The Glu-298→Asp (894G→T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease

We examined associations between the endothelial nitric oxide synthase (eNOS) gene Glu-298-->Asp (894G-->T) mutation and the occurrence and severity of angiographically defined coronary artery disease (CAD). eNOS mediates basal vascular wall nitric oxide production, and altered nitric oxide production has been implicated in atherosclerosis. The newly identified eNOS Glu-298-->Asp mutation in exon 7 is common and likely to be functional. It was found to be associated with myocardial infarction (MI) in Japanese but not in whites. We genotyped 763 white Australians undergoing coronary angiography for the eNOS Glu-298-->Asp mutation. The frequencies of the eNOS GG, TG and TT genotypes were 47.8%, 41.2% and 11.0% in men and 45.2%, 41.1% and 13.7% in women with CAD, and were not significantly different from those without CAD (43.2%, 40.7% and 16.0%, P=0.423 in men; 40.2%, 48.1% and 11.7%, P=0.582 in women). The mutation was also not associated with MI (P=0.469 in males; P=0.389 in females) or with the number of significantly stenosed vessels (P=0.954; P=0.734). The "T" allele frequency (32.5%) was much greater than that reported for the Japanese population (7.8% in controls and 10.0% in MI patients). In conclusion, the eNOS Glu-298-->Asp mutation is common, occurring with an allele frequency of 32.5%, but is not associated with either the occurrence or severity of CAD in the Australian population or with other established coronary risk factors assessed in our study. The mutation is significantly more frequent in the Australian than in the Japanese.     

Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study

The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.     

Polymorphisms of eNOS gene are associated with diabetic nephropathy: a meta-analysis

The aim of the current study is to assess the association between the alleles of endothelial nitric oxide synthases (eNOS) gene 4b/a, G894T, T786C polymorphisms and diabetic nephropathy (DN) through meta-analyses. We also performed a subgroup analysis based on ethnicity (Caucasians, East-Asian and other populations). A total of 3793 patients (DN) and 3161 controls (diabetes without nephropathy) for 4b/a, 2654 patients and 1993 controls for G894T and 1348 patients and 1175 controls for T786C were included in our analysis. Overall, allele contrast (4a versus 4b) of 4b/a polymorphism produced significant results in the global population [random effects model (RE) odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.10-1.61, P = 0.003] and East-Asian population (RE OR = 1.68; 95% CI = 1.23-2.30, P = 0.001), but not in the Caucasian population. In allele contrast of G894T, an obvious significant result was observed in the East-Asian population [fixed effects model OR = 1.69; 95% CI = 1.37-2.08, P < 0.0001], but not in the Caucasian population. Sensitivity analyses generated similar results to those of the primary analyses. The evidence accumulated suggested that 4b/a and G894T polymorphisms in the eNOS gene were associated with susceptibility to DN in Asian populations, but not in Caucasian populations.     

Association of the gene polymorphisms of platelet glycoprotein Ia and IIb/IIIa with myocardial infarction and extent of coronary artery disease in the Korean population

Platelet membrane receptor glycoproteins (GP) are essential for the platelet activation process, and the genetic polymorphisms in the genes that encode platelet glycoproteins have been proposed to influence the risk of acute coronary syndrome and atherosclerosis. In this study, we investigated the role of GPIa, HPA-1 and HPA-3 polymorphisms as putative risk factors for myocardial infarction (MI) and the extent of coronary artery disease. We selected 1,073 subjects who underwent coronary angiography; 242 had normal or minimal coronary atherosclerosis, and 831 patients had significant coronary artery disease (CAD). The genotype was determined by the methods of single base extension for C807T/G873A polymorphisms of GPIa, and restriction fragment length polymorphism for HPA-1 and HPA-3. The C807T and G873A polymorphisms of GPIa showed complete linkage in the Korean population. For HPA-1 gene polymorphism, only the HPA-1a/a (PlA1/A1) genotype was observed in 192 selected subjects from our study population. The distribution of GPIa (C807T/G873A) and HPA-3 genotypes did not differ significantly between normal subjects and CAD subjects. No significant association between MI and both gene polymorphisms was present. However, for the subgroup analysis of young male patients whose age was less than 56 years, the genotype frequency of HPA-3b/b was significantly lower in patients with MI compared to patients without a history of MI (7.5% vs. 20.0%, p=0.04). The odds ratio for HPA-3 b homozygosity versus the HPA-3a carrier was 0.32 (95% CI, 0.10- 0.99, p=0.04). Conclusively, HPA-3 polymorphism was associated with MI in Korean individuals younger than 56 years of age, but other polymorphisms of GP, which we studied, were not associated with both the extent of coronary atherosclerosis or MI.     

Polymorphism in the chemokine receptor 7 gene (CCR7) is associated with previous myocardial infarction in patients undergoing elective coronary angiography

Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate‐, multivariate‐ (including potential confounders) and haplotype‐based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13–3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.     

Intron 4 VNTR (4a/b) Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Breast Cancer in Mexican Women

The endothelial nitric oxide synthase (eNOS) gene plays an important role in several biological functions. Polymorphisms of the eNOS gene have been associated with cancer. It has been suggested that the VNTR 4 a/b polymorphism may affect the expression of eNOS and contributes to tumor promotion in the mammary gland. We examined the role of the eNOS4 a/b polymorphism by comparing the genotypes of 281 healthy Mexican women with the genotypes of 429 Mexican women with breast cancer (BC). The observed genotype frequencies for control and BC patients were 0.6% and 0.7% for a/a (polymorphic); 87% and 77% for a/a (wild type); and 12% and 22% for a/b respectively. We found that the odds ratio (OR) was 1.9, with a 95% confidence interval (95%CI) of 1.29-2.95, P = 0.001 for genotypes a/a-a/b, b/c. The association was also evident when comparing the distribution of the a/a-a/b genotypes in patients with high levels of glutamate-oxaloacetate transaminase (SGOT) (OR, 1.93; 95% CI, 1.14-3.28; P = 0.015); undergoing menopause with high levels of SGOT (OR, 2.0; 95% CI, 1.1-3.84); and with high levels of glutamic-pyruvic transaminase (SGPT) (OR, 3.5; 95% CI, 1.56-8.22). The genotypes a/a-a/b are associated with BC susceptibility in the analyzed samples from the Mexican population.     

ALOX5AP gene variants and risk of coronary artery disease: an angiography-based study

The aim of this study was to explore the role of variants of the gene encoding arachidonate 5-lipoxygenase-activating protein (ALOX5AP) as possible susceptibility factors for coronary artery disease (CAD) and myocardial infarction (MI) in patients with or without angiographically proven CAD. A total of 1431 patients with or without angiographically documented CAD were examined simultaneously for seven ALOX5AP single-nucleotide polymorphisms, allowing reconstruction of the at-risk haplotypes (HapA and HapB) previously identified in the Icelandic and British populations. Using a haplotype-based approach, HapA was not associated with either CAD or MI. On the other hand, HapB and another haplotype within the same region (that we named HapC) were significantly more represented in CAD versus CAD-free patients, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: odds ratio (OR) 1.67, 95% confidence interval (CI) 1.04-2.67; P=0.032; HapC: OR 2.41, 95% CI 1.09-5.32; P=0.030). No difference in haplotype distributions was observed between CAD subjects with or without a previously documented MI. Our angiography-based study suggests a possible modest role of ALOX5AP in the development of the atheroma rather than in its late thrombotic complications such as MI.     

Association of plasma nitric oxide concentration and endothelial nitric oxide synthase T-786C gene polymorphism in coronary artery disease

Nitric oxide (NO) is synthesized from l-arginine by endothelium nitric oxide synthase (NOS3) and plays important roles in many physiologic and pathologic processes. NO involved in the pathogenesis of coronary atherosclerosis. In the present study we hypothesized that polymorphisms of NOS gene might be associated with increased risk of coronary artery disease (CAD) and plasma NO concentrations. The eNOS gene polymorphism was investigated in 241 unrelated CAD patients with positive coronary angiograms and 261 ages matched control subjects without a history of symptomatic CAD. The NOS3 gene polymorphisms were analyzed by RFLP. Plasma NO, lipid profile and other risk factors were also assessed. The genotype frequencies for T-786C polymorphism differed significantly between CAD patients and controls (p=0.041). The mean plasma NO(x) concentrations showed significant differences according to genotypes of T-786C polymorphism in total population only. The mean plasma NO(x) increased in those individuals that are homozygote for C allele in promoter compared with those individuals are heterozygote for this allele and homozygote for T allele in total population and Controls, but no in CAD patients. The present study provides evidences that T-786C polymorphism of the NOS3 gene is associated with CAD. T-786C polymorphism was not associated with increased plasma NO in CAD patients.     

Association of endothelial dysfunction with endothelin, nitric oxide and eNOS Glu298Asp gene polymorphism in coronary artery disease

The endothelial dysfunction has been implicated as a major event in the pathogenesis of atherosclerosis. Therefore, this study was planned to determine (a) role of endothelium-derived nitric oxide (NO) and endothelin as coronary artery disease (CAD) risk markers and (b) intergenotypic variation of endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism in CAD.The endothelin, NO and eNOS genotypes were determined in 60 patients with documented history of CAD. These were compared with 50 age- and sex- matched healthy controls. The genotype frequencies for eNOS gene polymorphism were determined by PCR and RFLP. The plasma endothelin in CAD patients was significantly higher (p< 0.001) whereas, the NO level in CAD group was significantly lower (p< 0.001) than the control group. The genotype frequencies for Glu298/Asp (Glu/Glu and Glu/Asp) genotypes were 75% and 25% in CAD subjects and 88% and 12% in control subjects, respectively. No Asp/Asp was found in any of the groups. The genotype frequencies differed significantly (p< 0.05) between the controls and cases. In conclusion, endothelin and NO may be used as markers of endothelial dysfunction in CAD. Asp allele might be a risk factor for CAD in the North Indian population.     

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.     

Diabetes and chronic nitrate therapy as co-determinants of somatic DNA damage in patients with coronary artery disease

Somatic DNA damage has been linked to coronary artery disease (CAD). However, whether genetic instability is linked to CAD per se or to concomitant potentially genotoxic metabolic and pharmacological factors remains still unclear. The aim of this study was to evaluate the determinants of somatic DNA damage in a large population of patients undergoing coronary angiography. A total of 278 in-hospital patients (215 men, age 61.8±0.7 years) were studied by using micronucleus assay (MN) in human lymphocytes, which is one of the most commonly used biomarker for somatic DNA damage. Significant CAD (>50% diameter stenosis) was present in 210 patients (179 men, age 62.3±0.7 years). Normal coronary arteries were observed in 68 patients (35 men, age 60.2±1.7 years). There were no significant differences between patients with and without CAD, but patients with multivessel disease had the highest MN levels (P=0.01). MN frequency was also found significantly higher in presence of type 2 diabetes (P<0.0001), dyslipidemia (P=0.048) and nitrate therapy (P=0.0002). A significant additive effect was also observed between diabetes and nitrate therapy (P=0.02). On multivariate logistic regression analysis, diabetes [odds ratio =6.8 (95% confidence interval, 3.2–14.5), P<0.0001] and nitrate therapy [odds ratio =2.4 (95% confidence interval, 1.3–4.7), P=0.01] remained the only significant determinants for the 50th percentile of MN (>12). These results indicated that diabetes and, to a lesser extent, chronic nitrate therapy are major determinants of somatic DNA instability in patients with CAD. DNA damage might represent an additional pathogenetic dimension and a possible therapeutic target in the still challenging management of coronary artery disease concerning diabetics.     

Association between NOD2/CARD15 polymorphisms and coronary artery disease: a case-control study

Inflammation and immune response play an important role in the pathogenesis of atherosclerosis. In this prospective study we tested the hypothesis of whether polymorphic variations in the NOD2/CARD15 gene may influence the risk of developing clinically evident coronary artery disease (CAD). ARG702TRP, GLY908ARG, and Leu1007fsinsC NOD2/CARD15 polymorphisms were analyzed in 109 consecutive patients with angiographically documented CAD and in 109 age- and sex-matched healthy controls. The ARG702TRP, GLY908ARG, and Leu1007fsinsC polymorphisms were analyzed by polymerase chain reaction followed by restriction digestion. The prevalence of the Leu1007fsinsC polymorphism was significantly increased in CAD patients compared with controls (11.9% vs 1.8%; odds ratios (OR) 7.2, 95% confidence interval (95% CI) 1.5-32.9; p = 0.01), especially in those presenting with an acute coronary syndrome (OR 5.7; 95% CI 1.1-39.7; p = 0.034 vs stable angina). In CAD patients the frequency of GLY908ARG polymorphism was significantly lower (1.8% vs 6.4% in controls; OR 0.05, 95% CI 0.01-0.69; p = 0.031, at multivariable analysis) and the prevalence of the ARG702TRP polymorphism was higher compared with controls (10.1% vs 3.7%; OR 2.9, 95% CI 0.91-9.6; p = 0.07). We report in a Caucasian population that NOD2/CARD15 polymorphisms influence the development of clinically evident and angiographically documented coronary artery disease. In particular, the Leu1007fsinsC polymorphism was associated with an increased risk of clinically evident and angiographically documented coronary atherosclerosis and clinical destabilization of coronary plaques, whereas the GLY908ARG polymorphism demonstrated a protective effect on coronary atherogenesis. These correlations were independent of cardiovascular risk factors at multivariable analysis. These findings may contribute to the identification of a novel genetic approach for the stratification of cardiovascular risk profile.     

Association between the CD14−260C>T gene polymorphism and susceptibility to myocardial infarction: Evidence from case−control studies

Numerous published studies have investigated the relationship between the CD14?260C>T (rs2569190) polymorphism and the risk of myocardial infarction (MI). However, the results are still conflicting and inconclusive. Potentially eligible published articles were searched in four databases including PubMed, Web of Science, EMBASE and Chinese Biomedical Database (CBM). The odds ratio (OR) with its 95% confidence interval (CI) was used to estimate the strength of the associations. Thirteen papers including 17 case–control studies were included, reporting a total of 6,443 MI patients and 6,315 controls. A significant increase in overall MI susceptibility was identified in the homozygote model. In the subgroup analysis, with respect to the type of MI, a significantly increasing acute MI susceptibility was found in the homozygote model. In the subgroup analysis for ethnicity, a significant increased susceptibility was found in Asian populations in allele, homozygote, recessive and dominant models. However, no significant association was found among Caucasian populations. In conclusion, there may be a moderate association between the CD14?260C>T polymorphism and acute MI susceptibility. This association may be different between ethnicities with the CD14?260C>T polymorphism being a risk factor for myocardial infarction in Asian populations.     

The interaction between aggrecan gene VNTR polymorphism and cigarette smoking in predicting incident symptomatic intervertebral disc degeneration

An association between the aggrecan variable number of tandem repeat (VNTR) polymorphism and the disc degeneration has been previously reported in Finnish men, and smoking had previously been suspected of causing disc degeneration. However, the interaction between aggrecan gene VNTR polymorphism and smoking in symptomatic intervertebral disc degeneration (IDD) has not been well studied. To examine the interaction between aggrecan gene VNTR and smoking in the susceptibility of symptomatic IDD of Chinese Han in northern China, intervertebral discs of 132 participants were evaluated on magnetic resonance imaging, using decreased signal intensity. After harvesting the blood samples, the aggrecan gene VNTR region was analyzed using polymerase chain reaction (PCR). The data indicated that between the two groups, participants carrying one or two alleles ≤25 repeats who did not smoke showed a 1.102-fold increased risk for symptomatic IDD (p= 0.855; 95% confidence interval 0.389–3.119), and participants carrying two alleles >25 repeats who smoked more than 1 pack-year showed a 1.013-fold higher risk (p = 0.982; 95% confidence interval 0.333–3.084), whereas participants carrying one or two alleles ≤25 repeats who smoked more than 1 pack-year showed a 4.5-fold increased risk for symptomatic IDD (p = 0.005; 95% confidence interval 1.589–12.743). Overall, we observed an underlying additive and multiplicative interaction between the aggrecan gene VNTR polymorphism and smoking in symptomatic IDD.     

Manganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patients

Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy. Two candidate genes that affect the oxidative stress are manganese mitochondrial superoxide dismutase (Mn-SOD) and endothelial nitric oxide synthase (eNOS). The aim of the present study was to examine the role of the V16A polymorphism of the Mn-SOD gene and the 4a/b polymorphism of the eNOS gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. In this cross sectional case-control study 426 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 283 patients with diabetic retinopathy and the control group of 143 subjects with type 2 diabetes of duration of more than 10 years who had no clinical signs of diabetic retinopathy. A significantly higher frequency of the VV genotype of the V16A polymorphism of the Mn-SOD was found in patients with diabetic retinopathy compared to those without diabetic retinopathy (OR=2.1, 95% whereas the 4a/b polymorphism of the eNOS gene failed to yield an association with diabetic retinopathy. We may conclude that the VV genotype of the V16A polymorphism of the Mn-SOD gene was associated with diabetic retinopathy in Caucasians with type 2 diabetes, therefore it might be used as a genetic marker of diabetic retinopathy in Caucasians.     

Common carotid arterial diameter and coronary artery disease

The clinical significance of the diameter of common carotid artery (CCA) measured ultrasonographically has not been sufficiently established. The object of this cross-sectional study was to investigate the relationship of the ultrasonic CCA diameter with coronary artery disease (CAD). In the male patients (n=169, mean age: 61 years) who had no apparent carotid arterial stenosis and cerebrovascular disease, a history of CAD, current smoking, body mass index, blood pressure, hemoglobin A1c, serum low-density-lipoprotein cholesterol, estimated glomerular filtration rate and ultrasonic measures of CCA diameter were analyzed. A total of 25 patients had a history of CAD (15%). The CCA diameters of patients with CAD were significantly higher than those of patients without CAD (7.9 +/- 1.0 mm and 7.4 +/- 0.9 mm; p = 0.01). Receiver operating characteristic curve of boundary value of CCA diameter revealed an area under the curve to identify the patients with CAD (0.63, p = 0.04). When the cut off value was considered 8.5 mm, the odds ratio was 4.50 (95% confidence interval = 1.71-11.84, p < 0.01), and the ratio were not largely altered in multivariate logistic regression analyses. The CCA diameter may therefore serve as a useful predictive marker for CAD in men.     

Endothelial nitric oxide synthase gene polymorphism in a cohort of Egyptian women with recurrent spontaneous miscarriage

The risk of miscarriage is enhanced by genetic and environmental factors. Several studies indicated that there was an association between endothelial nitric oxide synthase activity, implantation, and the maintenance of pregnancy. However, the results of these studies remain controversial. The aim of our study was to determine the association between recurrent spontaneous miscarriage (RSM) in Egyptian women and two common polymorphisms of the endothelial nitric oxide synthase (eNOS) gene: intron 4 and T-786C. The study was conducted on a total number of 100 participants, 50 patients with RSM and 50 age-matched healthy controls. Patients and controls were investigated for the two polymorphisms. Genotyping of the eNOS intron 4 polymorphisms was performed by PCR assay. Our results indicated that there was a significant difference in the frequencies of the genotypes between case and control groups for the polymorphisms in both intron 4 (odds ratio (OR) 5.09, 95 % confidence interval (CI) 2.091–12.396, P?<?0.001) and T-786C (OR 7.389, 95 % CI 3.043–17.942, P?<?0.001). In our study, the eNOS polymorphisms (in intron 4 and T-786C) were found to be significantly associated with increased risk of RSM in Egyptian women.     

A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry

A 58 kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n = 548) of patients with documented CAD < 60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.07 to 0.50, P = 0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n = 990, P = 0.024, OR = 0.779, 95% CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.