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Abstract: Objective: Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes. Methods: AAA patients (n =1151) and controls (n =727) were genotyped for CARD8 SNP rs2043211 and NLRP3 SNP rs35829419 using TaqMan SNP assays. IL1-β, C-reactive protein (CRP), and lipoprotein (a) [Lp(a)] were measured in the plasma of a subset of study participants. The Kruskal–Wallis Rank test was conducted to test for differences in mean concentration of IL1-β, CRP and Lp(a). Logistic regression was used to test for interaction between CARD8 and NLRP3. Results: Significantly higher mean concentration of plasma IL1-β was observed in study participants who were homozygous for the common C allele of NLRP3 rs35829419 (p =0.010). Interaction between rs2043211 and rs35829419 was observed in this dataset (χ 2 =6.22; p =0.044), which strengthened when adjusted for age, gender, smoking, diabetes, hypertension, and dyslipidemia (χ 2 =14.75; p =0.012); and separately for NOD2 genotype (χ 2 =14.06; p =0.015). Conclusion: Our finding suggests genetic variability within the NLRP3 inflammasome may be important in the pathophysiology of AAA. [Copyright &y& Elsevier]

Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5α reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C>T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P=0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs. [ABSTRACT FROM AUTHOR]

Background: Abdominal aortic aneurysm (AAA) is an important cause of mortality for the aged, a group that has been denied surgery in the past for fear of peri-operative mortality. Is this attitude still justified? Methods: Analysis of prospectively gathered data from a vascular database. Results: 10.9% of all open AAA operations were in patients older than 79 years with an 8% mortality cate compared to 3% for younger patients. For fit elderly patients with ASA scores less than 3, mortality was just under 4%. Renal failure and wound dehiscence were more common in the elderly. Conclusion: When endovascular repair is not possible in a fit elderly patient, open surgery can be performed with acceptable results. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The role of transforming growth factor (TGF)-beta in abdominal aortic aneurysm (AAA) is controversial. The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) within TGFBR1 and TGFBR2 with AAA and infrarenal aortic diameter by combining data from previously published studies. Methods: We performed a meta-analysis using individual subject data from three independent case-control groups from Western Australia (n =1675), New Zealand (n =1209), and the Netherlands (n =1636) with 610, 601, and 693 cases of AAA (maximum infrarenal aortic diameter ≥30mm), respectively. Data were available for two TGFBR1 (rs10819634, rs1571590) and six TGFBR2 (rs304839, rs1346907, rs1036095, rs9831477, rs9843143, rs764522) SNPs. Results: There was marked heterogeneity between studies. The G alleles of the TGFBR2 rs764522 and rs1036095 SNPs were associated with AAA under a recessive model (OR=1.69, 95% CI 1.28–2.25, P <0.001 and OR=1.59, 95% CI 1.23–2.07, P <0.001) when a fixed effects model was used. Both associations remained significant after adjustment for multiple testing. Conclusion: This study suggests that two common genetic polymorphisms in TGFBR2 are associated with the risk of developing AAA although this association was mainly driven by findings in the Netherlands group and marked between study heterogeneity was detected. [Copyright &y& Elsevier]

Abstract: Objectives: Abdominal Aortic Aneurysm (AAA) has a strong genetic predisposition. Transforming growth factor beta 1 (TGF-β1) is a causal factor in ascending aortic dilatation; however, a role in AAA pathology is unclear. The aim of the study was to determine whether genes coding TGF-β and its binding protein are associated with the presence and expansion of AAA. Methods: Four geographically distinct case control studies, totaling 1890 AAA cases and 3785 controls, were genotyped and compared to the presence, size and growth rate of AAA. 26 single nucleotide polymorphisms (SNPs) in 5 genes were genotyped in the UK cohort and the result was replicated in 3 independent cohorts. Results: No associations between genotypes or haplotypes and the presence of AAA disease were confirmed. Five SNPs in Latent TGF-β Binding Protein (LTBP4) and an allelic variant of TGFB3 were associated with a significant decrease in AAA growth (p ≤0.02), in the UK cohort. Altered growth was demonstrated in carriers of two common haplotypes of LTBP4 (+0.38mm/year, p =0.003; −0.41mm/year, p =0.02, per haplotype copy) and a single haplotype of TGFB3 (−0.53mm/year, p =0.05). This association with AAA growth could not be demonstrated in two other independent cohorts. Meta-analysis of AAA size and growth rates in larger AAA (≥45mm), in all four cohorts, demonstrated a significant association with the LTBP4 21011A>T genotype (a 2% decrease in AAA diameter, or a 0.53mm/year reduction in AAA growth rate, per T allele [p =0.03, p =0.01]). Conclusion: This study suggests that the LTBP4 gene may contribute to AAA progression. [Copyright &y& Elsevier]