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Lei Liu,
Yanyan Cao, Guanglin Cui,
Zongzhe Li,
Jing Sun,
Lina Zhang,
Chen Chen,
Yan Wang,
Peihua Wang,
Hu Ding,
Dao Wen Wang
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ABSTRACT: Rho-kinase (ROCK) has been shown to play an important role in cardiovascular disease such as coronary artery disease (CAD) and hypertension. Recently, common variants of ROCK2 have been reported to influence blood pressure, but the relationship between common ROCK2 variants and cardiovascular disease has not been extensively studied in the Chinese population.
To derive a more precise estimation of their relationship, we screened for the common variants by direct sequencing of all exons of ROCK2, and then we performed genetic association analyses in a CAD case-control study, including a total of 1344 cases and 1267 ethnically and geographically matched controls.
Unconditional logistic regression showed that no significant association between common variants in the coding region of ROCK2 and CAD was observed in our study (for rs978906, OR = 0.92, 95% CI 0.72-1.20 and P = 0.63; for rs2230774, OR = 0.90, 95% CI 0.70-1.16 and P = 0.47; for rs56304104, OR = 0.97, 95% CI 0.70-1.31 and P = 0.83; respectively).
The relationship between the ROCK2 polymorphisms and cardiovascular disease risk cannot be entirely discounted and warrants further evaluation in a large population.
PLoS ONE 01/2013; 8(1):e53905. · 4.09 Impact Factor
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ABSTRACT: Recent studies have demonstrated that alleles at single nucleotide polymorphisms (SNPs) rs2187668 and rs4664308 within genes HLA-DQA1 and PLA2R1, respectively, had a significant impact on the susceptibility to idiopathic membranous nephropathy (IMN). Analysis of the two genomic loci could identify alleles for individuals at risk for IMN. Conventional methods for genotyping are labor intensive, expensive or time consuming. High resolution melting (HRM) is a new technique for genotyping and has the advantages of simplicity, speed, high sensitivity and low cost. Here, we describe genotyping of SNPs rs2187668 and rs4664308 using HRM. In this study, we identified polymorphisms of rs2187668 and rs4664308 in 480 healthy unrelated Chinese volunteers of two ethnic groups from three different geographical areas in China. The two genomic loci were genotyped by HRM using a saturating fluorescent dye SYTO® 9 on 7900 HT and RG 6000 instruments, and were further confirmed by direct DNA sequencing. Three different SNP genotypes were sufficiently distinguished by HRM with mean sensitivity of 98.8% and mean error rate of 1.9%. In addition, the allele frequencies varied greatly based on ethnic or geographic origins. In conclusion, HRM is a rapid, cost efficient, sensitive, suitable technique for genotyping, and simple enough to be readily implemented in a diagnostic laboratory. We believe this will be a valuable technique for determining the genotype of rs2187668 and rs4664308 and for assessing individual susceptibility to IMN.
Gene 11/2012; · 2.34 Impact Factor
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ABSTRACT: BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-alpha in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-alpha have been contradictory. FINDINGS: In this study, a 2-kb length of the proximal promoter of the TNF-alpha was screened and four polymorphisms were investigated in the case--control study. Our data confirmed the association between -308G/A variant with stroke in 1,388 stroke patients and 1,027 controls and replicated in an independent population of 961 stroke patients and 822 controls (odds ratio (OR) = 1.34, 95% confidence interval (CI) =1.02 to 1.77 and OR = 1.56, 95% CI = 1.09 to 2.23, respectively). To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 15 published studies in an Asian population. Our results demonstrated an association between rs1800629 and ischemic stroke (OR = 1.43, 95% CI = 1.21 to 1.69). Another meta-analysis results of 14 studies demonstrated that ischemic stroke patients have higher serum TNF-alpha level than the control subjects (standardized mean difference (SMD) =2.33, 95% CI 1.85 to 2.81). In vitro evaluation of potential interaction between variants of the TNF-alpha gene (-308G/A, -857C/T, and -1031T/C) demonstrated that these three polymorphisms can interact together to determine the overall activity of the TNF-alpha gene. CONCLUSIONS: These findings strongly implicate the involvement of TNF-alpha in the pathogenesis of stroke.
Journal of Neuroinflammation 10/2012; 9(1):235. · 3.83 Impact Factor
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ABSTRACT: Current screening methods, such as single strand conformational polymorphism (SSCP), denaturing high performance liquid chromatography (dHPLC) and direct DNA sequencing that are used for detecting mutation in Leber's hereditary optic neuropathy (LHON) subjects are time consuming and costly. Here we tested high-resolution melt (HRM) analysis for mtDNA primary mutations in LHON patients. In this study, we applied the high resolution melting (HRM) technology to screen mtDNA primary mutations in 50 LHON patients from their peripheral blood. In order to evaluate the reliability of this technique, we compared the results obtained by HRM and direct mtDNA sequencing. We also investigated the spectrum of three most common mtDNA mutations implicated in LHON in the Han Chinese population. The results showed HRM analysis differentiated all of the mtDNA primary mutations and identified 4 additional mtDNA mutations from 50 patients in the blind study. The prevalence of three primary mutations were 11778G>A (87.9%), 14484T>C (6.5%) and 3460G>A (1.7%) in the Han Chinese population. In conclusion, HRM analysis is a rapid, reliable, and low-cost tool for detecting mtDNA primary mutations and has practical applications in molecular genetics.
Gene 10/2012; · 2.34 Impact Factor
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ABSTRACT: Recent publications have found an association between variants of exostosin 2 (EXT2) gene and the risk of type 2 diabetes in some population but not in others. In an attempt to address these inconsistencies, we investigated EXT2 variants in two independent cohorts, and conducted a literature-based meta-analysis. Through regression model, we assessed the relationship between the EXT2 single nucleotide polymorphisms (SNPs) (rs3740878, rs11037909 and rs1113132) and the risk of type 2 diabetes in Han Chinese population, including a total of 2,533 cases and 2,643 controls. We combined our data with that from previously published studies and performed a meta-analysis to evaluate the effect size of the gene. Consistent with some studies, we found marginal association for the rs3740878 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.09), rs11037909 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.08), and rs1113132 (OR = 1.08, 95 % CI = 1.00, 1.17, p = 0.06) in our 2 cohorts. Meta-analysis, comprising 9,224 type 2 diabetes and 10,484 controls, revealed that three SNPs (rs3740878, rs11037909 and rs1113132) in EXT2 were significantly associated with type 2 diabetes (ORs range from 1.06 to 1.07, p = 0.038, p = 0.008 and p = 0.005, respectively). Variation in the EXT2 locus appears to be associated with a small increase in the risk of type 2 diabetes. However, well-designed prospective studies with larger sample size and more ethnic groups are needed to further validate the results.
Human Genetics 09/2012; · 5.07 Impact Factor
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ABSTRACT: Common polymorphisms within cytochrome P450 2J2 (CYP2J2) and epoxide hydrolase 2 (EPHX2), which are involved in the generation or hydrolysis of epoxyeicosatrienoic acids, may determine susceptibility to the development of cardiovascular disease. To derive a more precise estimation of their relationship, we undertook a case-control study as well as a meta-analysis to assess possible associations of coronary artery disease (CAD) risk with CYP2J2 and EPHX2 genetic variations.
Associations among four single nucleotide polymorphisms in CYP2J2 and five in EPHX2 with CAD were examined in a total of 1344 cases and 1267 ethnically and geographically matched controls. To further confirm the effect of two functional variants (G-50T and R287Q) in the development of CAD, we conducted a meta-analysis including seven studies on G-50T polymorphism and six studies on R287Q polymorphism before June 2010.
No significant association between common polymorphisms within these two genes and CAD was observed in our sample, either using methods of single-locus analysis or haplotype-based analysis. In addition, no association was detected in our meta-analysis between these two functional variants and the risk of developing CAD.
This case-control study as well as meta-analysis suggested no association between CYP2J2 G-50T and EPHX2 R287Q and the risk of developing CAD.
Pharmacogenetics and Genomics 06/2011; 21(8):489-94. · 3.48 Impact Factor
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ABSTRACT: OBJECTIVE: The renin-angiotensin-aldosterone system is important for cerebrovascular research because it influences blood pressure, vasoconstriction, thrombosis, and vessel wall damage. We hypothesized that genetic variations in CYP11B2 gene might contribute to the susceptibility for stroke. METHODS AND RESULTS: Here, we present genetic association analyses on CYP11B2 gene variants in two independent ischemic stroke (IS) cohorts. Four single nucleotide polymorphisms (SNPs) from CYP11B2 gene were genotyped in 558 Chinese patients and 557 matched controls. Another replication was conducted in an independent sample of 525 IS cases and 694 controls. In addition, meta-analyses was performed to assess the association between the rs1799998 (-344C/T) CYP11B2 polymorphism and IS. Only one SNP rs1799998 (-344C/T)showed association with overall IS in the first study (P(dominant)=0.003, P(additive)=0.003, respectively), but this was not replicated in our second cohort. No associations were found for the rest of SNPs in both the studies. Meta-analyses (including our study) revealed that-344C/T of CYP11B2 was associated with IS both in a dominant effect (odds ratio=1.51, 95% CI: 1.06-2.16, P=0.023) and a recessive effect (odds ratio=1.57, 95% CI:1.14-2.16). Above all, our results suggest that genetic variation rs1799998 (-344C/T) of CYP11B2 gene may contribute to the risk of IS with moderate effect in Han Chinese population.
Pharmacogenetics and Genomics 03/2011; 21(3):115-20. · 3.48 Impact Factor
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ABSTRACT: Recent genome-wide association (GWA) studies have identified two intergenic single nucleotide polymorphisms (SNPs) (rs11833579 and rs12425791) on chromosome 12p13 and within 11 kb of the NINJ2 gene that were significantly associated with stroke in Caucasians. However, the validity of the association has remained controversial. We performed genetic association analyses in three independent cohorts, including total of 3042 cases and 2973 controls. No significant association between these two SNPs and ischemic stroke was detected by meta-analysis after adjustment for cardiovascular risk factors under the additive model. Our data does not support that the common variants on 12p13 are major contributors of ischemic stroke in the Chinese Han population.
Atherosclerosis 03/2011; 216(2):381-2. · 3.79 Impact Factor
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ABSTRACT: Congenital adrenal hyperplasia owing to 17α-hydroxylase/17, 20-lyase deficiency is caused by genetic mutations in the CYP17A1 gene. To date, more than 80 different genetic lesions have been described in patients suffering from this disorder. We aimed to estimate the prevalence of CYP17A1 common mutations in Chinese Han population.
We first reported two female patients with 17α-hydroxylase deficiency based on their clinical features and molecular genetics, and then summarized all the mutations of CYP17A1 gene reported around the world. The most common mutations of CYP17A1 among Chinese Han were genotyped in additional 3245 healthy Chinese using Taqman-assays.
The mutation spectrum in Asian is different from European decent. All healthy controls could detect two CYP17A1 mutations, D487-S488-F489 deletion and TAC329AA, with a prevalence of 1 in 1000 or 2 in 1000, respectively.
Our data demonstrates that these two mutations are major causes of 17α-hydroxylase deficiency in Chinese Han population.
Clinica chimica acta; international journal of clinical chemistry 03/2011; 412(13-14):1240-3. · 2.54 Impact Factor
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Li Zhou,
Hu Ding,
Xiaomin Zhang,
Meian He,
Suli Huang,
Yujun Xu,
Ying Shi, Guanglin Cui,
Longxian Cheng,
Qing K Wang,
Frank B Hu,
Daowen Wang,
Tangchun Wu
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ABSTRACT: Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population.
We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10(-8)), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10(-4) and 0.001, respectively).
We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.
PLoS ONE 01/2011; 6(11):e27481. · 4.09 Impact Factor
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Hu Ding, Guanglin Cui,
Lan Zhang,
Yujun Xu,
Xunna Bao,
Yuanchao Tu,
Bin Wu,
Qi Wang,
Rutai Hui,
Wei Wang,
Ryan T Dackor,
Grace E Kissling,
Darryl C Zeldin,
Dao Wen Wang
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ABSTRACT: 20-Hydroxyeicosatetraenoic acid has been shown to play an important role in cerebral vascular function. We hypothesized that polymorphisms in genes encoding 20-Hydroxyeicosatetraenoic acid synthesizing enzymes might confer susceptibility to stroke.
To test the hypothesis, haplotype tagging single nucleotide polymorphisms and potential functional polymorphisms of CYP4A11 and CYP4F2 genes were genotyped in 558 ischemic stroke patients, 221 hemorrhagic stroke patients and 557 controls. The association analyses were performed at both single nucleotide polymorphism and haplotype levels. We further verified our findings in an independent cohort of 551 ischemic stroke cases and 48 hemorrhagic stroke cases and 694 unaffected controls. We identified CYP4A11 C-296T and CYP4F2 V433M were associated with significantly increased risk of ischemic stroke (CT+TT vs. CC, adjusted odds ratio: 1.50, 95% confidence interval: 1.17-1.93, Pcombined=0.001, Pcorr=0.008; V/M+M/M vs. V/V, odds ratio: 1.38, 95% confidence interval: 1.15-1.65, Pcombined=5.6x10, Pcorr=0.005, respectively). Interestingly, the effects of CYP4F2 V433M on ischemic stroke in our study was only evident in male individuals.
Our results suggest that genetic variation in CYP4A11 and CYP4F2 alters susceptibility to stroke in the Han Chinese population.
Pharmacogenetics and Genomics 03/2010; 20(3):187-94. · 3.48 Impact Factor
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ABSTRACT: The first genomewide association study of ischemic stroke in whites has identified multiple susceptibility loci. We confirmed this study by examining associations with ischemic stroke in a Chinese Han population.
Twenty-five common variants were genotyped in a relatively large sample size including 1123 subjects with ischemic stroke cases (thrombosis stroke=716, lacunar infarction=407) and 557 normal control subjects. The association analyses were performed at both single nucleotide polymorphism and haplotype levels. False discovery rate q value method was applied for multiple testing corrections.
rs11052413, a intergenic single nucleotide polymorphism, was most significantly associated with ischemic stroke independent of traditional cardiovascular risk factors in additive (OR=1.51, 95% CI=1.19 to 1.92, P=7.4 x 10(-4), q=0.018) and dominant models (OR=1.59, 95% CI=1.20 to 2.08, P=9.2 x 10(-4), q=0.023). In addition, both ZNF650 rs10204475 and intergenic single nucleotide polymorphism rs10486776 were associated with ischemic stroke as well as independent of traditional cardiovascular risk factors in dominant models (OR=1.47, 95% CI=1.12 to 1.96, P=0.005, q=0.040 and OR=1.53, 95% CI=1.15 to 2.02, P=0.003, q=0.036, respectively). No significant results were found in stroke subtype analysis after multiple corrections.
Our study confirmed previously reported associations between ischemic stroke and rs11052413, rs10486776, and ZNF 650 rs10204475 in a Chinese Han population. The mechanism whereby the genetic variants exert their effects on ischemic stroke remains to be further elucidated.
Stroke 11/2009; 41(1):177-80. · 5.73 Impact Factor
