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.

Total WBC count is confirmed to be an independent predictor of death/MI in patients with or at high risk for CAD, but greater predictive ability is provided by high N (Q4 >6.6 x 10(3)/microl) or low L counts. The greatest risk prediction is given by the N/L ratio, with Q4 versus Q1 (>4.71 versus <1.96) increasing the hazard 2.2-fold. These findings have important implications for CAD risk assessment.

Background-Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. Methods and Results-Consenting patients (nϭ206) being initiated on warfarin were randomized to pharmacogeneticguided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1 C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight.

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AF ablation patients have a significantly lower risk of death, stroke, and dementia in comparison to AF patients without ablation. AF ablation may eliminate the increased risk of death and stroke associated with AF.

clinicaltrials.gov Identifier: NCT00488033.

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-Chlamydia pneumoniae infection has been associated with atherosclerosis by serological studies and detection of bacterial antigen within plaque. We sought to evaluate a possible causal role in an animal model. Methods and Results-Thirty New Zealand White rabbits were given three separate intranasal inoculations of either C pneumoniae (nϭ20) or saline (nϭ10) at 3-week intervals and fed chow enriched with a small amount (0.25%) of cholesterol. Immediately after the final inoculation, infected and control rabbits were randomized and begun on a 7-week course of azithromycin or no therapy. Three months after the final inoculation, rabbits were euthanatized and sections of thoracic aortas were blindly evaluated microscopically for maximal intimal thickness (MIT) Recently, infectious agents have been proposed as a possible additional coronary risk factor. Chlamydia pneumoniae is a newly discovered third species of chlamydia shown to cause pneumonia, bronchitis, pharyngitis, and sinusitis.1 C pneumoniae also has been associated with coronary heart disease and myocardial infarction in serological studies.2-4 More specifically, C pneumoniae antigen and elementary bodies have been found in atheromas from coronary arteries, 5-7 carotid arteries, 8 and aorta. 9 However, these findings do not establish a causal role. Animal models would be useful in determining causality and assessing the role of antibiotic therapy. C pneumoniae causes pneumonitis in the rabbit, 10 and the cholesterol-fed rabbit is an established model for accelerated atherosclerosis. Thus, the rabbit may be a suitable model to study a pathogenetic role of C pneumoniae in atherosclerosis. Fong et al 11 recently reported on a small study of rabbits nasally infected with C pneumoniae.Two of 11 animals demonstrated early and intermediate histological lesions of atherosclerosis. We hypothesized that repeat infections and the addition of a small supplement of dietary cholesterol would yield more consistent and accelerated development of atherosclerotic lesions and that antibiotic therapy might prevent this process. MethodsThe objectives of the present study were (1) to determine whether repeated intranasal C pneumoniae infection of rabbits fed with chow supplemented with a small amount (0.25%) of cholesterol would result in significant acceleration of atherosclerosis compared with saline inoculation and (2) to assess the efficacy of azithromycin, an antibiotic known to be effective against C pneumoniae, in preventing accelerated development of atherosclerosis. C pneumoniae Strain and InoculumThe TWAR American Type Culture Collection strain VR 1310 12 was used. We harvested viable organisms from infected cultures of HeLa 229 cells by disrupting infected cells with glass beads and sonification. Organisms were partially purified by centrifugation, quantitated, and resuspended in sucrose phosphate glutamic acid with 10% dimethyl Received October 21, 1997; revision received December 11, 1997; accepted December 17, 1997. From the University of Utah, LDS Hospi...