Interleukin-1 beta and interleukin-6 gene polymorphism associations with angiographically assessed coronary artery disease in Brazilians.

The inflammatory process has been considered an important mediator for the development of atherosclerosis. Interleukin-1 beta (IL1B) is a precursor of interleukin-6 (IL6) in the acute phase of inflammatory response and their levels are elevated in patients with coronary artery disease. The aim of the present study was to further investigate the association of IL-1B and IL-6 gene polymorphisms and angiographically assessed coronary artery disease (CAD) in African- and Caucasian-Brazilians. This report analyzed the IL-1B-511C>T and IL-6-174G>C polymorphisms in 667 patients (253 African-Brazilians and 414 Caucasian-Brazilians) who underwent coronary angiography. Patients with a coronary obstructive lesion 50% presented a higher frequency of the IL-1B-511CC genotype (30.4%) compared to lesion-free individuals (16.5%, p=0.032) in African- but not in Caucasian-Brazilians. No significant genotype frequency difference was identified for the IL-6-174G>C polymorphism in either ethnic groups. However, after correction for other CAD risk factors using multivariate logistic regression, both the IL-1B-511CC [Odds ratio (OR)=2.3; p=0.019] and the IL-6-174GG (OR=2.0; p=0.028) genotypes were considered independent CAD risk predictors in African-Brazilians. This report shows that the IL-1B-511C>T and IL-6-174G>C polymorphisms were associated with CAD risk in African-Brazilians and no association was detected among Caucasian-Brazilians.

Smoking-dependent and haplotype-specific effects of endothelial nitric oxide synthase gene polymorphisms on angiographically assessed coronary artery disease in Caucasian- and African-Brazilians.

The nitric oxide produced by endothelial nitric oxide synthase (eNOS) plays a pivotal role in protecting the arterial wall from damages and atherosclerosis. The T-786C, the 27-bp repeat in intron 4, and the E298D eNOS gene polymorphisms were studied in 715 Brazilian patients (447 Caucasian- and 268 African-Brazilians) who underwent coronary angiography. The -786C frequency was increased in coronary artery disease (CAD) cases with significant lesions (> or =50% luminal obstruction) when compared with lesion-free controls; this difference was detected in smokers but not in nonsmokers, both in Caucasian- (p=0.011) and African-Brazilians (p=0.005). The interaction between -786C carriers and smoking was an independent CAD predictor (OR: 2.9, 95% CI: 1.4-5.9; p=0.003) in multiple logistic regression. The 298D mutation frequency was also higher among CAD cases (p=0.036) in African-Brazilian smokers, but this effect was not independent from other variables in the regression model. Though not associated with CAD, the 4-repeat allele combined with different T-786C alleles showed protective and susceptible effects in Caucasian-Brazilian smokers. The -786C/4-repeat/298E haplotype frequency was higher (p=0.020), whereas -786T/4-repeat/298E was lower (p=0.023) in these cases. These results showed a smoking-dependent effect of the T-786C eNOS polymorphism on CAD in both Caucasian- and African-Brazilians. Additionally, the haplotype analysis revealed different eNOS haplotypes associated with protection and susceptibility to the disease.

Endothelial nitric oxide synthase and fractalkine chemokine receptor polymorphisms on angiographically assessed coronary atherosclerosis.

BACKGROUND: The CX3CR1 is a fractalkine chemokine receptor expressed by leukocytes attracting them to the arterial wall inflammation. The endothelial nitric oxide synthase (eNOS) produces nitric oxide that acts on the vascular wall and circulating blood cells, lessening the inflammatory atherogenic damage. We determined if -786T > C and E298D eNOS and 745G>A CX3CR1 variants were associated with CAD risk and/or severity in Southern Brazilians of European descent. METHODS: We investigated these polymorphisms in 358 patients who had undergone coronary angiography and 129 non-symptomatic controls by PCR followed by restriction analyses. RESULTS: The 745 G > A CX3CR1 variant was not associated with CAD in this sample. Patients with significant CAD (coronary stenosis >or = 75%) presented higher frequencies of the eNOS -786C, but not of 298D allele than those observed among patients in whom significant CAD was ruled out by angiography (control group 1, p = 0.022) and non-symptomatic controls (control group 2, p < 0.001). The eNOS haplotypes derived from these 2 sites revealed that the frequency of haplotypes carrying the -786C allele (-786C/298D and -786C/298E) was increased and of the wild haplotype (-786T/298E) was decreased in patients with significant CAD (p = 0.003). After controlling for other classical risk factors carriers of haplotypes containing the -786C allele were at increased CAD risk (-786C/298D, OR = 2.95, p = 0.007; and -786C/298E, OR = 2.41, p = 0.030). CONCLUSIONS: The -786T > C was the polymorphism associated with severe CAD in this study. Haplotype analyses can be extremely helpful in unraveling the influence of different markers within a gene.

Sex-specific effect of the thermolabile C677T mutation in the methylenetetrahydrofolate reductase gene on angiographically assessed coronary artery disease in Brazilians.

Hyperhomocysteinemia is associated with increased coronary artery disease (CAD) risk. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine and presents a common mutation (C677T) that leads to a thermolabile enzyme, mild hyperhomocysteinemia, and increased CAD risk. The C677T MTHFR mutation was studied in 772 subjects (480 Caucasian Brazilians and 292 African Brazilians) who underwent coronary angiography at the hemodynamic center of the Santa Izabel Hospital in Salvador, Bahia State, Brazil. The 677T allele frequency was increased in Caucasian Brazilians (28.1%) compared to the frequency observed in African Brazilians (18.3%; p < 0.001). In Caucasian Brazilians the frequency of the 677T homozygous genotype was increased in CAD cases (10.4%) compared to control subjects (1.4%; p = 0.014) in males but not in females. In African Brazilians the mutation was not associated with CAD in either sex. The multivariate logistic regression analysis of all the samples shows that the 677T homozygous interaction with sex was a significant CAD predictor, independent of other classical risk factors and ethnic group. The odds ratio associated with male 677T homozygotes was increased 9.2-fold (p = 0.021) compared to the 677C carriers. The present study suggests that the C677T MTHFR mutation is associated with increased CAD risk in a sex-dependent manner in Brazilians.

Paraoxonase 1 gene polymorphisms in angiographically assessed coronary artery disease: evidence for gender interaction among Brazilians.

BACKGROUND: Paraoxonases (PON) are members of an enzyme family involved in preventing low-density lipoprotein oxidation and therefore protecting against atherosclerotic plaque formation. METHODS: We studied the Met55Leu and Gln192Arg PON1 polymorphisms in 712 patients (437 Caucasian- and 275 African-Brazilians) who underwent coronary angiography. RESULTS: Among Caucasian-Brazilians, the homozygous 55LeuLeu frequency was higher among patients with significant coronary artery disease (CAD, obstructive lesions >/=50%) than among lesion-free controls (51% vs. 30.3%; p=0.022) in females, but not in males. The Gln192Arg PON1 polymorphism was not associated with CAD, although 192GlnGln homozygotes presented lower high-density lipoprotein (HDL)-cholesterol (p=0.035) and higher triglyceride (p=0.012) levels than 192Arg allele carriers among Caucasian-Brazilian males, but not females. No other lipid-genotype association was detected. Multivariate logistic regression corrected for classic CAD risk factors shows that 55LeuLeu PON1 homozygotes were at increased CAD risk (odds ratio OR=2.852; p=0.003) and that this genotype interacted with gender in its association with CAD risk (OR=0.290; p=0.006) among Caucasian-Brazilians. CONCLUSIONS: This report shows that the 55LeuLeu PON1 genotype increases CAD risk among female Caucasian-Brazilians, irrespective of other CAD risk factors. In addition, 192GlnGln PON1 homozygotes show higher triglyceride and lower HDL-cholesterol levels in male Caucasian-Brazilians. No associations were detected among African-Brazilians.

Common variants in the lipoprotein lipase gene in Brazil: association with lipids and angiographically assessed coronary atherosclerosis.

Lipoprotein lipase is the rate-limiting enzyme in the lipolysis of plasma triglyceride-rich lipoproteins. We studied six variants (T-93G, D9N, N291S, PvuII, HindIII and S447X) in the lipoprotein lipase (LPL) gene in 309 non-diabetic patients with angiographically assessed coronary artery disease and in 197 controls in a southern Brazilian population of European descent. The HindIII H-allele was associated with lower triglycerides (p < 0.01) and higher high-density lipoprotein cholesterol (p = 0.03) levels, and the S447X mutation was associated with lower triglyceride levels (p < 0.01) in males, but not females. No other significant lipid associations were observed. Haplotypes were derived from these two sites (HindIII/S447X), and carriers of H-S and H-X haplotypes showed lower triglycerides (p < 0.01) and increased high-density lipoprotein cholesterol (p = 0.01) levels when compared to the H+S haplotype in males. In this gender, the H-X haplotype was associated with a protective effect (OR = 0.36, 95%CI = 0.13-0.97) for significant disease (> or = 60% of luminal coronary stenosis), even controlling for other classical risk factors.