Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: role of ACE D/-240T haplotype.
OBJECTIVE
Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease.


METHODS
The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex.


RESULTS
The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found.


CONCLUSIONS
The present study contributes data to highlight the role of the ACED/-240T haplotype in predisposing to PAD, also in the absence of other atherosclerotic comorbidities.
Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. cinziafatini@hotmail.com
Cinzia
C
Fatini
Elena
E
Sticchi
Francesco
F
Sofi
Abdihakim Abdullahi
AA
Said
Giovanni
G
Pratesi
Raffaele
R
Pulli
Carlo
C
Pratesi
Rosanna
R
Abbate
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000808:Angiotensinogen / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D016491:Peripheral Vascular Diseases / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index
C544065:AGTR1 protein, human; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A