Angiotensinogen M235T and T174M Gene Polymorphisms in Combination Doubles the Risk of Mortality in Heart Failure

Abstract

Abstract-Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (nϭ451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (nϭ86) were 3 years younger at admission (Pϭ0.011), and, in those with hypertension, diagnosis was made Ϸ10 years earlier than other patients. Patients carrying Ն1 174M allele (nϭ94) were more likely to have a previous history of heart failure (Pϭ0.044) and increased mortality during follow-up (risk ratio: Key Words: angiotensinogen Ⅲ polymorphism Ⅲ single nucleotide Ⅲ mortality Ⅲ heart failure Ⅲ congestive Ⅲ association T he renin-angiotensin system (RAS) is a key element in pressure/volume homeostasis and exerts a wide range of systemic and local effects through endocrine, paracrine, and autocrine signaling. 1 In patients with cardiovascular disease, activity of the RAS is often increased and contributes to a poor prognosis. 2 Detrimental effects include promotion of inappropriate sodium and water retention, increased peripheral vascular resistance, and promotion of adverse vascular and cardiac remodeling in response to cardiac injury. 3 Gene polymorphisms that increase baseline RAS activity are, therefore, candidates for increasing risk of, and adverse outcomes in, heart disease.The gene encoding angiotensinogen (AGT) has been implicated in hypertension both through genetic linkage studies 4,5 and by allelic association. A missense mutation in exon 2 of the gene (AGT M235T) has been associated with elevated levels of AGT, with 235TT homozygotes having between 10% and 20% more plasma AGT than 235MM individuals. 4,6,7 These individuals also have increased blood pressure, 4,8 -11 although a large-scale study of 9100 men and women from the Danish general population found that this was only true in women. 7 The frequency of the 235T allele has been shown to be significantly greater in hypertensive patients than in normotensive control subjects 4,12-14 and has also been linked with pre-eclampsia, 15 left ventricular hypertrophy, 16 increased risk of coronary heart disease, 17,18 and atrial fibrillation. 19 A second variant within the AGT gene, T174M, has also been associated with hypertension, with the M allele associated with an increased risk. 4,14 The M235T and T174M variants are in linkage disequilibrium. 4,14 However, a large-scale meta-analysis found no consistent association between either AGT polymorphism and increased risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease in the Danish population. 20 To date, no studies have examined the combined influence of AGT M235T and T174M variants in heart failure (HF). Neither has the influence of these variants on long-term patients survival been explored. We hypothesized that these gene ...

Genetic variation in the renin–angiotensin–aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease

“…Several meta-analyses have reported small positive associations between both the 235T and T174 alleles and hypertension, 12 with blood pressure and arterial stiffness, 21 and with increased heart failure mortality. 22 AGT 235 'TT' homozygotes have also been shown to have approximately 20% higher concentrations of plasma AGT. 23 Consistent with these findings, in the current study, participants with the AGT 235 'TT' genotype were younger at the time of recruitment by 2.9 years.…”

Hereditary Determinants of Human Hypertension

“…High-risk combination genotypes were predictive of mortality. 46 In another study, only one 3Ј noncoding SNP (rs943580) in AGT was associated with transmitral early peak filling velocity. 47 Among 80 cardiovascular candidate genes, APOE, SCN7A, and SLC20A1 associated with ventricular mass, whereas ADRB1 associated with relative wall thickness in blacks.…”

O polimorfismo AGT*M235T na disfunção cardíaca de etiologia isquêmica aguda: projeto gisca

“…Others, however, found different prevalences, as in the case-control study conducted in Minas Gerais 30 , which assessed 201 patients with coronary artery disease (with and without MI); in Pilbrow et al's study 8 on mortality in heart failure in New Zealand; and in Bauters et al's 6 study, in France, regarding ventricular remodeling three and 12 months after anterior wall myocardial infarction.…”

“…The frequencies of AGT*M235T polymorphism genotypes and alleles vary in the different studies published 6,8,30 , according to the populations analyzed. Natural selection of the genotypes more favorable to adaptation to local environmental characteristics and the different degrees of miscegenation in the different geographic regions are some of the possible explanations for these differences.…”