Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis

Abstract

Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5-29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6 -388], P ‫؍‬ 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes. Diabetes 56:863-871, 2007 P atients with type 1 diabetes have a dramatically higher risk of coronary artery disease (CAD) compared with the general population (1,2). Coronary artery calcification (CAC), a marker of coronary artery plaque burden, correlates very well with the established CAD risk factor profile in patients with type 1 diabetes (3-5). There is growing evidence that CAC strongly predicts future coronary events in asymptomatic nondiabetic and diabetic subjects (4 -6).Diabetic nephropathy plays an important role in the pathogenesis of advanced CAD in type 1 diabetes (2). However, little is known concerning determinants of subclinical atherosclerosis detected as rapidly progressing CAC. Activation of the renin-angiotensin system (RAS) by hyperglycemia may be the key mechanism (7,8). The RAS involves enzymatic processing of angiotensinogen (AGT) to angiotensin I, further cleaved by ACE to angiotensin II. Treatment with ACE inhibitors lowers the risk of cardiovascular death, myocardial infarction, and coronary revascularization in the general population and in diabetic patients (9 -11).The RAS activity is modified by variants of the genes coding functional proteins of this pathway (12-14). The AGT gene, localized on chromosome 1q41-qter, encodes AGT. There is only one haplotype block at the AGT locus, and all common single nucleotide polymorphisms (SNPs) identified appear to be in complete linkage disequilibrium with the most intensively studied M235T polymorphism (13,15). Although the functional variant has not yet been definitively identified (16), the T235 allele has been consistently associated with cardiovascular disease (13,17) and ...

Angiotensin-converting enzyme single nucleotide polymorphism is a genetic risk factor for cardiovascular disease: a cohort study of hypertensive patients

“…24 As we previously reported, the association between RAS inhibition and ACE I/D polymorphism is very important. 18 Although some studies have reported that administration of ACE-Is and/or ARBs vary the effect of the ACE I/D genotype on cardiovascular events, 25 others have not. 15 Although we only have baseline information about antihypertensive treatments, the ACE DD genotype was an independent risk factor for CVD after adjusting for ACE-I/ARB drugs and antihypertensive drugs.…”

Coronary Artery Calcification Progression Is Heritable

“…Although no one has identified candidate genes associated with the rate of progression of CAC, others have identified candidate genes associated with CAC progression when defined as a qualitative trait (ie, progressors versus nonprogressors 29 ) in individuals with type 1 diabetes. 30,31 It would be important to investigate whether any identified genes are unique for CAC progression or whether they also are associated with cross-sectional measures of CAC prevalence or quantity.…”

Comment on: Kretowski et al. (2007) Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis: Diabetes 56:863–871

“…The OR of CAC progression with the AGT TT genotype versus other genotypes was 5.1 (see Table 5 in ref. 1), which is well in range of the 95% CI of the OR (4.5-29.6) for the AGT TT-ACE ID-ATR1 AA/AC genotype. Therefore, we believe that this study does support a relation of AGT M235T polymorphism with CAC in patients with type 1 diabetes but does not support the suggestion that certain genetic variants of proteins involved in the renin-angiotensin system pathway have an additive effect on progression of CAC.…”

“…n their recently published study, Kretowski et al (1) explored the role of some genetic variants of proteins involved in the renin-angiotensin system, in subjects with type 1 diabetes, as predictors of progression of coronary artery calcification (CAC), a marker of subclinical coronary artery disease. Three polymorphisms were studied: variants of angiotensinogen (AGT) (M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1) (A1166C).…”