Coronary Artery Disease Loci Research Articles

Forearm vasodilator reactivity in homozygous carriers of the 9p21·3 rs1333049 G>C polymorphism

Recently, a novel susceptibility locus for coronary artery disease (CAD) has been identified on chromosome 9p21.3, linked to the single-nucleotide polymorphism (SNP) rs1333049 G>C. However, the physiological mechanism through which this locus confers an increased CAD-risk is still unknown. The aim of the present case-control study was to test whether this chromosome 9p21.3 locus, represented by the rs1333049 variant, is associated with altered vasodilator resistance vessel function in healthy young volunteers. A total of 97 healthy male volunteers were screened for homozygous carriers of either the G- or the C-allele, the minor allele in European populations. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glycerol trinitrate (GTN) was then studied in 10 C/C-genotype carriers compared with 10 control subjects harbouring the G/G-genotype. FBF responses to ACh and GTN were reduced in subjects homozygous for the C-allele of the rs1333049 SNP (P < 0.05). FBF reactivity to the highest dose of ACh and GTN was 95% and 74% lower when compared with control subjects with the G/G-genotype. Our study revealed a functional impairment in forearm artery vasodilator resistance in carriers of the rs1333049 C/C-genotype, thus providing evidence for a first physiological functional link underlying the genetic association of the 9p21.3 locus with an increased cardiovascular risk.

Implications of Genetic Polymorphisms in Inflammation-Induced Atherosclerosis

Inflammation is the mainstay of atherosclerosis and is an important governing factor at all stages of the disease process from lesion formation to plaque build-up and final end-stage rupture and thrombosis. An overview of the numerous clinico-epidemiological studies on the association between inflammatory gene polymorphisms and Cardiovascular disease (CVD) and its co-morbidities have shown that the risk associated with any single genotype is modest while the haplotypes, especially those defined on the basis of tag-SNP approach, have better coverage of the gene and show moderately higher impact on disease risk. Nevertheless, even these associations have been inconsistent with low cross-race repeatability. This has been attributed to many plausible causes such as clinical heterogeneity, sample selection criteria, variable genetic landscapes across different ethnic groups, confounding effect of co-morbidities etc. On the other hand, unbiased studies such as the family-based linkage and case-control based associations that have taken into account, thousands of genotypic markers spanning the whole genome, have had the ability to identify novel genetic loci for coronary artery disease. These studies have shown that many inflammatory genes are involved in the regulation of specific biomarkers of inflammation that collectively contribute to the disease-associated risk. In addition, there appears to be considerable cross talk between the different biochemical and metabolic processes. Therefore, consideration of all these factors can build towards an 'atherosclerotic bionetwork' that can refine our quest for developing a robust risk stratification tool for cardiovascular disease.

A variant at chromosome 9p21 is associated with recurrent myocardial infarction and cardiac death after acute coronary syndrome: The GRACE Genetics Study

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). 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. In this large observational study, the 9p21 variant was independently associated with adverse cardiac outcome after ACS.

Implications of Genetic Polymorphisms in Inflammation-Induced Atherosclerosis~!2009-11-03~!2009-12-07~!2010-02-22~!

Inflammation is the mainstay of atherosclerosis and is an important governing factor at all stages of the disease process from lesion formation to plaque build-up and final end-stage rupture and thrombosis. An overview of the numerous clinico-epidemiological studies on the association between inflammatory gene polymorphisms and Cardiovascular disease (CVD) and its co-morbidities have shown that the risk associated with any single genotype is modest while the haplotypes, especially those defined on the basis of tag-SNP approach, have better coverage of the gene and show moderately higher impact on disease risk. Nevertheless, even these associations have been inconsistent with low cross-race repeatability. This has been attributed to many plausible causes such as clinical heterogeneity, sample selection criteria, variable genetic landscapes across different ethnic groups, confounding effect of co-morbidities etc. On the other hand, unbiased studies such as the family-based linkage and case-control based associations that have taken into account, thousands of genotypic markers spanning the whole genome, have had the ability to identify novel genetic loci for coronary artery disease. These studies have shown that many inflammatory genes are involved in the regulation of specific biomarkers of inflammation that collectively contribute to the disease-associated risk. In addition, there appears to be considerable cross talk between the different biochemical and metabolic processes. Therefore, consideration of all these factors can build towards an ‘atherosclerotic bionetwork’ that can refine our quest for developing a robust risk stratification tool for cardiovascular disease.

ANRIL Expression Is Associated With Atherosclerosis Risk at Chromosome 9p21

We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk. We replicated the locus for coronary artery disease (P=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (P=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (P=2.1x10(-12) and P=1.6x10(-5), respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; P=0.02 and P=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP. Our data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort.

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case-control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)=1.63, 95% confidence interval (CI); 1.41-1.89, P=5.0 x 10(-11), corrected P (Pc)=4.0 x 10(-10)) and Korean populations (OR=1.68, 95% CI; 1.41-2.00, P=6.5 x 10(-9), Pc=5.2 x 10(-9)), and a meta-analysis showed a significant association in the East Asian populations (OR=1.65, 95% CI; 1.48-1.85, P=1.8 x 10(-18), Pc=1.4 x 10(-17)), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations.

Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus

We have investigated the functional significance of conserved sequences within the 9p21.3 risk locus for coronary artery disease (CAD) and determined the relationship of 9p21.3 to expression of ANRIL and to whole genome gene expression. We demonstrate that a conserved sequence within the 9p21.3 locus has enhancer activity and that the risk variant significantly increases reporter gene expression in primary aortic smooth muscle cells. Whole blood RNA expression of the short variants of ANRIL was increased by 2.2-fold whereas expression of the long ANRIL variant was decreased by 1.2-fold in healthy subjects homozygous for the risk allele. Expression levels of the long and short ANRIL variants were positively correlated with that of the cyclin-dependent kinase inhibitor, CDKN2B (p15) and TDGF1 (Cripto), respectively. Relevant to atherosclerosis, genome-wide expression profiling demonstrated upregulation of gene sets modulating cellular proliferation in carriers of the risk allele. These findings are consistent with the hypothesis that the 9p21.3 risk allele contains a functional enhancer, the activity of which is altered in carriers of the risk allele. 9p21.3 may promote atherosclerosis by regulating expression of ANRIL, which in turn is associated with altered expression of genes controlling cellular proliferation pathways.

The discovery of genes implicated in myocardial infarction.

The era of Genome-Wide Association Studies (GWAS) commenced in 2007 with the study of the Wellcome Trust Case Control Consortium (WTCCC) which for the first time ever showed that risk loci can be identified by scanning the complete genome for sequence variation in large numbers of cases of disease and healthy controls. We and others have expanded on this effort and successfully identified the first 11 risk loci for myocardial infarction (MI) and coronary artery disease (CAD). Studies on quantitative traits provide an alternative approach to identify MI/CAD risk loci. This review captures the early successes in the emerging field of disease genomics.

Megakaryoblastic leukemia factor-1 gene in the susceptibility to coronary artery disease

Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six different candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, -184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These findings suggest that MKL1 is involved in the pathogenesis of CAD.

Weight of Pericardial Fat on Coronaropathy

The regional distribution of adipose tissue (AT) is a major determinant of metabolic and cardiovascular diseases. The mass of fat in the visceral area associates independently of obesity with the development and progression of cardiovascular diseases in a series of clinical and epidemiological studies.1 This led to the concept of a pathophysiological link between abdominal obesity and metabolic syndrome. More recently, fat depots localized around the heart, highly variable among individuals, were proposed to contribute to the pathogenesis of coronaropathy independently of other visceral depots (ie, in the omental and mesenteric area).2,3 The study by Greif et al3a in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology highlights the association between pericardial adipose tissue (PAT) and the number of atherosclerotic plaques evaluated concomitantly by Dual source CT scan. This measurement was qualitatively interpretable in 264 consecutive patients with a large range of age, a normal or moderately increased body mass index (BMI), and no a priori coronary disease. An estimated volume of pericardial fat more than 300 cm3 provided an incremental value for the presence of coronary atherosclerosis (odds ratio 4.1) independently of well known risk factors (hyperglycemia or diabetes, hypercholesterolemia, hypertension, and smoking). Ninety-five percent of patients with PAT volume >300 cm3 had one or more atherosclerotic plaques by ROC estimation. In univariate statistical analysis, PAT …

Update on the Genetics of Stroke and Cerebrovascular Disease 2008

2008 has brought us the first fruits from genomewide association studies (GWASs), an unbiased and comprehensive approach to identify common risk alleles for complex diseases of adulthood. By genotyping >310 000 single nucleotide polymorphisms (SNPs) in over 1700 intracranial aneurysm (IA) cases and 7400 controls from Finland and the Netherlands, a multinational team of investigators recently identified several common SNPs that showed significant association with IA.1 SNPs on chromosomes 2q, 8q and 9p were found to replicate in an independent sample from Japan with similar odds ratios (OR) in all 3 samples. Pooled OR were between 1.24 and 1.36, and analyses of the combined effects suggested a significant linear relationship with risk score in each cohort, with a more than 3-fold increase from the lowest to highest strata. Collectively, the 3 loci were calculated to account for 38% to 46% of the population–attributable fraction of IA, which is substantial. Although additional work in other ethnic groups is required, the consistency emphasizes the robustness of the findings. The critical genetic intervals on chromosomes 8q and 9p both harbor genes that are implicated in the regulation of stem (progenitor) cell populations and expressed in the adult vasculature. SOX17 , the main candidate gene on 8q, is required for both endothelial formation and maintenance—an interesting aspect when considering the predominant location of IA at arterial branch points and sites of endothelial shear stress. The association between common variants at 9p and IA had already been reported in another study earlier last year.2 The 9p21.3 region was originally identified as a major risk locus for coronary artery disease and myocardial infarction.3 Subsequent analyses revealed that the same chromosomal region is also implicated in the risk of IA and abdominal aortic aneurysms. The estimated risk for IA conferred by the main risk …

Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

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.

New susceptibility locus for coronary artery disease on chromosome 3q22.3.

We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in approximately 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).

The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis

BackgroundCase-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.MethodsExtensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.ResultsOnly Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.ConclusionWe conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

Large Scale Association Analysis of Novel Genetic Loci for Coronary Artery Disease

Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11,550 cases and 11,205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81 x 10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44 x 10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02 x 10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34 x 10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86 x 10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.

Abstract 3451: Risk for Coronary Artery Disease at the 9p21.3 Locus Is Abolished by a Protective Locus at 8p21.3 Identified by a Genome-Wide Association Study

Background : Coronary artery disease (CAD) is the leading cause of death in the western world. The only common genetic risk locus identified to date by us and others in genome wide association studies (GWAS) resides at 9p21.3. Methods: The Ottawa Heart Genomic Study compared genotypes of 1,542 early onset CAD patients (average 49y) and 1,455 elderly control Caucasians (average 75y). Results: Here, we report two protective haplotypes in the 3′ region of the lipoprotein lipase (LPL) gene at 8p21.3. LPL promotes lipolysis of circulating triglycerides (TG) and increases levels of atheroprotective high density lipoprotein (HDL) cholesterol. Since the 8p21.3 haplotypes are protective, we tested their interaction with the 9p21.3 risk allele. The rs10503669 haplotype associated with elevated TG and HDL levels but did not affect risk from 9p21.3. In contrast, the rs17411031 haplotype was not associated with TG or HDL levels and showed a significant interaction that abolished 9p21.3 risk independent of known risk factors. The interaction was confirmed using data of the Wellcome Trust Case Control Consortium. Excluding carriers of the interacting allele, accuracy of 9p21.3 to predict CAD risk is dramatically improved. Conclusion: Identification of the first modifier gene of the 9p21.3 risk locus for CAD improves CAD risk assessment and provides novel insight into coronary atherosclerosis. This protective 8p21.3 locus may provide a target for novel therapy.

Abstract 839: A Common Allele at the GRB14 Locus is Associated with Increased Cardiovascular Risk in Type 2 Diabetes: Evidence from a Pooled DNA GWA Study

Genetics factor have long been recognized as important modulators of the risk of coronary artery disease (CAD) in both the general and the diabetic population. Evidence from our group indicates that some of these genes may act synergistically with the diabetic milieu, resulting into an especially strong effect among diabetic individuals. To search the genome for variants having a major effect on CAD risk in type 2 diabetes (T2D), we conducted a 300K SNP genome-wide association (GWA) study using DNA pools made from 322 CAD-positive and 412 CAD-negative individuals with T2D of European origin from the Joslin Heart Study (JHS). SNPs associated with CAD were found to cluster on chromosomes 2q24, 5p14, 9p21, and 14q31. These association signals were confirmed by genotyping of individual DNA samples, with additive ORs in the 1.4–1.6 range. The signal on chromosome 9p21 corresponded to the CAD locus that had been identified in the general population in the vicinity of the CDKN2A/CDKN2B genes. Of the other three regions emerging from the GWA screen, chromosome 2q24 showed the strongest association with CAD. The most representative SNP at this location (rs631871, additive OR=1.53, 95%CI=1.24–1.88, p=7.5 × 10 −5 ) was placed in the 3′ flanking region of the Growth Factor Receptor-Bound 14 ( GRB14 ) gene, which codes for an adapter protein with inhibitory effects on insulin receptor signaling. A similar association was found between rs631871 and cardiovascular mortality in an independent group of 475 type 2 diabetic patients (mean age at baseline=57±10 y) who were recruited at the Joslin Clinic for genetic studies in 1994–1996. In this cohort, the cumulative 10-year cardiovascular mortality was 28.1% among homozygotes for the risk allele, 20.0% among heterozygotes, and 15.8% among homozygotes for the protective allele (age and sex adjusted additive HR=1.41, 95%CI 1.04–1.90, p=0.026). By contrast, the association with increased cardiovascular risk was not confirmed in this cohort for the signals on 5p14 and 14q31. These findings point to the insulin signaling inhibitor GRB14 as a possible modulator of cardiovascular risk among individuals with T2D.

Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study

A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

Identifying the susceptibility genes for coronary artery disease: from hyperbole through doubt to cautious optimism

The genetic basis of coronary artery disease (CAD) is complex, and the fact that an alarmingly high proportion of reported associations between genetic variants and CAD are not replicated has generated uncertainty as to whether molecular genetics is ever going to deliver on the promises delivered in the late 1990s. However, during 2007, the first generation of large-scale genome-wide association studies using high-density, single nucleotide polymorphism genotyping arrays have revealed genetic variants that are robustly associated with CAD and CAD-related traits such as type 2 diabetes and obesity. In particular, a robust susceptibility locus for CAD has been identified on chromosome 9p21. Also, evidence has been obtained that multiple rare alleles with fairly strong phenotypic effects may contribute to the genetic heritability of CAD, in addition to common variants with a modest impact on risk. Furthermore, new mechanistic connections have been discovered between different common complex diseases including CAD. This review focuses on the challenges and recent advances of molecular genetics in dissecting the molecular pathophysiology of atherothrombosis and defining novel targets for treatment.

Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations

Coronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR)=1.30, 95% confidence interval (CI); 1.13-1.49, p=0.00027, allele count model] and Koreans (OR=1.19, 95% CI; 1.02-1.38, p=0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.