Synergistic effects of the polymorphisms in the PAI-1 and IL-6 genes with smoking in determining their associated risk with coronary artery disease

ObjectivesTo 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 methodThe 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.ResultsThe 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).ConclusionsThere 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.     

A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population

BackgroundLRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimer's disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians.MethodsTo evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n = 361, age > 50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD.ResultsThe prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P < 0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR = 1.378, 95% CI: 1.017-1.867, P = 0.039), and the results were not influenced by age, gender, or APOE status (P = 0.441, P = 0.94, P = 0.432, respectively).ConclusionOur data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population.     

Effect of obesity on the association between ATF3 gene haplotypes and C-reactive protein level in Taiwanese

ObjectiveATF3 has traditionally been related to various inflammatory processes. Our aim was to test the statistical association between variations in the ATF3 gene and levels of nine serum inflammatory markers, including C reactive protein (CRP), in a Taiwanese population using interaction analysis.MethodsA sample population of 604 Taiwanese subjects was enrolled. Five tagging single nucleotide polymorphisms of the ATF3 gene from the Han Chinese HapMap Database were selected and genotyped.ResultsWith or without adjustment for clinical covariates, ATF3 genotypes were found to be associated with CRP levels but not with other inflammatory marker levels. Minor alleles of 2 of the 5 ATF3 SNPs were associated with decreased CRP levels predominantly in non-obese subjects (Bonferoni P = 0.018, and P = 0.002 for rs11571530, and rs10475, respectively). Two haplotypes inferred from the 5 SNPs, GATTA and TACCA, were also associated with increased or decreased CRP levels, respectively, in non-obese subjects (Bonferoni P = 0.012 and P = 0.01, respectively) but not in obese subjects. Interaction analysis revealed interaction of obesity with an ATF3 genotype associated with a high CRP level (interaction P = 0.006 for SNP rs10475). An effect of obesity on CRP level was also noted in haplotype interaction analysis (interaction P = 0.019 for haplotype TACCA).ConclusionsATF3 polymorphisms are independently associated with CRP levels in Taiwanese subjects. Further, ATF3 genotypes/haplotypes interact with obesity to set CRP levels. These findings may have implications for the prediction of atherosclerotic disease.     

Association of exonic variants of Klotho with metabolic syndrome in Asian Indians

BackgroundKlotho, an anti-aging gene, is a functional candidate for metabolic syndrome. We conducted a cross-sectional study to evaluate the association of the genetic variants of Klotho with metabolic syndrome and surrogates of insulin resistance in Asian Indians.MethodsWe recruited 428 clinically normal subjects for the study. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism.ResultsSignificant and borderline associations of the KL-VS (OR = 15.88 [95%CI, 2.56–98.70], p = 0.003) and C1818T (OR = 0.28 [95%CI, 0.07–1.07], p = 0.063) variants of the Klotho gene, respectively, were observed with metabolic syndrome. The association of the KL-VS variant with metabolic syndrome could be linked to its observed influence on high blood glucose (OR = 6.92 [95% CI = 1.75–27.44], p = 0.006), high blood pressure (OR = 5.21 [95%CI = 1.00–38.43], p = 0.046), insulin resistance (OR = 3.59, [95%CI = 1.01–12.79], p = 0.048) and trend towards its association with hypertriglyceridemia (OR = 3.69 [95%CI = 0.92–14.77], p = 0.065).ConclusionsThe genetic variants of Klotho might predict risk for metabolic syndrome and insulin resistance in Asian Indians. However, larger studies in other ethnic populations are warranted to determine the role of these gene variants in the etiology of metabolic syndrome.     

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.     

Polygenetic regression model of renin-angiotensin system genes and the risk of coronary artery disease in a large angiographic population

BackgroundPolygenetic effect has rarely been addressed in the genetic studies of coronary artery disease (CAD). We used the largest and ethnically homogeneous angiographic cohort to analyze multilocus data in renin-angiotensin system genes, and provide an explicit demonstration of gene–gene interactions.MethodsA total of 1254 consecutive patients who underwent cardiac catheterization (735 with coronary artery disease and 519 without) were recruited. Angiotensin converting enzyme(ACE) gene I/D polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects, adjust non-genetic confounding effects and detect gene–gene interaction between ACE and AT1R genes.ResultsWe found significant differences in global AGT gene haplotype profile and individual haplotypes between cases and controls. Significant two-way and three-way gene–gene interactions between ACE I/D, AT1R A1166C polymorphisms and AGT gene haplotypes were detected. However, subjects carrying both D allele and GGCATC haplotype had an increased risk of CAD (odds ratio = 1.63 [1.16–2.29]; P = 0.004). We also used haplotype counting to directly estimate the odds ratio of each specific AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups with different ACE or AT1R gene genotype.ConclusionsThe regression-based haplotype analyses permits simultaneous dectection of multi-locus and multi-gene effects in determining the risk of CAD. We provide the paradigm for genetic studies of complex-trait diseases using candidate genes based on biological pathways.     

Effect of obesity on the association between common variations in the HNF1A gene region and C-reactive protein level in Taiwanese

BackgroundThe level of C-reactive protein (CRP), an inflammatory biomarker that predicts future cardiovascular events, is a heritable trait that has been associated with variants of CRP and hepatic nuclear factor-1α (HNF1A) genes. Our aim was to test the statistical association between HNF1A genotypes/haplotypes and serum CRP level in Taiwanese.MethodsA sample population of 617 Taiwanese subjects (all Han-Chinese origin) was enrolled. Five HNF1A single nucleotide polymorphisms (SNPs) rs1920792, rs1169288, rs7310409, rs2464196, rs1169310 were genotyped and analyzed.ResultsAfter adjusting for clinical covariates, minor alleles of all the 5 study SNPs were associated with decreased CRP level (P = 0.0078, P = 0.0107, P = 0.0006, P = 0.0004 and P = 0.0003, respectively). A common haplotype (TGATA) tagged by the minor alleles of study SNPs was associated with significantly decreased CRP level (P = 0.0112). Subgroup analysis revealed that the association between HNF1A genotypes and CRP level occurred only in non-obese subjects.ConclusionsHNF1A polymorphisms are independently associated with CRP level in Taiwanese. Further, HNF1A genotypes interact with obesity to set CRP level, revealing that genetic determinants for CRP level may be different between obese and non-obese individuals.     

Effects of common FTO gene variants associated with BMI on dietary intake and physical activity in Koreans

BackgroundAssociations with FTO (fat mass and obesity associated) gene variants and BMI have been reported in western adult populations. To widen the ethnic and age coverage of the FTO studies, we investigated the effects of FTO gene variants on being overweight and related phenotypes in Korean children and adult with a consideration of lifestyle factors.MethodsWe genotyped 711 children for 2 FTO SNPs (rs9939973 and rs9939609), analyzed lifestyle factors, and investigated the potential involvement of FTO variants in being overweight comparing with 8842 adults in the KSNP database.ResultsWith a strong association between FTO gene variants and BMI levels, we further identified an association between rs9939973 or rs9939609 and being overweight both children (P = 0.025, OR = 1.47, 95% CI = 1.05–2.06; P = 0.023, OR = 1.53, 95% CI = 1.06–2.22) and adults (P = 0.018, OR = 1.10, 95% CI = 1.02–1.19; P = 0.001, OR = 1.16, 95% CI = 1.06–1.27). Significant association was observed between rs9939609 and dietary fat intake in children (P = 0.008) but not in adults. In low physical activity subgroup of children, rs9939609 A allele carriers had a higher BMI than TT carriers (P = 0.0147). A significant interaction effect of rs9939609 on BMI across 3 levels of adult physical activity was found.ConclusionsFTO variant rs9939609 is an overweight susceptibility gene in Koreans. By low physical activity, A allele greatly influenced greater BMI.     

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.     

The myeloperoxidase -463G/A polymorphism and coronary artery disease risk: A meta-analysis of 1938 cases and 1990 controls

ObjectivesGenetic polymorphism of human myeloperoxidase (MPO) -463G/A has been implicated to alter the risk of coronary artery disease (CAD), but the results are controversial. To improve the reliability of the conflicting results, we conducted a meta-analysis of studies relating the MPO -463G/A polymorphism with the risk of CAD.Design and methodsTwo investigators independently searched the MEDLINE, EMBASE and Cochrane Library up to June, 2012. Summary odds ratios (OR) and 95% confidence interval (CI) for the MPO -463G/A polymorphism and CAD risk were calculated, and potential sources of heterogeneity and publication bias were explored. Statistical analysis was performed with the software program of Stata 9.0.Results5 case–control studies were finally identified for analyses, involving 1938 cases with CAD and 1990 controls. We found that the MPO -463G/A polymorphism has no significant association with overall CAD risk (G/G vs A/A: OR = 0.595, 95%CI = 0.298–1.188, P = 0.141; G/G vs G/A + A/A: OR = 0.886, 95%CI = 0.779–1.008, P = 0.066; G/G + G/A vs A/A: OR = 0.611, 95%CI = 0.334–1.119, P = 0.111; OR = 0.886, 95%CI = 0.779–1.008, P = 0.066; G vs A: OR = 0.843, 95%CI = 0.675–1.053, P = 0.133). The heterogeneity test showed that there were significant differences between individual studies in additive, recessive and allelic genetic models (P = 0.008, P = 0.021, P = 0.019, respectively); further analyses revealed that age and sex possibly account for the heterogeneity.ConclusionsOur meta-analysis demonstrated the evidence that there was no significant association between the MPO -463G/A polymorphism and the risk of CAD; larger and well-designed multicenter studies are needed to confirm our results.     

Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's disease among ethnic Chinese in Taiwan

BackgroundInfluence of folate/homocysteine conversion is considered to be important in the pathogenesis of Parkinson's disease (PD). However, association of the folate metabolic pathway gene polymorphisms with PD susceptibility remains unclear.MethodsTo test this possibility in PD, we conducted a hospital-based case-control study constituting 211 patients and 218 age- and sex-matched controls of ethnic Chinese in Taiwan. Genotyping assay was performed to screen for polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T), methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR A1049G and C1783T) genes and assess the association between these genotype polymorphisms and PD risk using logistic regression analysis.ResultsOf these four non-synonymous polymorphisms, the MTRR 1049GG variant was significantly associated with PD susceptibility (OR = 3.17, 95%CI = 1.08–9.35). Furthermore, we stratified our patients based on the MTHFR 677TT genotype in different strata, a significant association between the joint effect of polymorphisms and PD risk was observed in those patients whose genotypes were MTRR A1049G/MTR A2756G or MTRR C1783T/MTR A2756G (P < 0.05).ConclusionOur findings provide support for the synergistic effects of polymorphisms in the folate metabolic pathway genes in PD susceptibility; the increased PD risk would be more significant in carriers with the polymorphisms of MTHFR, MTR, and MTRR genes.     

Functional glutathione peroxidase 3 polymorphisms associated with increased risk of Taiwanese patients with gastric cancer

BackgroundGlutathione peroxidase 3 (GPX3) can enhance an antioxidant's capacity and reduce genomic damage caused by oxidants and thus influence tumorigenesis. We investigated the role of GPX3 as a risk of gastric cancer.MethodsWe first conducted a case-control study to test for the association between 5 tagging single nucleotide polymorphisms (SNPs) of GPX3 and the risk of gastric cancer in Chinese. Multivariate logistic regression analysis was performed to estimate the genetic effect with adjustments for age and sex. Functional studies were performed by using the luciferase reporter assay to assess functional consequences of the significant SNPs.ResultsAmong five SNPs (rs3763013, rs8177412, rs3805435, rs3828599, and rs2070593) genotyped in 227 cases and 844 controls, 3 SNPs were significant: intronic SNP rs3805435 (OR = 0.70, P = 0.037), intronic SNP 3828599 (OR = 0.68, P = 0.025), and 3′ UTR SNP rs2070593 (OR = 0.48, P = 0.001). The two intronic SNPs rs3805435 and SNP rs3828599 were in linkage disequilibrium (D′ = 0.91).ConclusionsThe reporter assays showed significant difference in the luciferase expression between protective and risk alleles of 2o intronic SNPs (P = 0.004), whereas the 3′UTR SNP did not influence the luciferase expression. The intronic SNPs at GPX3 can influence gene expression leading to an alteration of gastric cancer risk.     

Implication of CLU gene polymorphisms in Chinese patients with Alzheimer's disease

BackgroundClusterin (also called apolipoprotein J) has a potential central role in the pathogenesis of Alzheimer's disease (AD). Recently, two genome-wide association studies have identified three variants in CLU gene encoding clusterin associated with AD risk in Caucasians, while there are no studies on the association of CLU with AD risk in Asians.MethodsThe study investigated 324 sporadic late-onset AD (LOAD) and 388 healthy controls matched for sex and age in a Han Chinese population. Three common genetic variants (rs2279590, rs11136000 and rs9331888) in CLU gene were genotyped using MALDI-TOF mass spectrometry.ResultsThe minor allele (G) of the rs9331888 polymorphism within CLU was significantly associated with an increased risk of LOAD (OR = 1.39, 95% CI = 1.13–1.72, P = 0.002). Logistic regression analysis revealed that the rs9331888 polymorphism presented strong associations with LOAD in the dominant, recessive and additive models. No significant differences in genotype and allele frequencies of the rs2279590 and rs11136000 polymorphisms were found between LOAD patients and controls. Haplotype analysis identified a risk haplotype (CCG) (OR = 1.66) and a protective haplotype (CCC)(OR = 0.70).ConclusionsOur findings implicate CLU as a susceptibility gene for LOAD in Han Chinese.     

Association study: SLC6A18 gene and myocardial infarction

ObjectiveSLC6A18 (solute carrier family 6, member 18) acts as a specific transporter for neurotransmitters, amino acids and osmolytes such as betaine, taurine and creatine. The aim of the present study was to investigate the relationship between the human SLC6A18 gene and myocardial infarction (MI) in a Japanese population.MethodsUsing 5 single nucleotide polymorphisms in the SLC6A18 gene (rs7728646, rs4975625, rs12522796, rs4975623 and rs7447815) we performed a case-control study based on each SNP and haplotype in 289 MI patients and 223 controls.ResultsLogistic regression analysis revealed that the frequency of the CC + CG genotype of rs7447815 was significantly higher in all patients and the male MI patients than in controls (P = 0.005, P = 0.036, respectively). The frequency of the T-C haplotype (rs7728646–rs7447815) was significantly higher for the MI patients when compared with controls (P = 0.037).ConclusionsThese results suggest that SLC6A18 or neighboring genes are associated with increased susceptibility to MI.     

Association of angiotensin-converting enzyme polymorphism with coronary artery disease in Iranian patients with unipolar depression

ObjectivesMajor depressive disorder (MDD) is an increasingly recognized risk factor of coronary artery disease (CAD). The aim of this study was to assess the relationship between renin-angiotensin system (RAS) genetic polymorphisms and CAD in a sample of depressed Iranian patients.Design and methodsA total of 191 patients with a history of unipolar depression were enrolled in a case/control study. The presence of MDD was reconfirmed at study entry using DSM-IV criteria and CAD was diagnosed by coronary angiography. Genotyping of six RAS genes polymorphisms was performed by a modified PCR-RFLP method.ResultsDD genotype of ACE I/D was independently associated with the incidence of CAD in depressed patients (P = 0.011, OR = 9.41, 95% CI: 1.68–17.81). Moreover, serum creatinine (P = 0.033, OR = 11.91, 95%CI: 7.23–15.62) was an independent predictor of CAD among depressed individuals.ConclusionACE I/D polymorphism may play a major role in the development of CAD amongst Iranian depressed patients.     

Associations between genetic polymorphisms of paraoxonase genes and coronary artery disease in a Taiwanese population

ObjectiveWe evaluated the relationship between polymorphisms of the paraoxonase (PON) gene and the risk of coronary artery disease (CAD) in Taiwanese patients.MethodsOur sample set included 369 volunteers, classified into two groups: 162 healthy volunteers and 207 CAD patients aged 60.0 ± 9.7 and 64.3 ± 12.3 years, respectively. Polymorphisms of the PON1 and PON2 genes were determined using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) techniques.ResultsThe results indicate that for the PON1 gene, the homozygous genotype RR was found significantly more often among the CAD group compared with the healthy group (OR = 1.965, 95% CI = 1.223–3.159, p = 0.005). Furthermore, for the PON2 gene, the homozygous genotype CC was found significantly more often among the CAD group compared with the control group (OR = 2.525, 95% CI = 1.103–5.780, p = 0.026).ConclusionsIndividuals homozygous for the R allele of the PON1 gene and the C allele of the PON2 gene are more likely to have an increased risk of CAD.     

Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese

BackgroundImpaired ubiquitin–proteasome system function may contribute to the pathogenesis of Parkinson's disease (PD).MethodsWe conducted a case–control study in a cohort of 517 PD cases and 518 ethnically matched controls to investigate the association of ubiquitin specific proteases USP24 rs487230 C>T, USP40 rs1048603 C>T, and ubiquitin thiolesterase UCHL1 rs5030732 A>C polymorphisms with the risk of PD.ResultsNo significant difference in the genotype or allele distribution was found between PD and controls. After stratification by age, the genotype and allele frequencies of USP24 rs487230 are significantly different between PD and controls ≥ 60 years of age (P = 0.035 and 0.013, respectively). Multivariable logistic regression with adjusting for onset age and sex showed that, in a dominant model, USP24 T-carrying genotype was associated with risk reduction in developing PD in individuals ≥ 60 years of age (OR = 0.61; 95% CI = 0.41–0.90, P = 0.010). This is also true for T allele (OR = 0.64; 95% CI = 0.44–0.91, P = 0.023). When examining the interaction between genes on PD risk without age stratification, the protective effect of USP24 CT/TT genotype on PD risks was strengthened by the USP40 T-carrying genotype (OR = 0.42; 95% CI = 0.22–0.81, P = 0.009) and UCHL1 C-carrying genotype (OR = 0.67; 95% CI = 0.47–0.97, P = 0.032).ConclusionsOur results suggest that USP24 alone plays a role in PD susceptibility among Taiwanese people ≥ 60 years of age, or acting synergistically with USP40 and UCHL1 in the total subjects.     

The RANTES gene promoter polymorphisms are associated with the risk of atherothrombotic cerebral infarction in Northern Han Chinese

BackgroundRegulated upon activation, normal T-cell expressed and secreted (RANTES) plays an important role in the inflammatory process. This study is aimed at evaluating the potential association of the ? 403G/A (rs2107538) and ? 28C/G (rs2280788) polymorphisms of the RANTES gene promoter with the risk of atherothrombotic cerebral infarction (ACI) in Northern Han Chinese.MethodA total of 314 patients with ACI and 389 unrelated aged-matched healthy controls were recruited. Their genotypes of the RANTES gene promoter ? 403G/A (rs2107538) and ? 28C/G (rs2280788) were analyzed by multiplex polymerase chain reaction (multiplex PCR) and multiplex SNaPshot analysis. The potential association of genotyping and allele frequencies with ACI in this population was assessed statistically.ResultsThe frequencies of ? 403AA genotype and A allele in ACI male patients were significantly higher than that in healthy controls (P = 0.007, P = 0.009, respectively). Female patients were not different. Multiple logistic regression analysis revealed that the ? 403AA genotype in males was significantly associated with an increased risk of ACI, even after adjusting for confounding factors (OR = 4.344; 95% CI = 1.969–9.582; P < 0.001). Although there was no significant association of the ? 28C/G polymorphism with ACI, the A-₄₀₃C-₂₈ haplotype was significantly associated with an increased risk of ACI in Han Chinese [OR = 1.56, 95% CI = 1.23–1.98, P < 0.001].ConclusionsOur data suggest that the ? 403AA genotype and A allele of the RANTES promoter were associated with increased risk for the development of ACI in male Northern Han Chinese.     

Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia

BackgroundStatins are normally the first-line therapy for hypercholesterolemia (HC); however, the lipid-lowering response shows high interindividual variation. We investigated the effect of four polymorphisms in CYP3A4, CYP3A5 and ABCB1 genes on response to atorvastatin and CYP3A4 activity in Chilean subjects with HC.MethodsA total of 142 hypercholesterolemic individuals underwent atorvastatin therapy (10 mg/day/1 month). Serum lipid levels before and after treatment were measured. Genetic variants in CYP3A4 (? 290A>G, rs2740574), CYP3A5 (6986A>G, rs776746) and ABCB1 (2677G>A/T, rs2032582 and 3435C>T, rs1045642) were analyzed by PCR-RFLP. CYP3A4 enzyme activity in urine samples was assessed through determination of 6β-hydroxycortisol/cortisol free ratio (6βOHC/FC).ResultsAfter 4 weeks of therapy, a significant reduction in total cholesterol (TC) and LDL-c was observed (P < 0.001). The G allele for ? 290A>G polymorphism was related to higher percentage of variation in TC and LDL-c (P < 0.001). Moreover, same allele was associated with higher HDL-c variation (P = 0.017). In addition, CYP3A4 enzyme activity was lower in subjects carrying this polymorphism (P = 0.009). No differences were observed for CYP3A5 and ABCB1 variants.ConclusionOur results suggest that presence of G allele for ? 290A>G polymorphism determines a better response to atorvastatin, being also associated with lower CYP3A4 activity in vivo, causing an increased atorvastatin activity.     

Monocyte chemoattractant protein 1-2518 A/G polymorphism and susceptibility to type 2 diabetes in a Chinese population

BackgroundHyperglycemia could accelerate monocyte chemoattractant protein 1 (MCP-1) production in monocytes and vascular endothelial cells. Recently, a genetic polymorphism (–2518 A/G) located in MCP-1 gene promoter has been found that could influence the expression of MCP-1. A large cohort study of Caucasians reported that MCP-1 G–2518 gene variant was negatively correlated with the prevalence of insulin resistance and type 2 diabetes. However, it is unclear whether this polymorphism is associated with type 2 diabetes in Han Chinese.MethodsWe conducted a population-based case–control study of 416 type 2 diabetes cases and 416 controls.ResultsCompared with the wild genotype AA, MCP-1 G–2518 gene variant could significantly decrease the prevalence of type 2 diabetes in Han Chinese (adjusted OR = 0.49, 95% CI 0.32–0.77, P < 0.0001). The results of stratified analyses indicated that a decreased risk of type 2 diabetes related with variant genotypes was evident in younger participants (age ≤ 50) (adjusted OR = 0.35, 95% CI 0.20–0.61, P < 0.0001), and similar results were observed in males (adjusted OR = 0.37, 95% CI 0.21–0.66, P = 0.001) and urban participants (adjusted OR = 0.35, 95% CI 0.21–0.58, P < 0.0001). In addition, a statistically significant difference was observed between MCP-1–2518 A/G polymorphism and waist to hip ratio.ConclusionsOur present pilot study indicated that MCP-1 G–2518 gene variant could significantly decrease the risk of type 2 diabetes in a Chinese population.