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

Abstract

The role of renin-angiotensin system (RAS) genes on the risk of lower extremity arterial disease (LEAD) in elderly people remains unclear. We assessed the relationship of genetic polymorphisms in RAS: G-6A, T174M and M235T of the angiotensinogen (AGT) gene, and the angiotensin-converting enzyme insertion/deletion (ACE_I/D) variant to the risk of LEAD in the Health, Aging and Body Composition (Health ABC) Study. This analysis included 1228 black and 1306 white men and women whose age ranged between 70 and 79 years at the study enrollment. LEAD was defined as ankle-arm index (AAI) o0.9. Genotype-phenotype associations were estimated by regression analyses with and without adjustment for established cardiovascular disease (CVD) risk factors. The proportion of LEAD was significantly higher in black (21.1%) than that in white elderly people (10.1%, Po0.0001). The distribution of AGT polymorphisms was also significantly different between black and white participants. There was no statistically significant association between the selected RAS genetic variants and LEAD after adjustment for age, antihypertensive medications, lipid-lowering medication, pack-year smoking, body mass index, low-density lipoprotein cholesterol, and prevalent diabetes and coronary heart disease. However, A-T haplotype of G-6A and M235T interacting with homozygous ACE_II (b ¼ À1.07, P ¼ 0.006) and with ACE inhibitors (b ¼ À1.03, P ¼ 0.01) significantly decreased the risk of LEAD in white but not in black participants after adjustment for the selected CVD risk factors. In conclusion, the study observed a gene-gene and gene-drug interaction for LEAD in the white elderly.

Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: Role of ACE D/-240T haplotype

“…The data document an association between candidate genes in RAS and CAD, AAA, and CVD, 5,6,26 whereas few data are available concerning PAD. 2,7,8,27 Findings from the present study support that the ACE gene and particularly the ACE I/D polymorphism modulates the predisposition to PAD independently of traditional risk factors.…”

“…5,6 The few published reports on the relationship between RAS genes and PAD have had conflicting results. 2,7,8 A recent hypothesis is that people carrying susceptibility polymorphisms in RAS genes might exhibit higher angiotensin II levels, which may be crucial in the development of the disease.…”

“…These genes are involved in homocysteine metabolism and their association with the predisposition to PAD has been demonstrated. 2,3 The involvement of the RAS in atherosclerosis has been demonstrated, 4 and genes encoding for its components, such as angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), have been proposed as candidates that influence the predisposition to both CAD and CVD. 5,6 The few published reports on the relationship between RAS genes and PAD have had conflicting results.…”

Risk given byAGTpolymorphisms in inducing susceptibility to essential hypertension among isolated populations from a remote region of China: A case-control study among the isolated populations

“…In contrast, other studies, among the populations of northern Chinese Han individuals, 64,85 Asians, 39 Europeans, 39 African Americans, 33 and European Americans, 33 have indicated the absence of association of T174M with EH. In addition, other studies, among the Mexicans, 26 black and white participants, 119 Americans in the Delaware Valley Region, 106 Americans, 120 Caucasians, 121 Chinese Han, 122 and Taiwanese, 89 showed no association between this polymorphism and the risk of the non-familial atrial fibrillation, lower extremity arterial disease, decline in renal function post-transplantation, preeclampsia, pseudoxanthoma elasticum, coronary artery disease, and chronic kidney disease in this mutation, respectively. In our study, no association was observed between these two polymorphisms (including A-20C and T174M) and EH among the both Hani and Yi populations.…”

Hypertension and genes: perspectives from this journal

“…Genetic polymorphisms of RAAS genes could also play a role in arterial stiffness leading to an increased risk of development of lower extremity arterial disease and possibly, other vascular disease. Recently, Li et al 6 estimated the relationship of ACE I/D variant and G-6A, T174M and M235 T polymorphisms of the AGT gene to lower extremity arterial disease in a large population of elderly white and black participants. Apart from significant differences in the distribution of the RAAS genetic variants by ethnicity (consistent with previous reports) a major finding is the interaction between ACE inhibitors and the A-T haplotype of the AGT gene, a gene-drug interaction that reduces the risk of lower extremity arterial disease in the white population.…”