Jolanta Krauze

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.

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.

Synergistic effect between polymorphisms of PPARA and ABCA1 genes on the premature coronary artery disease.

Objective — Progression of atherosclerosis, the main reason of cardiovascular diseases, depends on multiple genetic and environmental factors. Polymorphic variants of genes involved in the lipids metabolism may genetically differentiate human populations and determine a susceptibility to the disease. The aim of the present study was to evaluate a possible interaction between R219K polymorphism of ABCA1 gene and G>C polymorphism in intron 7 of PPARA gene in determining the risk of the CAD. Methods — We studied 358subjects: 178patients with angiographically confirmed CAD and 180 blood donors without history of CAD. Polymorphisms were genotyped using the PCR-RFLP method. Results — In spite of a small or no correlation between single polymorphism and CAD we observed that the frequencies of AA+GC, CC genotype pattern (ABCA1 and PPARA gene) were significantly higher in CAD group than in controls. OR values were especially high in multiple logistic regression and were higher for male subgroups.The synergy index value equals 3.98 and indicates a quite strong synergistic effect between the analysed polymorphisms. We also observed that C allele carriers of PPARA gene had a significantly lower total and LDL-cholesterol level. Conclusion — The present study shows that R219K polymorphism of ABCA1 gene and G>C polymorphism in intron 7 of PPARA gene act cumulatively and synergistically in determining the risk of premature CAD.

Protective effect of R allele of PON1 gene on the coronary artery disease in the presence of specific genetic background.

Background: Genetic susceptibility to CAD may be determined by polymorphic variants of genes encoding isoforms involved in the processes important in the pathogenesis of atherosclerosis, including lipids disorders. Participation of single polymorphic variants is relatively small, however its significance may increase in the presence of specific genetic or environmental background. Aim: The aim of the study was an evaluation a possible association between single polymorphic variants of PON1, APOE, ABCA1 and PPARA genes and CAD and looking for specific multigene genotype patterns which differentiate study groups. Materials and methods: We studied 358 subjects:178 patients with angiographically confirmed CAD and 180 blood donors without history of CAD. Polymorphisms were genotyped using PCR-RFLP method. Results: We observed statistically significant differences in the frequencies of R allele and R allele carriers of PON1 gene between CAD and controls. The distribution of genotypes and alleles of other analyzed genes did not differentiate the study groups, however the presence of specific genotypes (APOE– ɛ3ɛ3, ɛ3ɛ2, ABCA1 – AG, PPARA – GG) increased the protective effect of R allele. Conclusion: The present study revealed an independent protective association between carrier-state of PON1 R allele and CAD. This protective effect was especially strong in the presence of specific genotype arrangements of other analyzed genes.

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.

Combined "pro-atherosclerotic" variants of the ACE and APOE genes increase the risk of the coronary artery disease associated with the presence of cigarette smoking.

Objective — Cigarette smoking increases the synthesis of angiotensin-I converting enzyme (ACE) and induces oxidative modifications of the apolipoprotein E (apo E).Thus we explored the gene-environment interactions between APOE gene epsilon and ACE gene insertion/deletion polymorphisms and cigarette smoking in coronary artery disease (CAD) patients. Methods — We analysed 360 subjects: 171 CAD patients and 189 blood donors without a history of cardiovascular diseases. ACE and APOE polymorphisms were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, respectively.To determine gene-environment interactions, epidemiological methodology was used. Results — The ACEDD genotype was a rather weak risk factor of CAD in the analysed population (OR = 1.87, P= 0.01).The differences in allele and genotype distribution of the APOE polymorphism were not statistically significant.The carriers of the combined genotype ACEDD + APOEɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 were more frequent in patients, however, the differences were on the bound of statistical significance (P= 0.08). Logistic regression analysis showed that the ACEDD + apo Eɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 cigarette smokers were much more frequent in the CAD group (OR = 11.68, 95%CI; 1.52-246.43, P= 0.009).We confirmed these results using the 4 ≈ 2 table approach and we found a synergistic effect of the ACEDD + APOEɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 combined genotype and cigarette smoking (SI = 10.52, SIM = 6.09). Conclusions — We demonstrated the existence of the synergistic effect between cigarette smoking and the contemporaneous carrier-state of APOE e4 and ACED alleles which increased the risk of CAD to a large extent.

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.

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.

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.

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.