The Association of ADAMTS7 Gene Polymorphisms with the Risk of Coronary Artery Disease Occurrence and Cardiovascular Survival in the Polish Population: A Case-Control and a Prospective Cohort Study.

The aim of this study was to investigate whether the polymorphisms of the ADAMTS7 gene affect the risk of occurrence and mortality due to CAD. The study group included 231 patients diagnosed with CAD and 240 control blood donors. The genotyping of specified polymorphisms, i.e., rs1994016, rs3825807, and rs7173743, was performed using the TaqMan-PCR. We found that the C allele carriers of the rs1994016 and A allele carriers of the rs3825807 polymorphisms increased the risk of CAD, respectively: OR = 1.72, p = 0.036; OR = 1.64, p = 0.04. Moreover, we studied the biological interactions of specified variants, i.e., rs3825807, rs1994016, and rs7173743, and previously approved risk factors of CAD. We demonstrated here that selected polymorphisms of ADAMTS7 increased the risk of CAD altogether with abnormalities of total cholesterol and LDL concentrations in serum. Although survival analyses did not reveal statistical significance, we observed a trend for the AA genotype of the rs3825807 ADAMTS7, which may predispose to death due to CAD in a 5-year follow-up. In conclusion, the ADAMTS7 polymorphisms investigated in this study may increase the risk of occurrence and/or death due to CAD in the Polish population.

Polymorphic Variants of AGT, ABCA1, and CYBA Genes Influence the Survival of Patients with Coronary Artery Disease: A Prospective Cohort Study.

Genetic factors can influence the risk of coronary artery disease (CAD) and the survival of patients. Our previous research led to the identification of genetic variants predisposing to CAD in the Polish population. Since many of them affect the clinical phenotype of the disease, the aim of this study was searching for genetic factors potentially influencing survival in patients with CAD. The study included 276 patients hospitalized due to coronary artery disease. The database of medical history and genotypic results of 29 polymorphisms were used. The endpoint was defined as death from cardiovascular causes. Survival was defined as the period from angiographic confirmation of CAD to death from cardiovascular causes. Three of all the analyzed genes were associated with survival. In the case of the AGT (rs699) and ABCA1 (rs2230806) genes polymorphisms, the risk of death was higher in GG homozygotes compared to the A allele carriers in the 10-year period. In the case of the CYBA (rs72811418) gene polymorphism, the effect on mortality was shown in both 5- and 10-year periods. The TA heterozygotes were predisposed to a higher risk of death than the TT homozygotes. Concluding, the AGT, ABCA1, and CYBA genes polymorphisms influence the risk of death in patients with CAD.

Polymorphisms of the 11q23.3 Locus Affect the Risk and Mortality of Coronary Artery Disease.

Background: The present study aimed to determine whether the polymorphisms of the 11q23.3 locus affect the risk and mortality of coronary artery disease in 5-year and 10-year observations. Methods: The study group consisted of 519 subjects: 276 patients with CAD and 243 blood donors as controls. The genotyping of polymorphisms (rs10750097, rs3741298, and rs1729410) was performed using the TaqMan-PCR method. Survival was defined as the period from the angiographic confirmation of CAD to cardiovascular death, and the endpoint was defined as death from cardiovascular causes. Results: The G allele of the rs1729410 polymorphism increased the risk of CAD (OR = 1.55, p = 0.04) and showed a synergistic correlation with overweight/obesity (additive synergy index (SI) = 11.01, p < 0.001). The carriers of the GG genotype and over-normative LDL levels increased the risk of CAD by over 12-fold higher than expected (multiplicative synergy index (SIM) = 12.34, p < 0.001). In the case of the rs10750097 variant, an effect on mortality was shown in both 5-year and 10-year periods. Conclusion: The results revealed that the rs1729410 polymorphism increases the risk of CAD in synergy with traditional risk factors, and the rs10750097 polymorphism of the 11q23.3 locus affects the risk of death in patients with CAD.

The relationship between CYP7A1 polymorphisms, coronary artery disease & serum lipid markers.

Polymorphic variants of the CYP7A1 gene can increase the risk of atherosclerosis-based coronary artery disease (CAD) and modify serum lipid markers. Method: We studied haplotype-tagging single nucleotide polymorphisms of CYP7A1 in the Caucasian population and if they are associated with CAD, its symptoms, and any of its risk factors. Results: We did not find the genetic variants of CYP7A1 to be associated with an increased risk of CAD. However, we did find that the common rs3808607 variant is associated with modified concentrations of serum total cholesterol and LDL. We also found that the C allele and the CC genotype of the rs11786580 are more frequent in patients with myocardial infarction. This association was especially strong after the group differentiation by sex.

Analysis of selected promoter polymorphisms and haplotypes of the CYBA gene encoding the p22phox, subunit of NADPH oxidases, in patients with coronary artery disease.

The p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA gene. It was shown that functionally relevant polymorphisms of the CYBA gene -930A > G, -852C > G, -675A > T, -536C > T, 214C > T (previously described as 242C > T), *24A > G (previously described as 640A > G), and *49A > G modulate generation of reactive oxygen species (ROS). To analyse whether the CYBA gene polymorphisms -852C > G, -675A > T, and -536C > T were associated with coronary artery disease (CAD), and to designate haplotype blocks. Four hundred and ninety subjects: 245 patients with CAD and 245 age and sex-matched controls. The polymorphisms were genotyped using the PCR-RFLP method and the TagMan® Pre-designed SNP Genotyping Assay. The analysed polymorphisms do not form haplotype blocks. Case-control study revealed that the -930 G/-675T and -930G/*49G diplotypes were a CAD risk factor. The 675T/*49G diplotype can modulate CAD risk in women. The protective effect reducing CAD risk in women was related to the -930A/-675T and -930A/*49A diplotypes. Carrier state of the -852C allele (-852C > G) was associated with multivessel stenosis while the CC genotype of the -536C > T polymorphism was more frequent in patients with peripheral artery disease. Hypercholesterolemic, cigarette smokers had an increased risk of CAD, especially C - 852 allele (-852C > G) carriers (SIM = 3.54; odds ratios (OR) = 10.01, p < 0.000). The CYBA gene polymorphisms modulate the risk of CAD but do not form a haplotype blocks.

Relationship between CETP gene polymorphisms with coronary artery disease in Polish population.

The cholesteryl ester transfer protein (CETP) gene encodes a hydrophobic glycoprotein that plays a crucial role in the reverse transport of cholesterol. The aim of the present study was to determine whether CETP polymorphisms (rs1532624, rs247616 and rs708272) are associated with coronary artery disease (CAD) in a Polish population. Serum lipid levels and single nucleotide polymorphisms of CETP genes were determined in 494 subjects: 248 patients with premature CAD and 246 blood donors as controls. Selected polymorphisms were examined using TaqMan PCR analysis. We found that CAD risk was significantly higher for CC homozygotes and C allele carriers of the rs247616 polymorphism than for carriers with the T allele (OR 1.89, 95% CI 1.29-2.76, p = 0.001 and OR 1.51, 95% CI 1.14-1.99, p = 0.003) and likewise for the CC genotype of the rs1532624 polymorphism than for those with the A allele (OR 1.59, 95% CI 1.05-2.40, p = 0.026). Moreover, T allele carriers of the rs708272 polymorphism had significantly higher total cholesterol levels compared to CC homozygotes (p < 0.05) in the healthy controls. We also observed an allelic pattern, C(rs2477616)C(rs708272)C(rs1532624), which increased susceptibility to CAD by 43% (OR = 1.43, 95% CI 1.10-1.85, p = 0.006). In conclusion, the rs247616 and rs1532624 polymorphisms of CETP may modulate the risk of CAD in Polish population.

Relationship between rs854560 PON1 Gene Polymorphism and Tobacco Smoking with Coronary Artery Disease.

Paraoxonase-1 (PON1) is the antioxidant marker of high-density lipoproteins protecting against atherosclerosis and coronary artery disease (CAD) phenotype. The purpose of the present study was to determine whether the PON1 gene rs854560 polymorphism (163T>A) is associated with CAD in Polish population. rs854560 was genotyped in 494 subjects: 248 patients with premature CAD and 246 blood donors as a control. We found that the risk of CAD was significantly higher in TT homozygotes than in A allele carriers (OR = 1.87, p = 0.041). The synergistic effect between the TT genotype and cigarette smoking was observed (SIM = 9.81; SI = 14.70). The relative increase in risk from interaction between factors was over 37 (RERI = 36.13). The PON1 polymorphism did not modulate the risk of CAD in response to exposure to other traditional risk factors. In conclusion, the rs854560 polymorphism may modulate the risk of CAD in response to cigarette smoking in Polish population. Carriers of TT genotype seem to be particularly at risk of CAD, when exposed to cigarette smoking.

The CYBA Gene (⁎)49A>G Polymorphism (rs7195830) Is Associated with Hypertension in Patients with Coronary Artery Disease.

Purpose. Single nucleotide polymorphisms of the CYBA gene may modify the risk of coronary artery disease (CAD). The aim of the present study was to investigate whether the (⁎)49A>G (rs7195830) polymorphism is associated with CAD. Materials and Methods. CYBA gene (⁎)49A>G polymorphism was determined in 481 subjects: 242 patients with premature CAD and 239 age and sex matched controls using the fluorescently labeled allele-specific oligonucleotides method. Results. The frequency of the (⁎)49G allele carrier state was significantly higher in patients than in controls (84.8% versus 76.6%, resp., P = 0.020), as well as the frequency of the (⁎)49G allele (62.2% versus 54.0%, P = 0.009). Both factors were associated with CAD in the analyzed population (OR = 1.70, 95% CI: 1.04-2.76 for GG+AG versus AA and OR = 1.40, 95% CI: 1.08-1.83 for (⁎)49G versus (⁎)49A). Carrier state of the (⁎)49G allele was a stronger and independent risk factor for CAD among women (OR = 4.35, 95% CI: 1.50-13.20, P = 0.002), as well as the (⁎)49G allele (OR = 2.25, 95% CI: 1.34-3.77, P = 0.001). The (⁎)49G allele carrier state was also associated with left ventricular hypertrophy in patients with coronary artery disease (P = 0.015). Conclusion. The CYBA gene (⁎)49A>G polymorphism modifies the risk of coronary artery disease.

The rs2516839 Polymorphism of the USF1 Gene May Modulate Serum Triglyceride Levels in Response to Cigarette Smoking.

Single nucleotide polymorphisms (SNPs) of the USF1 gene (upstream stimulatory factor 1) influence plasma lipid levels. This study aims to determine whether USF1 SNPs interact with traditional risk factors of atherosclerosis to increase coronary artery disease (CAD) risk. In the present study serum lipid levels and USF1 gene polymorphisms (rs2516839 and rs3737787) were determined in 470 subjects: 235 patients with premature CAD and 235 controls. A trend of increasing triglycerides (TG) levels in relation to the C allele dose of rs2516839 SNP was observed. The synergistic effect of cigarette smoking and C allele carrier state on CAD risk was also found (SIM = 2.69, p = 0.015). TG levels differentiated significantly particular genotypes in smokers (1.53 mmol/L for TT, 1.80 mmol/L for CT and 2.27 mmol/L for CC subjects). In contrast, these differences were not observed in the non-smokers subgroup (1.57 mmol/L for TT, 1.46 mmol/L for CT and 1.49 mmol/L for CC subjects). In conclusion, the rs2516839 polymorphism may modulate serum triglyceride levels in response to cigarette smoking. Carriers of the C allele seem to be particularly at risk of CAD, when exposed to cigarette smoking.

CYP7A1 gene polymorphism located in the 5' upstream region modifies the risk of coronary artery disease.

BACKGROUND: 7-Alpha cholesterol hydroxylase (CYP7A1), the first enzyme of classic conversion pathway leading from cholesterol to bile acids synthesis, is encoded by CYP7A1 gene. Its single nucleotide polymorphisms (SNPs) influence serum lipid levels and may be related to impaired lipid profile leading to coronary artery disease (CAD). The aim of the present study was to analyze the possible association between the rs7833904 CYP7A1 polymorphism and premature CAD. MATERIAL AND METHODS: Serum lipid levels and rs7833904 SNP were determined in 419 subjects: 200 patients with premature CAD and 219 age and sex matched controls. RESULTS: The A allele carrier state was associated with CAD (OR = 1.76, 95% CI; 1.14-2.71, P = 0.014). The effect was even stronger in the male subgroups (OR = 2.16, 95% CI; 1.28-3.65, P = 0.003). There was no effect in the females. Risk factors of CAD and clinical phenotype of atherosclerosis were not associated with genotype variants of the rs7833904 SNP. Lipid profiles also did not differ significantly between individual genotypes. CONCLUSION: The CYP7A1 rs7833904 polymorphism may modify the risk of CAD. This effect is especially strong in male subjects. The studied polymorphism does not significantly influence serum lipid levels, in the present study.

Coronary endarterectomy in left anterior descending artery combined with coronary artery bypass grafting - midterm mortality and morbidity.

INTRODUCTION: Completeness of myocardial revascularization is essential in surgical treatment of coronary artery disease. The aim of this study is to determine the effectiveness of coronary endarterectomy as an adjunct to coronary artery bypass grafting (CABG) in the most difficult cases. MATERIAL AND METHODS: Among 1559 patients who had CABG in our department, the cases of 17 who underwent an adjunct left anterior descending endarterectomy were analyzed. All procedures were performed with median sternotomy, extracorporeal circulation and in mild hypothermia (34°C), by the same surgeon. No coronary artery endarterectomy was planned before surgery. RESULTS: There was no infarction or cardiac arrest during hospitalization. Only one patient required mechanical circulatory support (intra-aortic balloon counterpulsation). Each patient was contacted and investigation for major adverse cardiac and cerebrovascular events (MACCE) was performed. Eleven patients (65%) already underwent midterm clinical evaluation. There was no death, myocardial infarction or cerebrovascular incident during the entire period (mean follow-up at 15.3 months). One patient required urgent coronarography due to chest pain. No other patient had chest pain or significant deterioration of ventricular function in echocardiography. CONCLUSIONS: Outcomes and potential indications for performing left anterior descending coronary endarterectomy as an adjunct to CABG are discussed.

The -930A>G polymorphism of the CYBA gene is associated with premature coronary artery disease. A case-control study and gene-risk factors interactions.

Reactive oxygen species (ROS) are involved in the pathogenesis of atherosclerosis and coronary artery disease (CAD). NADPH oxidases are the main source of ROS in the vasculature. p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA (cytochrome b245 alpha) gene. The -930A>G CYBA polymorphism (rs9932581:A>G) modulates the activity of the CYBA promoter, and influences CYBA transcriptional activity. The aim of the present study was to analyze a possible association between the -930A>G polymorphism and CAD and to search for gene-traditional risk factors interactions. 480 subjects were studied: 240 patients with premature CAD, 240 age and sex matched blood donors. The -930A>G polymorphism was genotyped using the TaqMan® Pre-designed SNP Genotyping Assay (Applied Biosystems). The -930G allele carrier state was a risk factor for CAD (OR 2.03, 95% CI 1.21-3.44, P=0.007). A synergistic effect of the -930G allele with overweight/obesity (BMI≥25) and cigarette smoking was found. The estimated CAD risk for BMI≥25 and the -930G allele interaction was about 160% greater than that predicted by assuming additivity of the effects, and about 40% greater for interaction of cigarette smoking and the -930G allele. Overweight/obesity was a risk factor for CAD only in the -930G allele carriers (P<10(-10)) but not in the AA homozygotes (P=1.00). In conclusion the -930A>G CYBA polymorphism is associated with CAD in the Polish population. The -930G allele carriers are particularly at risk of consequences of obesity and tobacco smoke exposure.

The rs10757278 polymorphism of the 9p21.3 locus is associated with premature coronary artery disease in Polish patients.

Recently, genome-wide association studies have revealed a locus associated with coronary artery disease (CAD) and myocardial infarction, namely, 9p21.3. Its participation in the conditioning of the disease has been proven in many populations of European descent, but not yet in Slavs. Allelic variants of the rs10757278 polymorphism functionally affect the activity of the 9p21.3 locus; therefore, we conducted a study to determine whether the rs10757278 is associated with premature CAD in Polish patients. We studied 320 subjects aged 25-55 years, divided into two groups matched by sex and age: (1) patients with angiographically proven premature CAD (n=160), and (2) blood donors as a control group (n=160). The rs10757278 was genotyped using the method of fluorescently labeled allele-specific oligonucleotides. The frequency of the G allele was significantly higher in patients than in controls (58.2% vs. 42.8%, respectively, p=0.011) and was similar to the frequency of the GG homozygotes (30.6% vs. 17.5%, respectively, p=0.006). Both the GG homozygosity (odds ratio [OR]=2.08, 95% confidence interval [CI]: 1.19-3.66) as well as the G allele (OR=1.49, 95% CI: 1.08-2.07) have been associated with CAD in the analyzed population. These variants may be considered as risk factors, also in the Polish population.

The TT genotype of the MTHFR 677C > T polymorphism increases susceptibility to premature coronary artery disease in interaction with some of the traditional risk factors.

BACKGROUND: The presence of several risk factors (genetic and non-genetic) has greater impact on the risk of premature coronary artery disease (CAD) than single risk factor. OBJECTIVE: The aim of the study was to establish possible relations between genotypes and alleles of 677C>T polymorphism of MTHFR gene and some traditional risk factors e.g. elevated levels of lipid parameters and smoking in development of premature CAD. METHODS: The groups comprised 152 patients with angiographically documented premature CAD (aged 42.9 +/- 5.5) and 121 age-matched blood donors (aged 42.3 +/- 6.5) were studied. The MTHFR 677C>T polymorphism was genotyped with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. RESULTS: Patients with TT genotype who simultaneously smoked had increased risk of premature CAD compared to non-smoking cases with CC genotype (OR = 24.62). We also found that individuals with TT genotype and elevated LDL-cholesterol (LDL-chol.) level had significantly higher risk of CAD (OR = 9.92) than individuals with normal LDL-chol. level and CC genotype. CONCLUSIONS: The present study shows that simultaneous presence of MTHFR TT genotype and smoking or elevated levels of LDL-chol. influences the risk of premature CAD. This findings give interesting contribution to gene-environment interaction problem that may have clinical implications in the future.

The CYBA gene A640G polymorphism influences predispositions to coronary artery disease through interactions with cigarette smoking and hypercholesterolemia.

The CYBA gene encodes the p22phox peptide, an essential subunit of vascular NADPH oxidases. The aim of the study was to analyze potential interactions between CYBA gene A640G polymorphism and traditional risk factors of atherosclerosis. We studied 320 subjects: 160 patients with coronary artery disease (CAD) and 160 controls. The results of interactions were interpreted on the basis of synergy index values (SI, SIM). The 640G allele interacted with cigarette smoking (SI = 2.02, SIM = 2.32). Even greater increase of the CAD risk was found whenever the 640G allele interacted with both smoking and hypercholesterolemia (SI = 2.70, SIM = 3.60). The results suggest that the A640G polymorphism may influence individual predispositions to CAD through interactions with smoking and hypercholesterolemia.

Interactions between rs5498 polymorphism in the ICAM1 gene and traditional risk factors influence susceptibility to coronary artery disease.

Coronary artery disease (CAD) depends on multiple genetic and environmental factors. Adhesion molecules are markers of endothelium dysfunction. Intercellular adhesion molecule-1 (ICAM-1) interacts with leukocyte integrins and promotes atherosclerotic process at the surface of endothelial cells. The aim of the study was to assess the association between ICAM1 rs5498 polymorphism and CAD and to establish whether there are any interactions between this polymorphism and traditional risk factors in determining the risk of CAD. We studied 191 cases with angiographically documented CAD and 203 controls with no signs of cardiovascular diseases. The ICAM1 polymorphism was genotyped using PCR-RFLP method. Data were analyzed with the STATISTICA 7.1 and EpiInfo 6 softwares. We did not observe significant differences in the distribution of genotypes and alleles of rs5498 between cases and controls. We only found a tendency to a higher prevalence of G allele carriers (AG + GG) in patients compared to controls (68 vs. 64%, P = 0.399). A synergistic effect of G allele carrier-state and smoking that had influenced the risk of CAD [synergy index multiplicative (SIM = 2.09)] was observed. Smoking carriers of G allele compared to non-smoking AA were more prevalent in CAD group (39.8%) than among controls (13.3%, P < 0.0001, OR 4.81). Moreover, there was also a synergistic effect between G allele carrier-state and an elevated level of triacylglycerols (TG) (SIM = 1.28) increasing the risk of CAD. There is a synergistic interaction between rs5498 genotype and smoking that increases the risk of CAD.

Synergistic effects between 561A > C and 98G > T polymorphisms of E-selectin gene and hypercholesterolemia in determining the susceptibility to coronary artery disease.

Coronary artery disease (CAD) is a multifactorial disease that results from the interaction between genetic and traditional risk factors. The endothelium dysfunction plays a key role in the progression of atherosclerotic lesions. E-selectin is a marker of endothelium dysfunction. The aim of the present study was to find a relationship between 561A > C and 98G > T polymorphisms of E-selectin gene and CAD as well as interactions between these polymorphic variants and traditional risk factors of the disease in determining the susceptibility to CAD. The study population included 191 patients with angiographically documented CAD and 203 blood donors. The analysis of genetic polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. We found that the frequencies of 561C and 98T alleles of E-selectin gene and carriers of C and T alleles were similar in the entire groups as well as in the age-and sex-matched subgroups. We observed a strong significant correlation between those two polymorphisms; almost all subjects possessing one "proatherosclerotic" allele of E-selectin gene also had the second allele (r = 0.963, P < 0.0001). There were also synergistic effects between both polymorphisms and hypercholesterolemia (but not with smoking or overweight) in determining the susceptibility to CAD. The present study points to synergistic interactions between 561A > C or 98G > T polymorphisms of E-selectin gene and hypercholesterolemia that cause a significant increase in the susceptibility to CAD.

Cigarette smoking, carrier state of A or G allele of 46A>G and 79C>G polymorphisms of beta2-adrenergic receptor gene, and the risk of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a multifactorial disorder which results from the interactions between a number of genetic and non-genetic factors. Beta-adrenergic receptors are cell-surface receptors which activate adenylyl cyclase by coupling to G proteins. The 46A>G and 79C>G polymorphisms of the beta2-adrenergic receptor gene (ADRB2) have been associated with altered response to sympathetic stimulation. AIM: To assess the relationship between 46A>G and 79C>G polymorphisms of the ADRB2 gene and CAD as well as the associations between these polymorphic variants and traditional risk factors, e.g. cigarette smoking, hypercholesterolaemia, hypertension and overweight or obesity, in determining the risk of CAD. METHODS: The study population consisted of 207 individuals (white Polish Caucasians aged 20-55 years): 98 patients with angiographically documented CAD (with more than 50% diameter stenosis of at least one of the major coronary vessels) and 109 blood donors with no signs of CAD. The analysis of genetic polymorphisms was performed by means of PCR-RFLP. RESULTS: The genotype frequencies of both analysed genes in the studied groups were compatible with Hardy-Weinberg equilibrium. We observed higher frequency of the 46A allele in CAD patients than in controls. We also found a tendency to higher prevalence of 46A allele carriers (subjects with genotypes AA+AG) in the CAD group compared to the control group. We did not find any differences in the distribution of genotypes and alleles of 79C>G polymorphism between patients and controls. Multivariate analysis showed that smoking and overweight were independent risk factors of CAD in patients. We found a synergistic effect between carrier state of the 46A allele or 79G allele and smoking, which influences the CAD risk. The 46A allele carriers who smoke as well as carriers of the 79G allele who smoke were much more frequent in the CAD group than in controls. The incidence of 46A allele carriers with hypercholesterolaemia is also higher in patients than in the blood donor group. CONCLUSION: Obtained results indicate a synergistic effect between cigarette smoking and carrier state of 46A allele or 79G allele of ADRB2 in determining the risk of CAD.

Synergistic effects of the polymorphisms in the PAI-1 and IL-6 genes with smoking in determining their associated risk with coronary artery disease.

OBJECTIVES: To assess the relationship between IL-6 and PAI-1 polymorphisms and coronary artery disease (CAD) and to observe the interactions between these polymorphic variants and smoking in the CAD risk. DESIGN AND METHOD: The study population consisted of 178 patients with angiographically documented CAD and 202 blood donors. The analyses of genetic polymorphisms were performed using the PCR-RFLP method. RESULTS: The frequency of PAI-1 5G allele was higher in the entire CAD group than in control group (p=0.04, OR=1.35). Also the 5G allele carriers (4G5G+5G5G) were more frequent in patients than in controls (p=0.03, OR=1.93). The number of women carrying 5G allele was again significantly higher among patients (OR=10.95 p=0.0075). The IL-6 C allele frequency was higher only in the CAD male subgroup (p=0.035, OR=1.44). We found synergistic and cumulative effects between specific genotype patterns and smoking in determining the risk of CAD, especially between PAI-1(4G5G+5G5G)+IL-6(CC) and smoking (SIM=4.18 and p=0.0005, OR=9.20, respectively). CONCLUSIONS: There are synergistic and cumulative effects of 5G allele of PAI-1 polymorphism and C allele of IL-6 polymorphism with smoking in determining their associated risk with CAD.