Association between inflammatory gene polymorphisms and coronary artery disease in an Indian population

Background Inflammation is one of the major components of atherosclerosis which is the underlying disorder that leads to various diseases including coronary artery disease (CAD). Genes that are involved in the inflammatory processes are therefore good candidates for the risk of CAD. Variations in the genes involved in various molecular pathways of inflammation have been implicated to exaggerated atherosclerosis and the risk of cardiovascular diseases. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (−159 C/T), TNFα (−308 G/A), IL-1α (−889 C/T), IL-6 (−174 G/C), PSMA6 (−8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to CAD in a North Indian population. Methods Angiographically proven CAD patients (n = 210) and age, sex and ethnically matched normal healthy controls (n = 232) were recruited for this case-control study. Genotypes were determined by PCR–RFLP method. Chi-square and logistic regression analyses were performed to compare the genotype and allele frequencies between the patient and the control groups. Results None of the SNPs showed significant association with CAD in the study population before and after adjustment for the confounding risk factors like age, sex, hypertension, smoking habit, and diabetes. Conclusion This study was unable to demonstrate any association between the six gene variants tested and CAD in the North Indian population.     

Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C>T polymorphisms on their association with coronary artery disease

The single nucleotide polymorphisms (SNPs) apolipoprotein E (APOE) 3/2/4, cholesteryl ester transfer protein (CETP) TaqIB, and apolipoprotein C3 (APOC3) −482 C > T have been associated with an atherogenic lipid profile and, in some studies, with increased cardiovascular risk. However, no data exist on their combined impact on atherosclerotic disease. We therefore aimed at investigating the combined impact of these SNPs on the presence of angiographically determined coronary artery disease (CAD). Genotyping was performed in 557 consecutive Caucasian patients undergoing coronary angiography for the evaluation of CAD.From the individual SNPs, only the APOE 34/44 genotype was significantly associated with an increased risk of significant coronary stenoses with lumen narrowing ≥50% (odds ratio (OR) = 1.77 [1.16–2.71]; p = 0.008). However, the risk of CAD strongly increased when more than one of the analysed genetic variants was present: ORs were 2.74 [1.29–5.83]; p = 0.009 for patients with both the APOE 34/44 and the CETP B1B1 genotype, 1.97 [1.06–3.66]; p = 0.031 for patients with both the APOE 34/44 genotype and the APOC3 −482T allele, 2.12 [1.31–3.44]; p = 0.002 for patients with both the CETP B1B1 genotype and the APOC3 −482T allele, and 3.99 [1.57–13.79]; p = 0.029 for patients with all three variants. Multivariate analyses confirmed these results.We conclude that there are strong synergistic effects of the APOE 3/2/4, the CETP TaqIB, and the APOC3 −482 C > T polymorphisms on their association with CAD.     

Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease

Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover, data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and gender-matched healthy subjects. Significantly higher frequency of 677T allele and homozygous 677T/T genotype were seen in patients vs. control subjects; the distribution of A1298C alleles and genotypes being comparable in the two groups. Specific MTHFR haplotypes comprising 677C/1298A (P < 0.001) and 677T/1298A (P < 0.001) were negatively and positively associated with CAD, respectively. Plasma homocysteine concentration was significantly higher in 677T/T genotype with respect to 677C/C and 677C/T genotypes in patients and controls, but homocysteine levels were generally comparable between both groups. Univariate analysis identified 677T/1298A (P = 0.033) haplotype to be positively associated with CAD, which remained significant by multivariate analysis after adjusting for a number of covariates (P = 0.038). MTHFR C677T, but not A1298C SNPs, is associated with CAD and with elevated homocysteine levels in a Tunisian population. The negative and positive association of the 1298A allele with CAD being indicative of a neutral (absent) effect of the A1298C SNP on disease pathogenesis.     

Association between paraoxonase-1 activity and lipid peroxidation indicator levels in people living in the Antalya region with angiographically documented coronary artery disease

Background: Paraoxonase‐1 (PON1) is a high‐density lipoprotein (HDL)‐associated enzyme capable of hydrolyzing lipid peroxides. Thus, PON1 plays a preventing role in atherosclerosis by protecting against lipid peroxidation. Hypothesis: The incidence of coronary artery disease (CAD) is high in the Turkish population, and many risk factors have been studied as determinants of CAD. In Turkish people living in the Antalya region, we aimed to determine serum PON1 activity and its relation to lipoproteins and lipid peroxidation markers. Methods: We measured the activity of serum PON1 together with concentrations of a variety of lipid constituents—total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), very low‐density lipoprotein cholesterol (VLDL‐C), HDL cholesterol (HDL‐C), triglycerides (TG), apolipoprotein (apo) A‐I, apoB, and lipid peroxidation indicators (conjugated diene [CD] and thiobarbituric acid‐reactive substances [TBARS])—in 108 patients with CAD and 64 healthy subjects (controls). Results: We found that the PON1 activity was significantly reduced in patients with CAD (222.37 ± 11.31 IU/l)compared with controls (331.75 ± 20.98 IU/l). These patients had significantly lower HDL‐C, PON1/HDL‐C, apoA‐I, PON1/ApoA‐I, and ApoA‐I/ApoB, and higher LDL‐C, TC/HDL‐C, LDL‐C/HDL‐C, apoB, CD and TBARS than did controls. Total cholesterol and apoA‐I concentrations were significantly higher in women than in men in both groups. After multiple logistic regression analysis, TBARS (odds ratio [OR] 568.87; p = 0.000), age (OR 1.10; p = 0.000), gender (OR 4.58; p = 0.008), apoA‐I/apoB (OR 0.046; p = 0.003), and PON1/apoA‐I (OR 0.58; p = 0.007) were independently indicative of the presence of CAD. Conclusions: This is the first report of decreased serum PON1 activity and increased lipid peroxidation indicators (CD and TBARS) of patients with CAD living in Antalya, Turkey. Our results indicate that TBARS levels, age, gender, apoA‐1/ApoB, and PON1/apoA‐I ratios are important markers of CAD.     

Interleukin-1 gene cluster polymorphisms and risk of coronary artery disease

BACKGROUND AND OBJECTIVES: The pro-inflammatory cytokine interleukin (IL)-1 has been suggested to play a role in atherosclerosis. Several genetic polymorphisms have been described in the genes of the IL-1 cluster and associations with coronary artery disease (CAD) have been reported, although with contrasting results. DESIGN AND METHODS: The associations of a variable number tandem repeat (86 bp) polymorphism in intron 2 of interleukin-1 receptor antagonist (IL1-RA) and of the 511 C/T polymorphism of IL-1b with the risk of CAD were studied. Three hundred and thirty-five case (CAD+) patients with angiographically documented CAD (stenosis >50% in at least one major coronary artery) were compared with 205 unrelated individuals free of CAD signs at angiogram (CAD- controls). One hundred and two (30.5%) CAD+ patients had single-vessel disease (SVD) and 233 (69.5%) multiple-vessel disease (MVD). RESULTS: There was no statistically significant difference in either genotype distribution or allele frequency of both IL-1 RA and IL-1b 511 C/T polymorphisms between CAD+ cases and CAD- controls. Moreover in multivariate analysis, adjusting for multiple comparisons and confounding factors, no difference was found in IL-1 RA genotype distribution between patients with SVD or MVD. INTERPRETATION AND CONCLUSIONS: Our study does not support the association between IL-1 RA intron 2 VNTR and IL-1b 511 C/T polymorphisms and the risk of CAD in individuals undergoing coronary angiography.     

Association of coronary artery disease, erectile dysfunction, and endothelial nitric oxide synthase polymorphisms

The purpose of this study was to determine the relationship between erectile dysfunction (ED), coronary artery disease (CAD), and T⁻⁷⁸⁶C and intron 4 a/b endothelial nitric oxide synthase (eNOS) polymorphisms in 419 patients with suspected or known CAD referred for coronary angiography. The patients had a high prevalence of risk factors for both CAD and ED: hypercholesterolemia (64%), hypertension (74%), diabetes mellitus (25%), obesity (30%), and smoking (63%). Three hundred and twenty-one patients had significant coronary atherosclerosis (luminal diameter narrowing of 50% or more of at least 1 coronary artery), 41 had insignificant coronary stenoses, and 57 patients were found to have coronary arteries without the evidence of atherosclerosis. The prevalence of ED in these groups was 79%, 76%, and 67% (P = NS), respectively. As compared to patients without ED, those with ED exhibited significantly higher probability of having significant coronary atherosclerosis (69% vs 79%, P = 0.04), higher number of significant coronary stenoses (median, 1 vs 2, P = 0.004), and a higher prevalence of a triple-vessel disease (12% vs 25%, P = 0.004). We did not find any relationship between T⁻⁷⁸⁶C and intron 4 a/b polymorphisms and the manifestation of coronary atherosclerosis or the presence of ED. In conclusion, in patients with numerous cardiovascular risk factors referred for coronary angiography, there was a high prevalence of ED in patients with both the presence and the absence of coronary atherosclerosis. The coincidence of CAD and ED identified patients at increased risk of severe forms of CAD.     

MCP-1, dM2-PK and traditional risk factors for coronary artery disease among type II diabetes patients

Inflammatory markers are considered promising new risk markers for coronary artery disease (CAD) as traditional risk factors have been unable to fully explain the increased risk of CAD in type II diabetes mellitus (T2DM) patients. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, is involved in recruitment of monocytes to the arterial wall. Dimeric pyruvate kinase M2 (dM2-PK), a glycolytic enzyme, is elevated in conditions with high rate of inflammation and proliferation . The objective of the present study was to assess the association of two newer risk factors, MCP-1 and dM2-PK along with various traditional CAD risk factors, with T2DM patients. To the best of our knowledge, there hasn’t been any previous report on MCP-1 and dM2-PK as CAD markers in T2DM patients. Fasting blood samples were taken from N = 300 subjects including N = 100 T2DM patients with CAD, N = 100 T2DM patients without CAD, N = 50 CAD patients without any history of diabetes and N = 50 healthy subjects. Various traditional CAD risk factors i.e. obesity, total body fat, lipid profile and blood pressure were measured using standard procedures. Plasma MCP-1 and dM2-PK were quantitatively estimated by sandwich ELISA. Mean plasma MCP-1 concentration was significantly higher in diabetic patients with CAD than those without CAD. There was no significant difference in the mean plasma dM2-PK concentration among diabetic patients with and without CAD. In multivariate regression analysis, elevated plasma MCP-1 was significant risk factor for CAD in diabetic patients as well as non-diabetic subjects. MCP-1 was found to have a high sensitivity as a CAD marker. However dM2-PK was not significantly associated with CAD in diabetic patients as well as non-diabetic subjects. Among the traditional risk factors, age, duration of diabetes, reduced HDL-cholesterol (both sexes), increased SBP (females) and alcohol consumption (males) were significant risk factors for CAD in T2DM patients. Body mass index(BMI), Waist –Hip Ratio (WHR), percent body fat, cholesterol and LDL-cholesterol were significant risk factors in the non-diabetic subjects but not in diabetic patients. Hence the present study implied that plasma MCP-1, along with traditional risk factors (i.e. age, duration of diabetes and reduced HDL-cholesterol), could be used for identification of T2DM patients at risk of CAD.

     

Monitoring of Lipids, Enzymes, and Creatine Kinase in Patients on Lipid-Lowering Drug Therapy

Despite the critical importance of plasma lipoproteins in the development of atherosclerosis, varying degrees of evidence surround the causal associations of lipoproteins with coronary artery disease (CAD). These causal contributions can be assessed by employing genetic variants as unbiased proxies for lipid levels. A relatively large number of low-density lipoprotein cholesterol (LDL-C) variants strongly associate with CAD, confirming the causal impact of this lipoprotein on atherosclerosis. Although not as firmly established, genetic evidence supporting a causal role of triglycerides (TG) in CAD is growing. Conversely, high-density lipoprotein cholesterol (HDL-C) variants not associated with LDL-C or TG have not yet been shown to be convincingly associated with CAD, raising questions about the causality of HDL-C in atherosclerosis. Finally, genetic variants at the LPA locus associated with lipoprotein(a) [Lp(a)] are decisively linked to CAD, indicating a causal role for Lp(a). Translational investigation of CAD-associated lipid variants may identify novel regulatory pathways with therapeutic potential to alter CAD risk.     

CD14 C(-260)-->T polymorphism,plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease

OBJECTIVES: We sought to investigate the association of CD14 genotype and plasma levels of soluble (s)CD14 with risk of stable coronary artery disease (CAD), chronic infections and sensitive markers of systemic inflammation. BACKGROUND: It has been suggested that genetic variation of the CD14 receptor with increased CD14 gene expression might play a role in atherogenesis. A mechanistic link would consist in its contribution to the inflammatory response seen in this disease. METHODS: We measured levels of sCD14 (microg/ml; ELISA) in 312 patients with angiographically proven CAD and stable angina pectoris, and in 477 age- and gender-matched healthy blood donors. CD14 genotype was determined by polymerase chain reaction. In addition, seropositivity to Chlamydia pneumoniae and Helicobacter pylori, a complete lipid profile and various sensitive systemic markers of inflammation were measured. RESULTS: CD14 C(-260)-->T genotype was not independently associated with increased risk of CAD after multivariable adjustments (odds ratio [OR] 1.34; 95% confidence interval [CI] 0.84 to 2.16). However, sCD14 plasma levels were higher in subjects with TT genotype compared with those with CT or CC genotype (p = 0.005). Plasma levels were not different between cases and controls (4.2 +/- 1.3 microg/ml vs. 4.3 +/- 1.3 microg/ml, p = NS). In multivariable logistic regression, the OR for the presence of CAD was 1.11 (95% CI, 0.65 to 1.91) if the top quintile of the sCD14 distribution was compared with the bottom quintile. There was no consistent association between seropositivity to either C. pneumoniae or H. pylori, or both, and sCD14 levels and between sCD14 levels or CD14 genotype and the various markers of inflammation. CONCLUSIONS: These results do not confirm an independent relationship between CD14 genotypes or plasma levels of sCD14 and risk of stable CAD in this population.     

rs629301 CELSR2 polymorphism confers a ten-year equivalent risk of critical stenosis assessed by coronary angiography

Background and aimsNovel genetic determinants associated with coronary artery disease (CAD) have been discovered by genome wide association studies. Variants encompassing the CELSR2- PSRC1-SORT1 gene cluster have been associated with CAD. This study is aimed to investigate the rs629301 polymorphism association with the extent of CAD evaluated by coronary angiography (CAG), and to evaluate its associations with an extensive panel of lipid and lipoprotein measurements in a large Italian cohort of 2429 patients.Methods and resultsThe patients were collected by four Intensive Care Units located in Palermo and Verona (Italy). Clinical Records were filed, blood samples were collected, lipids and apolipoproteins (apo) were measured in separate laboratories. CAD was defined by the presence of stenotic arteries (>50% lumen diameter) by CAG.The presence of CAD was associated with the rs629301 genotype. Patients with CAD were 78% and 73% (p = 0.007) of the T/T vs. T/G + G/G genotype carriers respectively. T/T genotype was also correlated with the number of stenotic arteries, with a 1.29 (1.04–1.61) risk to have a three-arteries disease. T/T genotype correlated with higher levels of LDL-, non-HDL cholesterol, apoB, apoE and apoCIII, and lower HDL-cholesterol. Logistic Regression confirmed that rs629301was associated with CAD independently from the common risk factors, with a risk similar to that conferred by ten years of age [odds ratios were 1.43 (1.04–1.96) and 1.39 (1.22–1.58) respectively].Conclusionsrs629301 risk allele was independently associated with the extension and severity of CAD and positively with apoE and apoB containing lipoproteins.     

Methylenetetrahydrofolate reductase C677T gene polymorphism and coronary artery disease in a Chinese Han population: a meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with increased coronary artery disease (CAD) risk. To explore the relationship between MTHFR C677T gene polymorphism and CAD in the Chinese Han population, a meta-analysis was performed. Fourteen separate studies were included and 2981 subjects were involved in the current meta-analysis. The pooled odds ratio (OR) between CAD size to CAD size and control size (CAD/CAD + control) and the corresponding 95% confidence interval (95% CI) between the CC and TT genotype groups were estimated by a random-effects model. Meta-regression was performed to explore the heterogeneity source. The CAD/CAD + control values were 0.45 for the CC genotype group and 0.62 for the TT genotype group. The pooled OR for the CAD/CAD + control between the CC and TT genotype groups was 0.55 (95% CI, 0.37-0.83; P(heterogeneity) = .0004, I(2) = 64.7%). These results indicated that MTHFR C677T gene polymorphism and CAD were significantly associated (P = .005) in the Chinese Han population. Publication year was detected as the main heterogeneity source. In a stratified analysis by publication year, the pooled OR was 0.76 (95% CI, 0.37-1.57; P(heterogeneity) = .0002; I(2) = 79.6%) in subgroup 1 (publication years 1999-2004). No significant association between gene polymorphism and CAD was found in this subgroup (P = .46). In subgroup 2 (publication years 2005-2011), the pooled OR was 0.39 (95% CI, 0.28-0.55; P(heterogeneity) = .53; I(2) = 0); and the association between gene polymorphism and CAD was significant (P < .00001). In the Chinese Han population, the TT genotype for the MTHFR C677T gene appeared to be associated with increased CAD risk.     

Interaction between ALOX15 polymorphisms and coronary artery disease in North Indian population

Background: Coronary artery disease (CAD) is major cause of death and morbidity worldwide. Arachidonate 12/15-lipoxygenase (ALOX) is a member of the lipid peroxidizing enzyme family and implicated in the pathogenesis of atherosclerosis, but with contradicting results. Aim: The present study aimed to investigate the association of two polymorphisms in ALOX15 (rs2619112 and rs7217186) and the risk of CAD in North Indian population. Methods: A total of 500 angiographically confirmed CAD patients and 500 control subjects of North Indian population were recruited in the case-control study and genotyped by PCR-RFLP. Results: The data showed a significant association between the two polymorphisms and CAD. Multiple logistic regression revealed heterozygous genotype of both the polymorphisms viz. GA of rs2619112 and CT of rs7217186 to be associated with significant high risk of CAD after adjustment for confounders (p = 0.034, OR = 2.274, 95% CI (1.062–4.870) and p = 0.000, OR = 3.407, 95% CI (2.092–5.548) respectively). Stratified analysis based on gender showed GA and AA of rs2619112 each significantly increased the risk of CAD in females (p = 0.001, OR = 13.120, CI = 2.780–61.928; p = 0.028, OR = 5.393, CI = 1.196–24.316 respectively) whereas only GA increased CAD risk in males (p = 0.005, OR = 2.277, CI = 1.290–4.020). In case of rs7217186, CT and TT showed a significant high risk of CAD in males (p = 0.000, OR = 4.048, CI = 2.678–6.119; p = 0.000, OR = 2.861, CI = 1.928–4.245). Conclusion: The present study shows that rs7217186:C > T and rs2619112:G > A of ALOX15 are associated with increased risk of CAD in the North Indian population.     

代谢综合征患者过氧化物酶体增殖物激活受体δ+294T/C基因多态性与血脂、肥胖和左室肥厚的关系

目的探讨代谢综合征(MS)患者过氧化物酶体增殖物激活受体δ(PPARδ)+294T/C基因多态性与血脂、肥胖和左室肥厚的关系。方法检测300例MS、174例高血压病(EH)和143例2型糖尿病(DM)患者的体重指数(BMI)、腰围、血压、血脂、空腹血糖(FBG)和空腹血浆胰岛素(FINS)。MS诊断根据1999年WHO亚太诊断标准,其中389例患者行超声心动图检测心脏结构改变,应用聚合酶链反应-限制性片段长度多态性方法测定PPARδ+294T/C基因多态性。结果PPARδ+294T/C基因多态性各基因型频率分布组间比较差异无统计学意义。MS组血浆总胆固醇、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)水平和BMI明显高于DM组。MS组和EH组的左室重量(LVM)、左室重量指数(LVMI)和左室肥厚罹患率均明显高于DM组。MS组CC型血浆总胆固醇和LDL-C水平明显高于TT型和TC型[总胆固醇:CC型(6.13±1.86)mmol/L比TC型(5.14±1.10)mmol/L或TT型(4.99±1.42mmol/L),P<0.05或P<0.01;LDL-C:CC型(3.82±1.52)mmol/L比TC型(3.14±0.88)mmol/L或TT型(2.90±0.87)mmol/L,P<0.05或P<0.01]。分析PPARδ各基因型与LVMI和BMI的关系,发现MS组C等位基因携带者(CC+TC)LVMI和BMI明显高于TT型[LVMI:CC+TC(46±10)g/m2.7比TT(44±10)g/m2.7;BMI:CC+TC(26±3)kg/m2比TT(25±3)kg/m2,P<0·05]。结论MS患者PPARδ+294T/C基因多态性与肥胖和脂质紊乱关系密切,C等位基因携带者较TT基因型患者左室重构明显。     

The 242T variant of the CYBA gene polymorphism increases the risk of coronary artery disease associated with cigarette smoking and hypercholesterolemia

OBJECTIVES: Hypercholesterolemia and cigarette smoking increase superoxide anion production, which is involved in many proatherosclerotic processes. NAD(P)H oxidases are the main source of superoxides in the vasculature, and the phagocyte oxidase (p22phox) encoded by the CYBA gene is a critical component of NAD(P)H oxidases. The 242T CYBA allele is associated with an increased low-density lipoprotein oxidation and superoxide production. This report focuses on the interactions between C242T CYBA polymorphism and traditional risk factors of coronary artery disease (CAD), such as cigarette smoking and hypercholesterolemia. METHODS: We have studied 341 individuals, including 172 patients with angiographically confirmed CAD and 169 blood donors with no known history of cardiovascular disease. The C242T CYBA polymorphism was genotyped using the PCR-restriction fragment-length polymorphism method. To determine the possible interactions between CYBA genotypes and the traditional risk factors for CAD, we used multivariate logistic regression analysis (cumulative effects) and the 4 x 2 table approach (synergistic/antagonistic effects). RESULTS: We have found a strong cumulative effect of the 242T allele carrier state and cigarette smoking and hypercholesterolemia. The risk of CAD associated with the presence of cigarette smoking and hypercholesterolemia was stronger in 242T carriers (odds ratio=17.88, P<0.00000) than in CC homozygotes (odds ratio=3.75, P<0.00000). Estimated CAD risk associated with the presence of the 242T allele and both traditional risk factors was approximately 500% greater than the risk predicted by assuming additivity of effects (synergy index, 5.08). CONCLUSION: The 242T allele interacts with cigarette smoking and hypercholesterolemia to increase the risk of CAD; this risk is probably associated with the cumulative/synergistic effect of the 242T allele and both the traditional risk factors.     

Association of G-protein beta3 subunit gene C825T polymorphism with cardiac and cerebrovascular events in Chinese hypertensive patients

Several recent studies showed that C825T polymorphism is related to cardiovascular diseases in normal population. However, studies on whether 825T allele influences the incidence of cardiovascular diseases in hypertensive patients are rare. In the current study, 729 patients (CC, n = 332; CT, n = 313; TT, n = 84) with essential hypertension were genotyped for C825T polymorphism of the GNB3 gene and followed 8 years for major adverse cardiovascular events (MACEs) which include stroke, the onset of coronary artery disease (CAD), and all-cause death. Established cardiovascular risk factors were used to adjust the multivariate Cox analysis. After a mean follow-up period of 7.60 ± 1.12 years, a significantly higher incidence of MACEs was seen in the TT genotype group than CC and CT genotypes. The TT variant was significantly and independently predictive of MACEs (relative risk = 2.574; p < 0.001), CAD (relative risk = 2.963; p < 0.001), but not stroke, CAD+stroke or death. The GNB3 TT genotype is a risk factor for CAD independent of other established cardiovascular risk factors in Chinese hypertensive patients.     

CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease--IVUS substudy of the ENCORE trials

BackgroundSeveral proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization by inflammatory processes are major determinants of ischemia and acute coronary syndromes. Intravascular ultrasound (IVUS) allows for quantification of plaque size in vivo. We therefore investigated the relation of plaque size with mutations of proinflammatory genes in patients with CAD.MethodsIn 196 patients with stable CAD enrolled in the ENCORE trials coronary plaque and vessel volume was assessed by IVUS. 173 patients were successfully genotyped for polymorphisms of proinflammatory genes CD14 C(?260)T and CRP C(+1444)T using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach.ResultsBaseline characteristics were comparable for all genotype groups. Higher ratios of plaque volume/vessel volume were observed in patients with the CRP 1444TT (n = 11) and CD14 260TT (n = 33) genotypes (p = 0.016 and p = 0.026, respectively).ConclusionIn patients with stable coronary artery disease the CRP 1444TT and CD14 260TT variants are associated with larger coronary plaque volume independently of concomitant cardiovascular risk factors.     

Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus

IntroductionThe polymorphic variants of endothelial nitric oxide synthase (eNOS) gene have been implicated in endothelial dysfunction and are highly relevant to macroangiopathies. We investigated the relationship between eNOS gene T-786C, G894T, intron 4a/b polymorphisms and coronary artery disease (CAD) in South Indian type 2 diabetic (T2DM) individuals.MethodsWe screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with myocardial infarction (MI), 89 without MI and 121 T2DM individuals with no evidence of CAD for eNOS gene polymorphisms.ResultsThere appeared to be a significant difference in the genotype and allele distribution of eNOS T-786C polymorphism between T2DM groups with and without CAD (p = 0.004), albeit no significant association with MI was observed. The frequencies of TC and CC genotypes and ? 786C allele were considerably higher in patients with triple vessel disease (TVD) as compared to those without CAD (p = 0.003), thereby associating this polymorphism with severity of CAD. Genotype and allele distributions of G894T and intron 4a/b polymorphisms were not significantly different between T2DM subjects with and without CAD/MI. Significant linkage disequilibrium was observed between intron 4a/b and T-786C polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of eNOS T-786C polymorphism and other putative risk factors with CAD/TVD in T2DM individuals.ConclusionsThese findings reveal a significant association between eNOS T-786C polymorphism, CAD/TVD and coincident putative risk factors in T2DM individuals in South Indian population.     

Homozygosity for angiotensinogen 235T variant increases the risk of myocardial infarction in patients with multi-vessel coronary artery disease

OBJECTIVE: Molecular variants of the angiotensinogen (AGT) and the angiotensin II type 1 receptor (ATR) genes have been associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI), but data so far available are conflicting. The primary object of the paper is to verify this possible association by a rigorous, angiographically controlled study in a large sample of patients with or without multi-vessel CAD. DESIGN: We designed a large case-control study in Italian patients candidates for coronary artery bypass grafting, with angiographically documented multi-vessel CAD, compared to subjects with angiographically documented normal coronary arteries. METHODS AND RESULTS: AGT M235T and ATR A1166C gene polymorphisms were analysed in 699 subjects; 454 patients were candidates for coronary artery bypass grafting, having angiographically documented (mainly multi-vessel) CAD. An appropriate documentation of previous MI was obtained from 404/454 (89%, 247 with and 157 without MI). Subjects (n = 245) with angiographically documented normal coronary arteries, were included as control group (CAD-free group). CAD patients had a substantial burden of conventional risk factors as compared with controls free of coronary atherosclerosis. Age, gender, smoking habit and number of stenosed vessels were the only differences between patients with or without previous myocardial infarction, who were similarly exposed to the other conventional risk factors (including hypertension). AGT M235T and ATR A1166C allele and genotype frequencies were similar between CAD and CAD-free patients. In the CAD group, AGT 235T allele was found more frequently in subjects with a previous myocardial infarction (0.494 versus 0.414; P < or = 0.05). By logistic regression, homozygosity for AGT 235T variant appeared to confer 1.9-fold increased risk for MI in both the univariate and the multivariate (adjusted for age, gender, smoking habit and number of stenosed vessels) model. CONCLUSIONS: AGT 235 T homozygous patients with multivessel CAD have an increased risk of myocardial infarction as compared with subjects with clinically similar phenotype but different genotype.     

Glutathione<Emphasis Type="Italic"> S</Emphasis>-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis

We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritic (RA) women without histories of smoking. We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography and evaluated relationships among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes, and markers of inflammation. Subjects with the GSTT1–0 genotype had greater IMT (P<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use, and the GSTT1–0 genotype (P<0.05). When compared to subjects with a double-positive GSTM1/T1 genotype, IMT in those with concurrent lack of the GSTM1 and GSTT1 genes was significantly increased (P=0.008). This study suggests that the GSTT1–0 genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women without histories of smoking.