Candidate Gene Association Studies in Abdominal Aortic Aneurysm Disease: A Review and Meta-Analysis

Abstract

Three of these polymorphisms were associated with a significant risk of AAA, ACE RR 1.33 [95% CI 1.20-1.48], MTHFR RR 1.14 [1.08-1.21] and MMP9 RR 1.09 [1.01-1.18]. These differences have been previously reported as equivocal, within a context of contradictory studies and as such this meta-analysis provides new evidence for their involvement in AAA disease. The plausibility of these findings is discussed within the context of a systems approach to the pathology of AAA disease.

Pathophysiology of Abdominal Aortic Aneurysm – Genetic Factors and Homocysteine Metabolism

“…A common polymorphism (G994T) in this gene reduces enzyme activity and results in increased levels of PAF. A significant association with the T-allele and AAA has been demonstrated (Thompson et al, 2008).…”

“…Several studies have investigated the link between MTHFR gene polymorphisms and AAA (Brunelli et al, 2000;Jones et al, 2002;Strauss et al, 2003;Ferrara et al, 2006). All but one of these demonstrated a link between the T allele polymorphism and AAA, a meta-analysis of these studies confirmed a significant effect in favour of the T-allele variant increasing the risk of AAA (Thompson et al, 2008). Interestingly, the study that did not provide evidence to suggest a link between the T-allele and AAA, did suggest that it may be a contributory factor in AAA severity as indicated by aneurysm size (Strauss et al, 2003).…”

“…Platelet Activating Factor (PAF) has been shown to induce MMP formation. An imbalance of MMP's and their inhibitors/activators leads to an excess of MMP's resulting in the degradation of the structural proteins elastin and collagen and subsequent aneurysm formation (Thompson et al, 2008;Sandford et al, 2007). Polymorphisms have been identified in the genes encoding each of these protein systems.…”

“…MMPs can be activated by a range of stimuli including other MMPs, cytokines released by the inflammatory cells, elastin degradation products, microbes such as chlamydiae pneumoniae, reactive oxygen species, and mechanical alteration in the aortic wall stress (Warsi et al, 2004). Several genetic polymorphisms are associated with MMP and some have been linked with increased frequency in AAA (Thompson et al, 2008;Sandford et al, 2007). Genetic polymorphism is a difference in DNA sequence among the population that gives rise to different forms such as in the case of human blood groups.…”

“…A guanine to thymidine substitution in position 994 of the exon 9 (PAF-AH +994 G>T) results in lower enzymatic activity of PAF-AH with increased PAF level. GT and TT genotype are associated with AAA with an odd ratio of 2.48 (CI 1.36-4.65) (Thompson et al, 2008). In general there is a lack of clear evidence that upregulation of MMPs in AAA has a genetic basis (Sandford et al, 2007).…”