-
Li-Na Zhang,
Pan-Pan Liu,
Jianqing Zhou,
R Stephanie Huang,
Fang Yuan,
Li-Juan Fei,
Yi Huang,
Limin Xu,
Ling-Mei Hao,
Xu-Jun Qiu,
Yanping Le,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang,
Meng Ye, Jiangfang Lian,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency <1%). Genotype rs2246942-GG of the LIPA gene was associated with an increased risk of CHD [CHD cases versus healthy controls: P=0.04; odds ratio (OR)=1.63; 95% confidence interval (CI)=1.02-2.60). Genotype rs7767084-CC of the LPA gene was identified as a protective factor against CHD in females (CHD cases versus non-CHD controls: P=0.04, OR=0.21; CHD cases versus healthy controls: P=0.02, OR=0.21). The results of our meta-analysis indicated that rs7767084 was not associated with a high risk of CHD (P=0.83; combined OR=0.93; 95% CI=0.47-1.85). In the present study, two single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism (rs2246942 and rs7767084) were identified to be significantly associated with CHD in the Han Chinese population. Specifically, rs2246942-GG of the LIPA gene was a risk factor for CHD, while rs7767084-CC of the LPA gene was a protective factor against CHD in females. However, our meta-analysis indicated that rs7767084 is not associated with a higher risk of CHD.
Molecular Medicine Reports 05/2013; · 0.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The goal of our study is to evaluate the contribution of CXCL12 rs1746048 (hg19, chr10:44775574) to the risk of CHD in Han Chinese, and to summarize its role in CHD through meta-analysis of existing studies among various ethnic groups. Significant association is observed between rs1746048-C and an increased risk of CHD in Han Chinese (χ(2) = 5.41, df = 1, P = 0.02). Post hoc analysis reveals an even stronger association of rs1746048 with the risk of CHD for subjects aged 65 years or older (genotype: χ(2) = 8.39, df = 2, P = 0.015; allele: χ2 = 9.13, df = 1, P = 0.003, odd ratio (OR) = 1.91, 95% confidential interval (CI) = 1.25 - 2.91). A break down analysis by gender shows that rs1746048 is likely a CHD risk factor under the recessive model in males (CC+CT versus TT: P = 0.05, χ(2) = 3.59, df = 1, OR = 1.72, 95% CI = 1.00 - 3.04). In addition, a meta-analysis of ten studies among over 107,000 individuals confirms that rs1746048 is a risk factor of CHD (P < 0.0001, OR = 1.12, 95% CI =1.09 - 1.15) and this agrees with the findings of our case-control study in Han Chinese.
Gene 03/2013; · 2.34 Impact Factor
-
Limin Xu,
Jianqing Zhou,
Stephanie Huang,
Yi Huang,
Yanping LE,
Danjie Jiang,
Feiming Wang,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang,
Changzheng Dong,
Lina Zhang,
Meng Ye, Jiangfang Lian,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: Previous genome-wide association studies (GWAS) have revealed seven single nucleotide polymorphisms (SNPs) that affect lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity or levels in American and European individuals. A total of 290 coronary heart disease (CHD) patients, 198 non-CHD patients and 331 unrelated healthy volunteers were recruited for the present case-control study of Han Chinese. Four SNPs (rs964184 of ZNF259, rs7528419 of CELSR2 and rs7756935 and rs1805017 of PLA2G7) were shown to be significantly associated with CHD. The rs964184-G allele of the ZNF259 gene was identified as a risk factor of CHD in females (odds ratio (OR) =1.49, 95% confidence interval (CI) =1.00-2.22, P=0.05). The rs7528419-G allele of the CELSR2 gene was protective against CHD in males (OR=0.48, 95% CI=0.25-0.93, P=0.04). The other two alleles (rs7756935-C and rs1805017-A) of the PLA2G7 gene acted as protective factors against CHD in females (rs7756935-C: OR=0.59, 95% CI=0.35-1.00, P=0.05; rs1805017-A: OR=0.51, 95% CI=0.28-0.93, P=0.03). Moreover, rs1805017 of the PLA2G7 gene was associated with the severity of CHD only in females (r(2)=0.02, P=0.04). We identified four Lp-PLA(2)-associated SNPs significantly associated with CHD in a Han Chinese population. Specifically, rs7528419 was protective factor against CHD in males, while the other two SNPs (rs7756935 and rs1805017 of the PLA2G7 gene) were protective factors against CHD in females and rs964184 of the ZNF259 gene was regarded as a risk factor for CHD in females.
Experimental and therapeutic medicine 03/2013; 5(3):742-750.
-
Lina Zhang,
Fang Yuan,
Panpan Liu,
Lijuan Fei,
Yi Huang,
Limin Xu,
Lingmei Hao,
Xujun Qiu,
Yanping Le,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang,
Meng Ye,
Jianqing Zhou, Jiangfang Lian,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese. METHODS: A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass-ARRAY iPLEX® platform. χ(2)-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD. RESULTS: No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P = 0.003, I(2) = 67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P = 0.148, I(2) = 36.7%). CONCLUSION: The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians.
Clinical biochemistry 02/2013; · 2.02 Impact Factor
-
Jiangfang Lian,
Yi Huang,
R Stephanie Huang,
Limin Xu,
Yanping Le,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang,
Meng Ye,
Jianqing Zhou,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: The goal of our study is to assess the contribution of four eosinophil related gene variants (rs12619285, rs1420101, rs3184504 and rs4143832) to the risk of coronary heart disease (CHD). We conducted four meta-analyses of studies examining the association between four eosinophil related gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. A case-control study was conducted between 162 CHD cases and 119 non-CHD controls to explore their contribution to CHD. For rs3184504 of SH2B3 gene, the meta-analysis was performed among 19 study stages among 94,555 participants. Significant association between rs3184504 and CHD risk was observed in European and South Asian populations (OR = 1.13, 95 % CI = 1.10-1.16, p < 0.0001, fixed-effect method). For the other SNPs (rs12619285, rs1420101, and rs4143832), we combined our case-control data with the previous studies and found no association of them with the risk of CHD. No significant contribution of the four genetic variants to CHD was observed in Han Chinese (p > 0.05). In conclusion, our results supported a significant association between rs3184504 of SH2B3 gene and the risk of CHD in Europeans and South Asians, although we were unable to observe association between the four variants and the risk of CHD in Han Chinese.
Journal of Thrombosis and Thrombolysis 01/2013; · 1.48 Impact Factor
-
Yi Huang, Jiangfang Lian,
R Stephanie Huang,
Feiming Wang,
Limin Xu,
Yanping Le,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang,
Meng Ye,
Jianqing Zhou,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: Westaway et al. have revealed a significant association between common variants of calsequestrin-2 (CASQ2) and nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP) and the risk of sudden death in patients of coronary heart disease (CHD). In light of the findings, we aim to explore the association between variants of the two genes and CHD risk in Han Chinese. Our results show a significant contribution of rs10918859 of the NOS1AP gene to CHD in Han Chinese (genotype: χ(2)=8.33, df=2, p=0.015; allele: χ(2)=4.00, df=1, p=0.047, odds ratio [OR]=1.44, 95% confidence interval [CI]=1.00-2.05). The association of rs10918859 with CHD is seen only in men (genotype: χ(2)=7.81, df=2, p=0.02; allele: χ(2)=4.49, df=1, p=0.03, OR=1.66, 95% CI=1.03-2.66). Moreover, rs10918859 is likely to exert its effect under a dominant model in men (χ(2)=7.6, df=1, p=0.005, OR=2.46, 95% CI=1.29-4.71). No association is observed between CASQ2 variants and CHD risk. The frequencies of rs12084280-C and rs10918859-A are higher in Han Chinese (36.7% and 41.6%) than those in Europeans (11% and 19.4%, respectively). These ethnic differences imply that further validation of NOS1AP in the susceptibility of CHD in other populations is warranted. We confirm that rs10918859 of the NOS1AP gene is associated with CHD in Han Chinese. In addition, here we report a gender effect in the association between rs10918859 of the NOS1AP gene and CHD.
Genetic Testing and Molecular Biomarkers 11/2012; · 1.11 Impact Factor
-
Jianqing Zhou,
Yi Huang,
R Stephanie Huang,
Feiming Wang,
Limin Xu,
Yanping Le,
Xi Yang,
Weifeng Xu,
Xiaoyan Huang, Jiangfang Lian,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese.
We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs.
Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p=0.04; OR=1.45, 95% CI=1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p=0.04; OR=1.83, 95% CI=1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR=1.08, 95% CI=1.05 - 1.11) in both Europeans and South Asians including Han Chinese.
Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect.
Thrombosis Research 06/2012; 130(4):602-6. · 2.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Long QT syndrome type 2 (LQT2) is the second most common type of all long QT syndromes. It is well-known that trafficking deficient mutant human ether-a-go-go-related gene (hERG) proteins are often involved in LQT2. Cells respond to misfolded and trafficking-deficient proteins by eliciting the unfolded protein response (UPR) and Activating Transcription Factor (ATF6) has been identified as a key regulator of the mammalian UPR. In this study, we investigated the role of ER chaperone proteins (Calnexin and Calreticulin) in the processing of G572R-hERG and E637K-hERG mutant proteins.
pcDNA3-WT-hERG, pcDNA3-G572R-hERG and pcDNA3-E637K-hERG plasmids were transfected into U2OS and HEK293 cells. Confocal microscopy and western blotting were used to analyze subcellular localization and protein expression. Interaction between WT or mutant hERGs and Calnexin/Calreticulin was tested by coimmunoprecipitation. To assess the role of the ubiquitin proteasome pathway in the degradation of mutant hERG proteins, transfected HEK293 cells were treated with proteasome inhibitors and their effects on the steady state protein levels of WT and mutant hERGs were examined.
Our results showed that levels of core-glycosylated immature forms of G572R-hERG and E637K-hERG in association with Calnexin and Calreticulin were higher than that in WT-hERG. Both mutant hERG proteins could activate the UPR by upregulating levels of active ATF6. Furthermore, proteasome inhibition increased the levels of core-glycosylated immature forms of WT and mutant hERGs. In addition, interaction between mutant hERGs and Calnexin/Calreticulin was stronger after proteasome inhibition, compared to WT-hERG. These results suggest that trafficking-deficient G572R-hERG and E637K-hERG mutant proteins can activate ER stress pathways and are targeted to the proteasome for degradation. Calnexin and Calreticulin play important roles in these processes.
PLoS ONE 01/2012; 7(1):e29885. · 4.09 Impact Factor
-
Ping Peng, Jiangfang Lian,
R Stephanie Huang,
Limin Xu,
Yi Huang,
Yanna Ba,
Xi Yang,
Xiaoyan Huang,
Changzhen Dong,
Lina Zhang,
Meng Ye,
Jianqing Zhou,
Shiwei Duan
[show abstract]
[hide abstract]
ABSTRACT: The goal of our study is to assess the contribution of KIF6 Trp719Arg to both the risk of CHD and the efficacy of statin therapy in CHD patients.
Meta-analysis of 8 prospective studies among 77,400 Caucasians provides evidence that 719Arg increases the risk of CHD (P<0.001, HR = 1.27, 95% CI = 1.15-1.41). However, another meta-analysis of 7 case-control studies among 65,200 individuals fails to find a significant relationship between Trp719Arg and the risk of CHD (P = 0.642, OR = 1.02, 95% CI = 0.95-1.08). This suggests that the contribution of Trp719Arg to CHD varies in different ethnic groups. Additional meta-analysis also shows that statin therapy only benefit the vascular patients carry 719Arg allele (P<0.001, relative ratio (RR) = 0.60, 95% CI = 0.54-0.67). To examine the role of this genetic variant in CHD risk in Han Chinese, we have conducted a case-control study with 289 CHD cases, 193 non-CHD controls, and 329 unrelated healthy volunteers as healthy controls. On post hoc analysis, significant allele frequency difference of 719Arg is observed between female CHD cases and female total controls under the dominant model (P = 0.04, χ(2) = 4.228, df = 1, odd ratio (OR) = 1.979, 95% confidence interval (CI) = 1.023-3.828). Similar trends are observed for post hoc analysis between female CHD cases and female healthy controls (dominant model: P = 0.04, χ(2) = 4.231, df = 1, OR = 2.015, 95% CI = 1.024-3.964). Non-genetic CHD risk factors are not controlled in these analyses.
Our meta-analysis demonstrates the role of Trp719Arg of KIF6 gene in the risk of CHD in Caucasians. The meta-analysis also suggests the role of this variant in statin therapeutic response in vascular diseases. Our case-control study suggests that Trp719Arg of KIF6 gene is associated with CHD in female Han Chinese through a post hoc analysis.
PLoS ONE 01/2012; 7(12):e50126. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Bone marrow endothelial progenitor cells (BMEPCs) are believed to be a promising cell source for regenerative medicine; however, their electrophysiology properties have not been fully clarified, which is important to the clinical application of BMEPCs. The current study was designed to determine the transmembrane ion currents and mRNA expression levels of related ion channel subunits in rat BMEPCs.
Bone marrow mononuclear cells were isolated by density gradient separation and cultured in EPC medium. The transmembrane ion currents were determined using whole-cell patch-voltage clamp technique, and the levels of mRNA and protein expressions of functional ionic channels were measured using RT-PCR and western immunoblot analysis.
We observed two types of ionic currents in undifferentiated rat BMEPCs. One was Ca(2+) -activated potassium current (I(kca) ), which was seen in approx. 90% of cells when 1 μm Ca(2+) was employed in pipette solution, and it was predominantly inhibited by intermediate-conductance I(kca) inhibitor clotrimazole. The other one was volume-sensitive chloride current (I(cl) ), which was detected in 85.7% of cells when BMEPCs were subjected to K(+) -free hypotonic extracellular solution, whose currents could be inhibited by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). The corresponding ion channel genes and proteins, KCNN4 for I(kca) and Clcn3 for I(cl) , were confirmed by RT-PCR and western immunoblot analysis of BMEPCs.
Our results demonstrated for the first time that rat BMEPCs expressed intermediate-conductance Ca(2+) -activated potassium currents and volume-sensitive chloride currents, and corresponding genes and proteins of these two channels are KCNN4 and Clcn3 respectively.
Acta Physiologica 12/2011; 205(2):302-13. · 3.09 Impact Factor
-
Jiangfang Lian,
Na Huang,
Junbo Zhou,
Shijun Ge,
Xiaoyan Huang,
Jianhua Huo,
Liying Liu,
Weifeng Xu,
Shun Zhang,
Xi Yang,
Jianqing Zhou,
Chen Huang
[show abstract]
[hide abstract]
ABSTRACT: The congenital long QT syndrome is a heterogeneous genetic disease associated with delayed cardiac repolarization, prolonged QT intervals, the development of ventricular arrhythmias and sudden death. Type 2 congenital long QT syndrome (LQT2) results from KCNH2 or hERG gene mutations. hERG encodes the K(v)11.1 alpha subunit of the rapidly activating delayed rectifier K(+) current in the heart. Studies of mutant hERG channels indicate that most LQT2 missense mutations generate trafficking-deficient K(v)11.1 channels.
To identify the mechanism underlying G572R-hERG by using molecular and electrophysiological analyses.
To elucidate the electrophysiological properties of the G572R-hERG mutant channels, mutant hERG subunits were heterologously expressed in HEK293 cells alone or in combination with wild-type (WT)-hERG subunits. Patch-clamp techniques were used to record currents, and double immunofluorescence protein tagging and Western blotting were performed to examine the cellular trafficking of mutant subunits. When expressed alone, G572R-hERG subunits were not present in the cell membrane and did not produce detectable currents. When coexpressed with WT-hERG subunits, G572R-hERG decreased current density and altered gating properties of the WT-hERG channel.
The hERG-associated missense mutation G572R, like most LQT2 missense mutations, generates a trafficking-deficient phenotype. Furthermore, G572R-hERG causes a loss of function in hERG by a strong dominant negative effect on the WT-hERG channel.
The Canadian journal of cardiology 10/2010; 26(8):417-22. · 3.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To perform mutation analysis in a family with long QT syndrome.
The medical record of the affected child and his parents were collected. The locus of gene associated with the long QT syndrome was mapped by linkage analysis. Mutation analysis was done by PCR-single strand conformation polymorphism (SSCP) and direct sequencing.
A mutation (L539fs/47) and a SNP (L564L) were found in exon 7 of the KCNH2 gene of the proband. The mutation was from the father.
A novel mutation of L539fs/47 in the KCNH2 gene was identified in the LQTS family, which might be the disease-causing mutation for the family.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 02/2010; 27(1):77-80.
-
[show abstract]
[hide abstract]
ABSTRACT: In order to assess the clinical manifestations and electrocardiogram (ECG) characteristics of Chinese long QT syndrome (LQTS) patients and describe the phenotype-genotype correlation, the subjects from 5 congenital LQTS families underwent clinical detailed examination including resting body surface ECG. QT interval and transmural dispersion of repolarization (TDR) were manually measured. Five families were genotyped by linkage analysis (polymerase chain reacting-short tandem repeat, PCR-STR). The phenotype-genotype correlation was analyzed. Four families were LQT2, 1 family was LQT3. Twenty-eight gene carriers were (14 males and 14 females) identified from 5 families. The mean QTc and TDRc were 0.56 +/- 0.04 s (range 0.42 to 0.63) and 0.16 +/- 0.04 s (range 0.09 to 0.24) respectively. 35.7% (10/28) had normal to borderline QTc (< or = 0.460 s). There was significant difference in QTc and TDRc between the patients with symptomatic LQTS and those with asymptomatic LQTS, and there was significant difference in TDRc between the asymptomatic patients and normal people also. A history of cardiac events was present in 50% (14/28), including 9 with syncope, 2 with sudden death (SD) and occurred in the absence of beta-blocker. Three SDs occurred prior to the diagnosis of LQTS and had no ECG record. Two out of 5 SDs (40%) occurred as the first symptom. Typical LQT2 T wave pattern were found in 40% (6/15) of all affected members. The appearing-normal T wave was found in one LQT3 family. Low penetrance of QTc and symptoms resulted in diagnostic challenge. ECG patterns and repolarization parameters may be used to predict the genotype in most families. Genetic test is very important for identification of gene carriers.
Journal of Huazhong University of Science and Technology 01/2004; 24(3):208-11. · 0.38 Impact Factor
