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Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: Based on several reports including genome-wide association studies, genetic variability has been linked with higher (nearly half) susceptibility toward coronary artery disease (CAD). We aimed to evaluate the association of chromosome 9p21 single nucleotide polymorphisms (SNPs): rs2383207, rs10757278, and rs10757274 with the risk and severity of CAD among Arab population. Materials and Methods: A prospective observational case-control study was conducted between 2011 and 2012, in which 236 patients with CAD were recruited from the Heart Hospital in Qatar. Patients were categorized according to their coronary angiographic findings. Also, 152 healthy volunteers were studied to determine if SNPs are associated with risk of CAD. All subjects were genotyped for SNPs (rs2383207, rs2383206, rs10757274 and rs10757278) using allele-specific real-time polymerase chain reaction. Results: Patients with CAD had a mean age of 57 ± 10; of them 77% were males, 54% diabetics, and 25% had family history of CAD. All SNPs were in Hardy-Weinberg equilibrium except rs2383206, with call rate >97%. After adjusting for age, sex and body mass index, the carriers of GG genotype for rs2383207 have increased the risk of having CAD with odds ratio (OR) of 1.52 (95% confidence interval [CI] = 1.01-2.961, P = 0.046). Also, rs2383207 contributed to CAD severity with adjusted OR 1.80 (95% CI = 1.04-3.12, P = 0.035) based on the dominant genetic model. The other SNPs (rs10757274 and rs10757278) showed no significant association with the risk of CAD or its severity. Conclusion: Among Arab population in Qatar, only G allele of rs2483207 SNP is significantly associated with risk of CAD and its severity. This study was made possible by a grant from the Qatar National Research Fund under its Undergraduate Research Experience Program# UREP (010 -030–3-070).

Coronary artery disease (CAD) is a complex disease driven by myriad interactions of genetics and environmental factors. Traditionally, studies have analyzed only one disease factor at a time, providing useful but limited understanding of the underlying etiology. Recent advances in cost-effective and high-throughput technologies, such as single nucleotide polymorphism (SNP) genotyping, exome/genome sequencing, gene expression microarrays and metabolomics assays have enabled the collection of millions of data points in many thousands of individuals. In order to make sense of such 'omics' data, effective analytical methods are needed. We review and highlight some of the main results in this area, focusing on integrative approaches that consider multiple modalities simultaneously. Such analyses have the potential to uncover the genetic basis of CAD, produce genomic risk scores (GRS) for disease prediction, disentangle the complex interactions underlying disease, and predict response to treatment.

GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD. SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881). METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change. A 13-SNP-myocardial-infarction-(MI)-genetic-risk-score was related to carotid atherosclerosis-markers in 4022 MDC-subjects. The MI-gene-score associated with carotid-bulb-intima-media-thickness (IMT) (beta=0.038 standard deviations of IMT per MI-gene-score-quintile; P-trend=0.005) and plaque (odds-ratio per MI-gene-score-quintile=1.11; 95% confidence interval (CI):1.04-1.18; P=0.001) in multivariable models. It was tested if eight blood-pressure-associated SNPs affected antihypertensive treatment-response in 3863 Swedish hypertensives from NORDIL. No robust associations were identified. Finally, interactions between life-style-factors and the CVD-SNP rs4977574 on chromosome 9p21 were evaluated in 24944 MDC-subjects during 15 years follow-up. There were interactions between rs4977574 and smoking on incident CAD (P=0.035) and CVD-mortality (P=0.012). The risk conferred by rs4977574 in never-smokers (n=9642; Hazard-ratio(HR) per risk-allele(CAD)=1.26; 95%CI:1.13-1.40; HR per risk-allele(CVD-mortality)=1.40; 95%CI:1.20-1.63) was attenuated in smokers (n=7000; HR per risk-allele(CAD)=1.05; 95%CI:0.95-1.16; HR per risk-allele(CVD-mortality)=1.08; 95%CI:0.94-1.23). CONCLUSIONS: CVD-genetics identifies subjects with markers of subclinical atherosclerosis, suggesting that early atherosclerosis-prevention may be targeted to such individuals. Smoking attenuates the relative influence of the thus far strongest identified polygenic CVD-risk-locus, implying potential utility of common CVD-genetics in mainly conventional lower-risk subjects. Lipid-polymorphisms may predict statin-induced HDL-increase in women, but eight blood-pressure-SNPs did not affect antihypertensive treatment-response.

The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the “gray zone” of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis., Author Summary Although cardiovascular events, such as myocardial infarction and stroke, usually occur at later ages, it is known that the atherogenic process begins much earlier in life. Detection of subclinical atherosclerosis would therefore offer the means to identify individuals who are at increased risk of developing cardiovascular events. What remains unclear is the relative contribution of genetic variation to the development of the early stages of atherosclerosis. To address this question, we searched for combinations of both genetic and clinical determinants that are the most predictive of the progression of subclinical carotid atherosclerosis in a sample of 1,027 young adults, aged between 24–39 years, from the Finnish general population (The Cardiovascular Risk in Young Finns Study). We demonstrate here, for the first time in a population-based follow-up study, a predictive relationship between individual's genotypic variation and early signs of atherosclerosis, which cannot be explained by conventional cardiovascular risk factors, such as obesity and elevated blood pressure levels. The predictive modeling framework facilitates the usability of genetic information by identifying informative panels of variants, along with conventional risk factors, which may prove to be useful in early detection and management of atherosclerosis. The clinical implications of these findings remain to be studied.

Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4(Delta70kb/Delta70kb) mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4(Delta70kb/Delta70kb) mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4(Delta70kb/Delta70kb) aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation. ispartof: NATURE vol:464 issue:7287 pages:409-U103 ispartof: location:England status: published

Aims Recent genetic studies identified the rs1333049 variant on chromosome 9p21 as a major susceptibility locus for coronary artery disease and myocardial infarction (MI). Here, we evaluated whether this variant also contributes to recurrent MI or cardiac death following an acute coronary syndrome (ACS). Methods and results A total of 3247 patients with ACS enrolled in the Global Registry of Acute Coronary Events (GRACE) in three distinct populations (UK, Belgium and Poland) were prospectively followed for 6 months and genotyped for rs1333049, in addition to 3004 and 2467 healthy controls from the UK and Belgium. After having confirmed that the at-risk C allele of rs1333049 was associated with index ACS in the UK and Belgian populations, we found that the rs1333049 at-risk C allele was significantly and independently associated with recurrent MI [age- and gender-adjusted hazard ratio (HR) 1.48, CI = 1.00–2.19, P = 0.048; and multivariable-adjusted HR 1.47, CI = 0.99–2.18; P = 0.053] and with recurrent MI or cardiac death (age- and gender-adjusted HR 1.58, CI = 1.00–2.48; P = 0.045; and multivariable adjusted HR 1.49, CI = 1.03–1.98; P = 0.028) within 6 months after an index ACS. Inclusion of rs1333049 into the GRACE risk score significantly improved classification for recurrent MI or cardiac death ( P = 0.040), as calculated by the integrated discrimination improvement method. Conclusion In this large observational study, the 9p21 variant was independently associated with adverse cardiac outcome after ACS.

Arterial calcification is a well-known risk factor for coronary artery disease (CAD) and myocardial infarction (MI). We performed a genome-wide association study on coronary artery calcification and aortic calcification as intermediate traits for CAD/MI. We tested ~2.5 million SNPs for association with coronary artery calcification and aortic calcification in 2620 male individuals of the NELSON trial, who underwent chest CT scans. All participants were current or former heavy smokers. No SNPs were associated with aortic calcification on a genome-wide scale. The 9p21 locus was significantly associated with coronary artery calcification (rs1537370, P=2.3×10-11). Since this locus corresponds to the strongest SNP association for CAD/MI, we tested 24 published and validated CAD/MI risk SNPs for association with arterial calcification. Besides the CAD/MI SNP at 9p21 (rs4977574, P=3.1×10-10), two additional loci at ADAMTS7 (rs3825807, P=6.5×10-6) and at PHACTR1 (rs12526453, P=1.0×10-3) show a nominally significant association with coronary artery calcification with MI/CAD risk alleles increasing the degree of arterial calcification. The 9p21 locus was also nominally associated with aortic calcification (P=3.2×10-4). These findings indicate that these CAD and MI risk loci are likely involved in arterial calcification. •We performed a GWAS of coronary artery and aorta calcification in a smokers cohort.•The 9p21 locus was significantly associated with coronary and aorta calcification.•We tested 24 SNPs CAD/MI risk SNPs for association with calcification.•3 loci (9p21, ADAMTS7, PHACTR1) are associated with arterial calcification.•These loci give insight into causal role of calcification in CAD/MI. © 2013 Elsevier Ireland Ltd.