Neuropeptide Y polymorphisms and ischemic stroke in Chinese population

BackgroundStroke is the second most common cause of death in developed countries and a major cause of adult disability and mortality worldwide. New data strongly suggest that neuropeptide Y (NPY) may be a candidate gene for ischemic stroke.MethodsWe investigated 450 ischemic stroke patients and 423 healthy controls matched for sex and age in a Han Chinese population. Three functional polymorphisms (? 883TGins/del, ? 602G/T and ? 399 T/C) located in NPY gene promoter were genotyped using DNA sequencing methods.ResultsOf 3 NPY polymorphisms investigated in our study, the ? 399CC genotype (OR: 1.699, 95% CI: 1.124–2.567, P = 0.011) and the ? 399C allele (OR: 1.254, 95% CI: 1.031–1.524, P = 0.023) were more frequent among ischemic stroke patients than in controls, especially in the small vessel disease (SVD) subtype patients. The similar results were observed in multivariable logistic regression analysis. Haplotype analysis revealed that the ? 883ins/?399C haplotype was a risk marker for ischemic stroke (P = 0.008).ConclusionsThe C allele of ? 399 T/C polymorphism in the promoter regions of NPY is an independent risk factor for ischemic stroke, suggesting that NYP system may involve in the mechanisms of stroke pathology.     

TNF-α −308G > A and IL-6 −174G > C polymorphisms in Tunisian patients with coronary artery disease

ObjectiveOur aim was to evaluate the contribution of tumor necrosis factor (TNF)-α ?308G > A and interleukin (IL)-6 ?174G > C gene promoter variants to the presence of coronary artery disease (CAD) in Tunisians.Design and methodsStudy subjects comprised 418 angiographically proven CAD patients and 406 age-, gender-, and ethnic origin-matched controls. Genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.ResultsThere were no significant differences in the allelic distribution of TNF-α ?308A (19.6% vs. 19.0%, P = 0.73), and IL-6 ?174C (15.6% vs. 14.3%, P = 0.47) promoter polymorphisms between CAD patients and control subjects, respectively. In addition, single locus analysis revealed no differences in genotype frequencies between the two study groups, and the combined distribution of both genotypes did not differ significantly between controls and CAD patients (P > 0.05).ConclusionThere is no allelic or genotypic association of TNF-α ?308G > A and IL-6 ?174G > C promoter polymorphisms with CAD in Tunisians, thereby confirming an ethnic-selective contribution of both gene variants to CAD presence.     

Apolipoprotein M promoter polymorphisms alter promoter activity and confer the susceptibility to the development of type 1 diabetes

ObjectivesApolipoprotein M plays an important role in the formation of preβ-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes.Design and methodsThe study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay.ResultsSNP T-778C was strongly associated with T1D in both Han Chinese (p = 0.002, OR = 2.188, CI 95% = 1.338–3.581) and Swedish (p = 0.021, OR = 2.865, CI 95% = 1.128–7.278) populations. The luciferase activity of ?778C promoter was 1.41 times as high as that of ?778T promoter (9.90 ± 1.92 vs. 7.04 ± 0.76, p = 0.001).ConclusionsAllele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.     

VEGF-A gene promoter polymorphisms and microvascular complications in patients with essential hypertension

ObjectivesWe investigated the possible involvement of vascular endothelial growth factor (VEGF-A) gene promoter polymorphisms in essential hypertension (EH).Design and methods1225 bp of the VEGF-A gene promoter were screened for polymorphisms using PCR amplification and direct DNA sequence analysis in 62 EH and 62 normotensive (HS) individuals. Circulating VEGF-A levels were determined by immunoassay.Results?152G/A (p = 0.009) and ?116G/A (p = 0.016) polymorphisms were correlated to hypertension (p < 0.05). Median platelet VEGF-A load in EH was 2.10 fg/plt. Patients with microvascular complications (MC) had higher platelet VEGF-A load than those without (p = 0.005). Multivariate analyses showed that ?116 A allele was an independent predictor of microalbuminuria (p = 0.014) and increased platelet VEGF-A load (p = 0.009) in EH. Platelet VEGF-A load independently predicted MC (p = 0.049) in addition to ?116G/A polymorphism (p = 0.035).ConclusionsAbnormal regulation of VEGF-A due to polymorphism at position ?116 might represent a genetic factor for increased VEGF-A production and MC in EH.     

A promoter polymorphism − 2122C>T of CHI3L1 is associated with serum low density lipoprotein cholesterol level in Korean subjects

ObjectivesThis study assessed the effects of 10 tagging single nucleotide polymorphisms (SNPs) of the CHI3L1 gene on serum LDL cholesterol levels in 290 Korean subjects.Design and methodsGenotyping analyses of SNPs were conducted by TaqMan® method. The effects of the promoter SNP on mRNA expression and nuclear factor binding were measured by real-time PCR and electrophoretic mobility shift assay, respectively.ResultsAmong 10 tagging SNPs, ? 2122C>T SNP (rs946261) in the promoter region was significantly associated with serum LDL cholesterol level (P = 0.005). The T allele of ? 2122C>T was associated with significantly increased mRNA expressions in peripheral blood cells of the subjects, and also increased a nuclear factor binding measured by an electrophoretic mobility shift assay.Conclusions? 2122C>T of CHI3L1, a promoter SNP which affects the mRNA expression and nuclear factor binding, is significantly associated with serum LDL cholesterol levels in Korean subjects.     

The nitric oxide synthase 3 gene polymorphisms and their association with deep vein thrombosis in Asian Indian patients

BackgroundEndothelium derived nitric oxide is formed from l-arginine by endothelial nitric oxide synthase encoded by the nitric oxide synthase 3 (NOS3) gene. Nitric oxide possesses a variety of protective effects on endothelial cells and therefore NOS3 is a logical candidate gene to be investigated for the susceptibility of deep vein thrombosis (DVT).MethodsOne hundred consecutive patients (M: F = 56:44) with idiopathic deep vein thrombosis and an equal number of age and sex matched healthy controls were the study subjects. All study subjects were typed for five NOS3 polymorphisms (? 786C/T, ? 922A/G, 894G/T, Intron 4 VNTR, and Intron 23 G10T).ResultsTwo polymorphisms (? 922A/G and 894G/T) are showing their association with DVT. ? 922A/G shows both genotypic (P = 0.0218; χ² = 5.25; O.R = 1.94) as well as allelic association (P = 0.0014; χ² = 10.19; O.R = 2.0) while 894G/T shows only allelic (P = 0.04; χ² = 3.93; O.R = 3.93) association with DVT.ConclusionSusceptibility to DVT in North Indian Asian patients may be associated with some variants of NOS3 gene.     

Lack of association between cellular repressor of E1A-stimulated genes (GREG) polymorphisms and coronary artery disease in the Han population of North China

BackgroundPhenotypic switching of smooth muscle cells (SMCs) plays a critical role in the pathogenesis of atherosclerotic lesions such as coronary artery disease (CAD). Accumulating evidence demonstrates that a cellular repressor of E1A-stimulated genes (CREG) plays a role in the maintenance of the mature phenotype of vascular SMCs. We assessed the possible association between CREG and CAD in the Han population of North China.MethodsThe promoter region of CREG by direct sequencing was conducted in 48 subjects. Then SNP rs2995073 and another 4 tagSNPs (rs4657669, rs3767443, rs16859185, and rs3753921) were selected for the association study. All five selected SNPs were determined in 1161 patients with angiographically proven CAD and 960 controls with normal coronary angiograms to investigate the possible involvement of CREG in CAD.ResultsGenotype frequencies of the 5 polymorphisms were similarly distributed between CAD group and controls (P > 0.05). Further haplotype analysis also found no significant differences in the distributions between CAD group and controls (P > 0.05).ConclusionThis study did not show an association between common variants of CREG and CAD in the northern Chinese Han population.     

Matrix metalloproteinase 9 gene haplotypes affect left ventricular hypertrophy in hypertensive patients

BackgroundMatrix metalloproteinases (MMPs) are involved in cardiac remodeling and are encoded by genes showing genetic polymorphisms that have functional implications. We examined whether MMP-9 genetic polymorphisms are associated with hypertension and with left ventricular (LV) remodeling in hypertensive patients.MethodsWe studied 173 hypertensive patients and 137 age, race and gender matched healthy controls. Heart echocardiography was performed in all patients and the following MMP-9 genetic polymorphisms were analyzed: C^? 1562T (rs3918242), ? 90 (CA)_14–24 (rs2234681) and Q279R (rs17576). Haplo.stats analysis was used to assess whether MMP-9 haplotypes are associated with hypertension. Linear regression analysis was performed to assess whether MMP-9 haplotypes affect LV mass index (LVMI) and other echocardiography parameters.ResultsMMP-9 ? 90 (CA)_14–24 “HH” genotype (H allele defined by number of CA repeats ≥ 21) was associated with hypertension (P = 0.0085; OR = 2.321, 95% confidence interval = 1.250 to 4.309). While one MMP-9 haplotype (“C, H, Q”) protects against LVMI and end-diastolic diameter increases due to remodeling (P = 0.0490 and P = 0.0367), another MMP-9 haplotype apparently has detrimental effects over both parameters in hypertensive patients (“T, H, Q”, P = 0.0015 and P = 0.0057, respectively).ConclusionGenetic polymorphisms in MMP-9 gene may modify the susceptibility of hypertensive patients to LV remodeling. Further studies are necessary to examine whether these polymorphisms affect clinical events in hypertensive patients.     

Matrix metalloproteinase-1 promoter genotypes and haplotypes are associated with carotid plaque presence

ObjectivesMatrix metalloproteinase (MMP)-1 degrades fibrillar collagens suggesting important role in vascular remodeling. Data about MMP-1 promoter polymorphisms and carotid atherosclerosis (CA) are scarce. The aim of this study was to evaluate association of MMP-1 genotypes/haplotypes with carotid plaque (CP) presence in Serbian population.Design and methodsStudy enrolled a total of 702 participants: 274 controls and 428 consecutive patients with CA who underwent carotid endarterectomy. MMP-1 polymorphisms ? 1607 1G/2G, ? 519 A/G and ? 340 T/C were genotyped by PCR and RFLP methods.ResultsIndividuals carrying MMP-1 ? 1607 2G allele had significantly increased allele dose-dependent risk for CP presence (1G1G vs. 1G2G vs. 2G2G; OR = 1; OR = 1.87 95% CI 1.29–2.07; OR = 3.49 95% CI 1.67–7.30, p = 0.0009, respectively). Compared to the referent haplotype 2G_? 1607-T_? 340-A_? 519, the haplotypes 1G_? 1607-T_? 340-A_? 519, 1G_? 1607-T_? 340-G_? 519 and 2G_? 1607-C_? 340-A_? 519 had statistically significant protective effect on CP presence (OR = 0.41, 95% CI 0.29–0.81, p = 0.01; OR = 0.56, 95% CI 0.44–0.89, p = 0.01; OR = 0.43, 95% CI 0.27–0.86, p = 0.02, respectively).ConclusionsMMP-1 ? 1607 G/2G polymorphism solely and specific haplotypes of three analyzed promoter polymorphisms are significantly and independently associated with occurrence of CP. Replication studies in other populations are needed.     

A meta-analysis of the bradykinin B2 receptor gene − 58C/T polymorphism with hypertension

Background and objectiveNumerous studies have attempted to associate ? 58C/T polymorphism of bradykinin B2 receptor gene (BDKRB2) with hypertension, whereas results were often irreproducible. We performed a meta-analysis aiming to provide a comprehensive evaluation of this polymorphism and hypertension.MethodsCase-control reports published in English were searched totaling four studies with six populations (823 cases and 916 controls). Random-effects model was applied irrespective of between-study heterogeneity, and study quality was assessed in duplicate.ResultsCompared with ? 58C allele carriers, those with ? 58T allele had a lower yet nonsignificant risk for hypertension (OR = 0.86; 95% CI: 0.68–1.09; P = 0.21). Lack of significance persisted after combining those with genotypes ? 58TC and ? 58TT together (OR = 0.87; 95% CI: 0.67–1.09; P = 0.21) or with ? 58TC and ? 58CC together (OR = 0.75; 95% CI: 0.48–1.18; P = 0.22) in association with hypertension. Sensitivity analyses by race indicated that comparison of ? 58T versus ? 58C generated a protective effect for hypertension in Asians (OR = 0.77; 95% CI: 0.58–1.02; P = 0.07) and African-Americans (OR = 0.65; 95% CI: 0.43–0.98; P = 0.04), but a risk effect in Caucasians (OR = 1.22; 95% CI: 0.92–1.61; P = 0.17). No publication bias was observed.ConclusionsOur results suggested that ? 58T allele exhibited a protective effect on hypertension in Asians and African-Americans, yet a risk effect in Caucasians.     

Endothelial nitric oxide synthetase,methylenetetrahydrofolate reductase polymorphisms,and cardiovascular complications in Tunisian patients with nondiabetic renal disease

ObjectivesThe relationship between endothelial nitric oxide synthase (eNOS), methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and cardiovascular disease (CVD) in Tunisian patients with chronic renal disease (CRD) has not been examined. We investigated (a) the relationship of these gene polymorphisms with the presence and the severity of renal disease, and (b) their relationships with CVD in these patients.Design and methodsWe used PCR-RFLP analysis to detect the eNOS G894T, MTHFR C677T and A1298C variants in 100 patients with CRD and in 120 healthy controls.ResultsMTHFR C677T and A1298C polymorphisms were not associated with the presence of renal disease. However, we found that eNOS G894T polymorphism was associated with the presence and severity of renal disease and with CVD in CRD patients (P = 0.028, P = 0.018, P = 0.016 respectively). We showed that 894T allele was an independent risk factor of severity of renal disease and the incidence of CVD (P = 0.01 and P < 0.01 respectively).ConclusionThe G894T polymorphism of the eNOS gene is associated with severity of renal disease. Presence of the 894T allele aggravated renal damage and increased the incidence of CVD in Tunisian CRD patients.     

The association between transforming growth factor β3 polymorphisms and left ventricular structure in hypertensive subjects

BackgroundTransforming growth factor β (TGF-β) may be a crucial regulator of cardiac remodeling. We investigated the association between the TGF-β gene polymorphisms and left ventricular structure.MethodsA total of 658 hypertensive subjects were genotyped for the TGF-β1 T869C and TGF-β3 (rs3917187 and rs4252338) polymorphisms.ResultsTGF-β3 rs3917187 AA homozygotes had, while accounting for covariates, greater left ventricular end-systolic (LVESD, P = 0.004) and end-diastolic dimension (LVEDD, P = 0.007) than G allele carriers. Moreover, left ventricular mass index (LVMI) in AA genotype was 123.0 ± 3.1 g/m² significantly higher than that in AG (114.6 ± 1.6 g/m²) and GG (115.4 ± 2.1 g/m², P = 0.03) genotypes. In multivariate regression analysis, TGF-β3 rs3917187 genotype as an independent predictor had statistically significant effects on LVESD (β = 0.164, P = 0.002), LVEDD (β = 0.172, P = 0.003) and LVMI (β = 0.136, P = 0.016), respectively. In further analyses, we observed a significant interaction between the rs3917187 and alcohol intake in relation to LVESD (P_int = 0.04) and left ventricular fractional shortening (LVFSH, P_int = 0.012). However, no relationship could be found between left ventricular parameters and the T869C or the rs4252338.ConclusionThe present results demonstrated that the TGF-β3 rs3917187 polymorphism was associated with left ventricular structure, and had an interactive influence with alcohol on LVESD and LVFSH in hypertensive subjects.     

The −351A/G polymorphism of ESR1 is associated with risk of myocardial infarction but not with extreme longevity

BackgroundWomen live longer than men. Some possible reasons for this advantage are the protection provided by high concentrations of 17β-estradiol (E2) during the premenopausal period and polymorphic variants of the estrogen receptors (ERs), which mediate various cardiovascular functions of E2.MethodsWe tested whether the ?351A/G and ?397T/C polymorphisms of the ERα-encoding ESR1 were associated with extreme longevity. The genomic DNA of 148 centenarians (C), 414 young controls (Y), and 208 myocardial infarction patients (MI) was analyzed by RFLP-PCR.ResultsBoth polymorphisms were equally distributed in the Y, C, and in centenarians never diagnosed with MI (HC). In centenarians, none of these polymorphisms was associated with a particular lipid profile. The AA genotype of the ?351A/G polymorphism was less frequent in the C, HC and Y groups than in MI patients (p = 0.058, p = 0.021, and p = 0.004, respectively). In MI patients, the GG genotype of the ?351A/G polymorphism was associated with significantly lower mean total cholesterol, LDL, and HDL levels compared to the AG (p = 0.0194, p = 0.0213, and p = 0.0367, respectively) and AA genotypes (p = 0.0014, p = 0.0078, and p = 0.0448, respectively).ConclusionsThe ?351A/G ESR1 polymorphism might be associated with MI, but not with extreme longevity.     

Common genetic polymorphisms in pre-microRNAs were associated with increased risk of dilated cardiomyopathy

BackgroundCommon single nucleotide polymorphisms (SNPs) in pre-microRNAs may change their property through altering microRNAs (miRNAs) expression and/or maturation, resulting diverse functional consequences. We conducted a pilot study to test whether SNPs in pre-microRNAs were associated with dilated cardiomyopathy (DCM).MethodsGenotypes of 3 SNPs in pre-miRNAs (has-mir-196a2 rs11614913 C/T, hsa-mir-499 rs3746444 A/G, hsa-mir-146a rs2910164 C/G) in 221 DCM patients and 321 control subjects were determined with the use of PCR-restriction fragment length polymorphism (RFLP) assay.ResultsSignificantly increased DCM risks were found to be associated with variant allele of has-mir-196a2 rs11614913 C/T (T allele) and hsa-mir-499 rs3746444 A/G (G allele) (P < 0.0001, OR = 1.730, 95% CI = 1.345–2.227, and P < 0.0001, OR = 1.794, 95% CI = 1.350–2.385, respectively). We found that increased DCM risk was statistically significantly associated with these 2 SNPs in a dominant model (P = 0.0001 and P < 0.0001 for rs11614913 and rs3746444, respectively). No association between DCM risk and hsa-mir-146a rs2910164 C/G was observed (P = 0.451, OR = 1.102, 95% CI = 0.856–1.418).ConclusionsBoth the has-mir-196a2 rs11614913 C/T and hsa-mir-499 rs3746444 A/G, but not hsa-mir-146a rs2910164 C/G, are associated with a significantly increased risk of DCM, indicating that common genetic polymorphisms in pre-microRNAs are associated with DCM.     

CYP11B2 gene haplotypes independently and in concurrence with aldosterone and aldosterone to renin ratio increase the risk of hypertension

ObjectivesAldosterone synthase produces aldosterone, which regulates electrolytes and thereby blood pressure. Polymorphisms in aldosterone-synthase gene (CYP11B2) may associate with heterogeneous aldosterone production and hypertension. Hence, we investigated ? 344T/C, Iw/Ic polymorphisms of CYP11B2, plasma renin activity (PRA) and aldosterone concentration (PAC).Design and methodsConsecutive ethnically-matched 450 hypertensive patients and 360 controls were screened by PCR-RFLP for genotypes and haplotypes; PRA and PAC were measured.ResultsThe Iw/Ic polymorphism distribution differed significantly between the two groups (LRT χ² = 15.8, df = 2, P = 0.000). The mutant allele-Ic and genotype-Ic/Ic were overrepresented in patients (35% versus 27% and 13% versus 7%). Overrepresentation of T-Ic haplotype in patients was identified as risk haplotype (P = 0.000). Patients had significantly higher PAC and aldosterone-to-renin ratio (ARR; P  = 0.000), which was Ic-allele dependent.ConclusionsThe haplotype T-Ic associated with hypertension susceptibility. Correlation between Ic-allele and raised ARR likely serve in hypertension management.     

Genetic variant in visfatin gene promoter is associated with decreased risk of coronary artery disease in a Chinese population

BackgroundVisfatin is a newly identified pro-inflammatory adipokine expressed predominantly in visceral fat. Previous studies have suggested a role for visfatin in low-grade inflammation and regulation of lipid metabolism. Most recently, a genetic polymorphism ? 1535C > T located in the visfatin gene promoter has been identified, and suggested to be associated with the regulation of visfatin expression, lipid levels. However, it is unclear whether this polymorphism has a linkage with CAD.MethodsWe conducted a hospital-based case-control study with 257 CAD patients and 292 controls to examine the potential association of the Visfatin ? 1535C > T polymorphism with CAD.ResultsThe frequencies of the CC, CT, and TT genotypes in cases were significantly different from those of controls (χ² = 6.223, P = 0.045). Subjects with the variant genotypes (CT + TT) had a 40% decreased risk of CAD relative to CC carriers (adjusted OR = 0.60, 95%CI = 0.40–0.89). Furthermore, the adjusted OR of a TT genotype for CAD was 0.52 (95%CI = 0.31–0.87). There was a significant association between Visfatin ? 1535C > T polymorphism and triglyceride levels in both CAD patients and controls (P = 0.003, 0.018, respectively). In stratified analyses, the T allele was significantly associated with reduced risk of CAD in males, subjects with age < 59 years, and non-smokers. Moreover, a borderline statistical significance (P = 0.058 for trend) was observed between the variant genotypes and severity of CAD.ConclusionOur results suggested that Visfatin ? 1535C > T polymorphism might be associated with reduced risk of CAD in a Chinese population.     

Polymorphisms of the NOS3 gene in Southern Chilean subjects with coronary artery disease and controls

BackgroundNitric oxide (NO) from the endothelium, produced by oxidation of l-arginine to l-citruline for the action at the endothelial nitric oxide synthase (eNOS) is considered an important atheroprotective factor. The 894G>T, ? 786T>C and 4a/4b polymorphic variants of the NOS3 gene have been implicated in the development of coronary artery disease (CAD). We investigated the association between occurrence of CAD documented by angiography and the 894G>T, ? 786T>C and 4a/4b polymorphisms of the NOS3 gene in Southern Chilean individuals.MethodsA total of 112 unrelated patients with diagnosis of CAD confirmed by angiography and 112 controls were included in this study. The 894G>T and ? 786T>C single nucleotide polymorphisms were analyzed by PCR-RFLP, and 4a/4b polymorphism just for PCR.ResultsThe genotype distribution and the relative allelic frequencies for the 3 variants investigated were not significantly different between CAD and control subjects (p = NS). Moreover, the odds ratio for CAD associated with the 894T (OR = 1.22, 95% CI 0.76–1.95), ? 786C (OR = 1.16, 95% CI 0.75–1.80) and 4a (OR = 0.97, 95% CI 0.48–1.95) variants failed to reach statistical significance.ConclusionThese findings suggest that the 894G>T, ? 786T>C and 4a/4b polymorphisms of the NOS3 were not associated with CAD in the studied subjects.