Angiotensin II Type 1 Receptor 1166C Polymorphism Is Associated With Abdominal Aortic Aneurysm in Three Independent Cohorts

Abstract

Objectives-Although polymorphic variations in genes of the RAS system have previously been associated with susceptibility to AAA, such studies have been significantly limited by small sample sizes. This study was undertaken, using the largest case series yet reported, to determine whether common genetic variants of the RAS are associated with either susceptibility or severity of AAA. Methods and Results-The frequencies of 4 common genetic variants of genes related to the renin-angiotensin system were investigated in 3 geographically distinct, but ethnically similar, case-control cohorts, resulting in comparison of 1226 AAA cases with 1723 controls. In all 3 the AGTR1 1166C allele was significantly more common in AAA patients than controls (overall adjusted OR 1. Key Words: abdominal aortic aneurysm Ⅲ angiotensinogen Ⅲ angiotensin converting enzyme Ⅲ angiotensin Ⅲ Bradykinin Ⅲ genetic association Ⅲ renin T he renin-angiotensin system (RAS) is a potent mediator of cardiovascular homeostasis. The principal effector, angiotensin II (Ang II), is most widely associated with its role in the regulation of arterial blood pressure, but has been implicated in a wide range of nonpressor related actions including vascular remodeling, fibrosis, endothelial dysfunction, oxidative stress, 1,2 and dyslipidemia. 3 Reduction of Ang II levels, by inhibition of its converting enzyme (ACE), has been shown to significantly reduce cardiovascular disease morbidity and mortality. 4 Abdominal aortic aneurysm (AAA) is a common condition, being present in approximately 4% of white men between the ages of 50 to 79 years. 5 The condition is associated with a distinct familial component, with up to 20% of patients having one or more first affected relatives. 6 Evidence of a link between the RAS and abdominal aortic degeneration has been shown in experimental animal models, with exogenous Ang II inducing abdominal aortic aneurysms in the apolipoprotein E-deficient mouse, 7 and RAS blockade reducing spontaneous aortic elastic tissue degeneration in the rat, independent of changes in blood pressure. 8 In humans, ACE inhibitors have been suggested to reduce AAA rupture, an effect not observed with other antihypertensive agents. 9 Genetic polymorphisms of the RAS have been implicated as potential susceptibility candidates in a variety of vascular disorders including coronary artery disease, myocardial infarction, and hypertension. The role of the RAS related polymorphisms has been previously investigated in AAA patients. 10 -13 Fatini and coworkers, in the largest and most recent of these studies, investigated 250 cases and reported a significant association between ACE deletion homozygotes and AAA susceptibility. 10 All of the studies to date have involved small patient cohorts without adequate independent replication.Recently, a combinational effect of ACE, AGT, and AGTR1 SNPs has been reported for susceptibility to diabetic nephrop-

Multifaceted Role of Angiotensin II in Vascular Inflammation and Aortic Aneurysmal Disease

“…Also in aged C57BL/6J mice, Ang II produces both suprarenal and ascending thoracic aneurysms and dissections, albeit at a lower frequency than in the presence of hyperlipidemia (Tieu, et al, 2009). Moreover, Ang II type I receptor and ACE polymorphisms are associated with AAA in humans (Jones, et al, 2008), suggesting that Ang II is tightly associated with aneurysmal diseases. The mouse models of acute Ang II infusion showed significant vascular inflammatory responses in aneurysmal tissues, including enhanced aortic cytokine/chemokine production, early macrophage recruitment, elastin degeneration, and intramural hematoma formation.…”

“…In the cell, TGF-signals through both Smad-dependent (Jones, et al, 2008) and Smad-independent (p38 MAP kinase-mediated) pathways (Funaba, et al, 2006). In the classic Smad-dependent pathway, ligand binding of TGF-dimers leads to autophosphorylation and activation of a TGF-RII homodimer, which in turn recruits and phosphorylates a TGF-RI homodimer (Figure 1).…”

A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm

“…Any SNPs found to be significantly associated with aortic diameter were further assessed in an independent cohort of subjects from New Zealand. 9 These subjects included 513 men with large AAAs (80% had undergone aortic repair) and 269 healthy elderly men from the same region of Otago. All subjects included in both cohorts had undergone abdominal ultrasound.…”

“…Ultrasound reproducibility was assessed during subject recruitment and 95% confidence intervals were o3 mm. 9 The definitions of clinical risk factors such as hypertension, dyslipidemia, diabetes, coronary heart disease and waist-to-hip ratio were as previously described. 7 …”

“…Genotyping in the New Zealand cohort was carried out using polymerase chain reaction as previously described. 9 …”