angiotensinogen and Aortic-Aneurysm--Abdominal

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.. 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 1.60, 95% CI 1.32 to 1.93, P=1.1x10(-6)). Overall, the ACE ID genotype was associated with AAA (OR 1.33, 95% CI 1.06 to 1.67, P<0.02). The AGT 268T allele appeared to have an epistatic effect on large aneurysm size.. This study has identified a strong and repeated association between the AGTR1 1166C allele and susceptibility to AAA, and a weaker effect associated with the ACE deletion allele, in 3 geographically distinct, but ethnically similar, case-control cohorts. This study highlights the key role of the RAS in AAA and emphasizes the need for replication and validation of results in suitable independent cohorts.

Topics: Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Angiotensinogen; Aortic Aneurysm, Abdominal; Australia; Base Sequence; Cohort Studies; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Mutagenesis, Insertional; New Zealand; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Renin-Angiotensin System; Sequence Deletion; United Kingdom

To investigate whether an inflammatory response occurs in patients undergoing infrarenal aortic abdominal aneurysm repair, the localization and timing (ischemia and/or reperfusion) of this activation, and finally whether it affects postoperative pulmonary function.. Prospective, observational study.. Academic referral center in Italy.. We included 12 patients undergoing infrarenal aortic abdominal aneurysm repair and 12 patients undergoing major abdominal surgery.. Timed measurement of gene activation (angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes) in muscle biopsies by reverse transcriptase-polymerase chain reaction (RT-PCR), and prospective assessment of interleukin-6 plasma concentration and pulmonary function (Pao2/FIO2 and Pao2/PAO2 ratios).. After 30 mins of aortic clamping, angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes were all overexpressed at RT-PCR studies in quadriceps muscle of patients undergoing aortic abdominal aneurysm repair, and the overexpression persisted after reperfusion. In situ hybridization and immunohistochemistry revealed that the inflammatory response was localized in endothelial cells. A significant increase in plasma interleukin-6 concentrations was then detectable at 6 and 12 hrs after reperfusion in aortic abdominal aneurysm surgery compared with patients undergoing abdominal surgery (p < .05). The increase in interleukin-6 plasma concentration was then followed (12 and 24 hrs after surgery) by a significant reduction of Pao2/ FIO2 and Pao2/PAO2 ratios (p < .05 vs. abdominal surgery).. The present study shows that a) during aortic surgery, the genes for interleukin-6 and for the components of the local renin-angiotensin system (angiotensinogen, angiotensin-converting enzyme, and angiotensin type 1 receptor subtype) are activated early in the ischemic muscle, and activation persists during reperfusion; b) interleukin-6 plasma concentration increases only in patients with tissue ischemia (aortic abdominal aneurysm), whereas no changes are detectable in patients with abdominal surgery; and finally c) the occurrence of systemic inflammatory reaction with increased interleukin-6 plasma concentrations is followed by impaired pulmonary function.

Topics: Aged; Angiotensinogen; Aortic Aneurysm, Abdominal; Colectomy; Female; Gastrectomy; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Lung Diseases; Male; Middle Aged; Muscle, Skeletal; Nephrectomy; Peptidyl-Dipeptidase A; Postoperative Complications; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reperfusion Injury; Systemic Inflammatory Response Syndrome; Thigh; Transcriptional Activation; Treatment Outcome