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.

Contemporaneous carrier-state of two or three "proatherosclerotic" variants of APOE, ICAM1, PPARA and PAI-1 genes differentiate CAD patients from healthy individuals.

BACKGROUND: Atherosclerosis is the most important cause of coronary artery disease (CAD). Genetic predisposition to CAD is related to polymorphisms of genes encoding products functionally involved in pathogenesis of atherosclerosis. Polymorphisms of genes participating in monocyte adhesion and diapedesis, lipid metabolism and fibrinolysis regulation may be partially responsible for this process. The aim of our study was to assess the polymorphic variants frequencies of ICAM1, APOE, PPARA and PAI-1 genes in CAD patients and healthy blood donors and to find specific arrangement of polymorphic variants which would differentiate both groups. METHODS: We studied 146 CAD patients and 121 healthy blood donors. Polymorphisms in analyzed genes were examined using PCR-RFLP analysis. RESULTS: We found significantly higher frequency of 5G allele of PAI-1 gene in patients than in control subjects (p = 0.038, OR = 1.44). We observed also a considerably higher frequency of contemporaneous carriers of two or three "proatherosclerotic" variants: 1) PPARA and PAI-1, 2) APOE and ICAM1 and 3) PPARA, ICAM1 and PAI-1 in CAD group comparing to control subjects. The number of "proatherosclerotic" variants carriers differentiate studied groups also independently of specific genotype arrangement. CONCLUSION: In conclusion, contemporaneous carrier-state of two or three polymorphic variants within analyzed genes is associated with CAD.

Carrier-state of D allele in ACE gene insertion/deletion polymorphism is associated with coronary artery disease, in contrast to the C677-->T transition in the MTHFR gene.

Angiotensin I-converting enzyme (ACE), which plays an important role in blood pressure regulation, and methylenetetrahydrofolate reductase (MTHFR) involved in homocysteine metabolism belong to a large group of polypeptides which may be potential risk factors for atherosclerosis and coronary artery disease (CAD). To assess whether polymorphisms of the genes encoding these peptides are associated with CAD in Silesian we conducted a study among 68 individuals suffering from CAD (including 52 cases after myocardial infarction), 51 subjects with positive family history of CAD and 111 controls. We analysed the distribution of genotypes and allele frequencies of the insertion/deletion (I/D) polymorphism in the ACE gene using PCR amplification, and the C677-->T polymorphism in the MTHFR gene using PCR-RFLP analysis. We found that D allele frequency was significantly higher in CAD patients (61%) than in controls (43%) (P = 0.001, OR = 2.06). The D allele carriers (DD + ID genotypes) were more frequent in the CAD patients (85%) compared to control group (65%) (P = 0.003, OR = 3.14), whereas the familial CAD risk group shows the highest frequency of the ID genotype (57% vs 43% in controls). In contrast, the MTHFR polymorphism does not seem to be associated with the disease. Our data indicate that in Silesian CAD patients the disease is strongly associated with carrier-state of the ACE D allele, but not with the C677-->T transition in the MTHFR gene.