␣-adducin gene but for the angiotensinogen and S A genes (also associated with hypertension). 31 Therefore, it is very important to recognise the local relevance for hypertension of the specific genetic markers within different ethnic groups.…”

Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study

“…The AGT polymorphism M235T corresponds to a change from methionine to threonine at position 235. 4,5 The polymorphism T174M in a tight linkage disequilibrium with the M235T variant 4 encodes methionine instead of threonine. Studies 4,6 have found higher plasma AGT levels among 235T allele carriers, but no association between T174M variant and AGT levels.…”

Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic

“…24 The Copenhagen City Heart Study 25 reported that women who were homozygous for the T allele of the M235T polymorphism had higher levels of angiotensinogen than heterozygotes or women who were noncarriers, and that the levels were positively correlated with BP in women, but not in men. The M235T polymorphism is in tight linkage disequilibrium with the functional AGT G-6A polymorphism in most populations 26 and in the sample analyzed in this study (data not shown). One conclusion emerging from this study and previously reported pharmacogenetic and pharmaco-epidemiologic data is that application of genetic and other predictive information to tailor drug therapies will need to take into account both gender and ethnic background.…”