We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Background: The risk of recurrence of cardiovascular events among patients using aspirin (acetylsalicylic acid) for secondary prevention of such events remains high. Persistent platelet reactivity despite aspirin therapy, a laboratory-defined phenomenon called aspirin resistance (hereinafter, laboratory aspirin resistance), might explain this in part, but its actual contribution to the risk remains unclear. The objective of this study was to systematically review all available evidence on whether laboratory aspirin resistance is related to a higher risk of cardiovascular recurrent events. Methods: Using a predefined search strategy, we searched electronic databases. To be included in our analysis, articles had to report on patients who used aspirin for secondary cardiovascular prevention, had to contain a clear description of a method to establish the effects of aspirin on platelet reactivity, and had to report recurrence rates of cardiovascular events. Odds ratios of cardiovas-cular outcome of eligible studies were pooled in a randomeffects model. Results: We included 15 full-text articles and 1 meeting abstract. Fifteen of these studies revealed an adverse association between laboratory aspirin resistance and occurrence of cardiovascular events. The pooled odds ratio of all cardiovascular outcomes was 3.8 (95% confidence interval, 2.3-6.1) for laboratory aspirin resistance. Conclusion: This systematic review and meta-analysis shows that patients biochemically identified as having laboratory aspirin resistance are more likely to also have "clinical resistance" to aspirin because they exhibit significantly higher risks of recurrent cardiovascular events compared with patients who are identified as (laboratory) aspirin sensitive.

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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.

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