Rationale Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Background: The authors' experience of lower limb arterial injury (LLAI) management was analysed and risk factors associated with limb loss were identified. Methods: Between 1987 and 1997, data on 550 patients with 646 LLAIs were analysed retrospectively. Results: The mechanism of LLAI was gunshot wounds in 46 per cent, blunt trauma in 19 per cent, stabbing in 12 per cent and shotgun in 9 per cent. The most frequently injured vessel was the superficial femoral artery (37 per cent) followed by the popliteal (31 per cent), crural (11 per cent), common femoral (9 per cent) and profunda (59 per cent) arteries. In 3 per cent of patients there was a combined injury on either side of the knee. Associated injuries included bony injury in 35 per cent, nerve injury in 8 per cent and remote injuries affecting the head, chest or abdomen in 4 per cent. Surgery was carried out in 96 per cent of patients with a limb salvage rate of 84 per cent and a survival rate of 98 per cent. Despite a rising trend in LLAI, total and delayed amputation rates remained stable. On stepwise logistic regression analysis, significant (P < 0·01) independent risk factors for amputation were blocked graft (odds ratio (OR) 16·7), combined above‐ and below‐knee injury (OR 4·4), tense compartment at presentation (OR 4·2), arterial transection (OR 2·8) and associated compound fractures (OR 2·7). Factors such as simple fractures, venous injury/ligation and the use of synthetic grafts were not associated with increased risk of limb loss. Conclusion: LLAI carries a high amputation rate. Stab injuries are the least likely to lead to amputation whereas injuries associated with severe soft tissue damage, such as high‐velocity firearm injuries and blunt trauma with compound fractures, are the most likely to do so. The most significant independent risk factor for limb loss was failed revascularization. © 2000 British Journal of Surgery Society Ltd

LLAI carries a high amputation rate. Stab injuries are the least likely to lead to amputations, whereas high-velocity firearm injuries are the most likely to do so. The most significant independent risk factor for limb loss was failed revascularization.

Diabetes or its medications, or both, have a negative effect on AAA growth. Because of polypharmacy, demonstrating the independent effects of individual drugs affecting the renin-angiotensin system was not possible. In light of this analysis, however, strong associations between angiotensin-receptor blockers and aldosterone-receptor blockers and slowed AAA progression are credible.