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Background: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting., Methods: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up., Results: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3)., Conclusions: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

Background: Isolated negative T waves (INTW) are considered a common and minor electrocardiographic (ECG) abnormality. However, few recent studies have associated the presence of INTW with an increased risk of all-causes and cardiovascular mortalities. The aim was to evaluate the predictive value of INTW for coronary heart disease (CHD) and all-cause mortality., Methods: Between 1991 and 1994, 12-lead ECGs were recorded in a sample of 10,600 men (PRIME Study). Among them, 1284 (12.1%) were excluded because of major ECG abnormalities at entry according to Minnesota code, a history of CHD or likely ischemic chest pain on the Rose Questionnaire. INTW were found in 256 subjects (2.74%). The primary outcome was myocardial infarction and angina pectoris after a 10 year follow-up (9.6 ± 1.4). Secondary outcome was all causes of death., Results: After multivariate adjustment, INTW < 1 mm in anterior or inferior leads was associated with a higher risk of angina pectoris [HR 3.04 95% CI (1.13-8.22) and HR 3.67 95% CI (1.35-9.96) respectively] and INTW ≥ 1 mm in lateral or anterior leads were associated with a higher incidence of myocardial infarction [HR 2.75, 95% CI (1.29-5.88) and HR 3.20 95% CI (1.68-6.09) respectively]. The association of INTW ≥ 1 mm in leads V1 to V5 with mortality remained highly significant [HR 3.17 95% CI (1.77-5.65)] after multivariate adjustment., Conclusions: In middle-age men, INTW is associated with a 2 to 3-fold higher risk of death, myocardial infarction and angina pectoris.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Background and Purpose: To date, the association between depressive symptoms and the risk of cardiovascular diseases remains controversial. We investigated prospectively, within the same population, the time course of the association between baseline depressive symptoms and first stroke or coronary heart disease event., Methods: In the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicenter, observational, prospective cohort, 9601 men from France and Northern Ireland were surveyed for the occurrence of first coronary heart disease (n=647) and stroke events (n=136) over 10 years. At baseline, the fourth quartile of a 13-item modified Center for Epidemiological Studies questionnaire was used to define the presence of depressive symptoms. We sought the best time-dependent function to assess the association between depressive symptoms and outcomes. Thus, the hazard ratios were estimated by a Cox proportional hazard model after splitting the follow-up before and after 5 years of follow-up time periods., Results: Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10-1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21-3.19) after adjustment for age, study centers, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48; 1.45-4.25)., Conclusions: The current study suggests that in healthy, European, middle-aged men, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term, and for stroke in the long-term.

Background: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD)., Methods and Results: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3))., Conclusions: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

The role of plasma retinol and carotenoids in coronary heart disease (CHD) remains unclear. The PRIME Study prospectively evaluated these in France and Northern Ireland in 9758 men aged 50-59 years who were free of CHD at baseline. After five years' follow-up 150 incident cases of CHD (non-fatal myocardial infarction and fatal CHD) were compared with 285 controls matched for age, date of blood collection and study centre. Geometric means of major carotenoids did not differ significantly between cases and controls (P>0.05), whereas the absolute and lipid-standardized plasma retinol levels were 9% lower in cases than controls in both countries (P<0.002), without correlation with carotenoids. After adjusting for risk factors, the relative risks (RRs) of CHD in the first four quintiles of retinol distribution in controls (< or =601, -683, -760, and -846 microg/l) were 2.65 (P=0.0009), 1.70, 1.03, and 1.12 (all P>0.05) respectively, relative to the top quintile (retinol > or =846 microg/l; linear trend P=0.0001). The 10th percentile of lipid-standardized retinol (< or =544 microg/l) predicted an RR of 4.7 (P<0.001). The risk associated with low retinol was comparable to strong risk factors (e.g. HDL-cholesterol, Interleukin-6) and behaved additively. In conclusion, plasma retinol levels of < 601 microg/l in a fifth of middle-aged European men place them at an approximately threefold RR of developing CHD. Thus the intake of vitamin A might be too low in middle-aged men. These findings must be confirmed., (Copyright (c) 2009. Published by Elsevier Ireland Ltd.)

We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either.

Complement factor H (CFH) plays a critical role in the protection of host cells and tissues from damage by complement activation and has been suggested to protect against the progression of atherosclerosis. A polymorphism in the CFH gene, Y402H, known to be strongly associated with age-related macular degeneration, has been analyzed in relation to coronary artery disease (CAD) in several studies with conflicting results. We investigated the association of polymorphisms of the CFH gene in two large-scale studies on CAD and myocardial infarction (MI). The AtheroGene Study included a cohort of cases with CAD (n = 1,303) prospectively followed for a median period of 6.2 years, among whom198 experienced a cardiovascular event, and a group of 483 control subjects. The AtheroGene Study population was genotyped for the Y402H, I62V, and E936D polymorphisms. There was no significant difference in genotypic or allelic frequencies between CAD cases and controls. Among cases, no significant association was found with prospective cardiovascular outcome. Many inflammatory proteins, including the C-reactive protein, were measured, and none of the polymorphisms showed an association with these markers. The Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) Study compared 1,034 patients with MI and 1,039 controls from France and United Kingdom. The ECTIM Study population was genotyped for the Y402H polymorphism. Genotype and allele frequencies were similar in cases and controls. These results do not support an involvement of common nonsynonymous polymorphisms of the CFH gene in predisposition to CAD and its complications.

Background: Data on the recent evolution in coronary heart disease (CHD) mortality and incidence rates are lacking in France. This paper aims to investigate whether the declining trends observed from 1985-1993 still persist in the second half of the 1990s., Methods: Population registers of acute CHD have been implemented in three specific geographical areas, first as part of the MONICA Project (1985-1993) and, since 1997, according to a simplified registration procedure. Weighted Poisson regressions have been used to investigate time trends in CHD events in men and women aged 35-64 after correction for registration differences., Results: Data obtained from 1997-2000 showed that the north-to-south gradient of decreasing frequency of CHD events in France was still present. Besides, they revealed no specific trend in CHD morbidity by centre and gender, except in Lille (in the north of France) where events tended to increase in women. Coronary heart disease mortality rates in recent years were decreasing in men, particularly in the north and east of France, but were stable in women with, even, a rising tendency in the north., Conclusion: The decreasing trend in CHD events in France observed from the mid 1980s to the early 1990s seemed to markedly slow down in the second half of the 1990s.

Background and Objectives: Exposure to traffic is an established risk factor for the triggering of myocardial infarction (MI). Particulate matter, mainly emitted by diesel vehicles, appears to be the most important stressor. However, the possible influence of benzene from gasoline-fueled cars has not been explored so far. Methods and Results: We conducted a case-crossover study from 2,134 MI cases recorded by the local Coronary Heart Disease Registry (2000–2007) in the Strasbourg Metropolitan Area (France). Available individual data were age, gender, previous history of ischemic heart disease and address of residence at the time of the event. Nitrogen dioxide, particles of median aerodynamic diameter <10 µm (PM10), ozone, carbon monoxide and benzene air concentrations were modeled on an hourly basis at the census block level over the study period using the deterministic ADMS-Urban air dispersion model. Model input data were emissions inventories, background pollution measurements, and meteorological data. We have found a positive, statistically significant association between concentrations of benzene and the onset of MI: per cent increase in risk for a 1 µg/m3 increase in benzene concentration in the previous 0, 0–1 and 1 day was 10.4 (95% confidence interval 3–18.2), 10.7 (2.7–19.2) and 7.2 (0.3–14.5), respectively. The associations between the other pollutants and outcome were much lower and in accordance with the literature. Conclusion: We have observed that benzene in ambient air is strongly associated with the triggering of MI. This novel finding needs confirmation. If so, this would mean that not only diesel vehicles, the main particulate matter emitters, but also gasoline-fueled cars –main benzene emitters–, should be taken into account for public health action. [ABSTRACT FROM AUTHOR]

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Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either. [ABSTRACT FROM AUTHOR]