Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women

BACKGROUND: Recently, klotho has been proposed as a link between cardiovascular diseases and premature aging, but the relationship between KLOTHO genes and cardiovascular risk factors, especially glucose metabolism, in humans is unclear. OBJECTIVES: We investigate the relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. MATERIAL AND METHODS: In 251 women (mean age 51.3+/-6.9 yr), body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, insulin and lipid profiles were measured. The genotyping of polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene was performed by allelic discrimination using a 5' nuclease polymerase chain reaction assay. RESULTS: Allele frequencies of G395A polymorphism was 0.829 for the G allele and 0.171 for the A allele and allele frequencies of C1818T polymorphism were 0.804 for the C allele and 0.196 for the T allele, both of which were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in linkage disequilibrium (D'=0.43, p<0.01). Mean systolic blood pressure was significantly higher in A allele carriers of G395A polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Mean fasting plasma glucose was significantly higher in T allele carriers of C1818T polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Subjects without any minor allele from either single nucleotide polymorphisms (SNP) had significantly lower mean values for systolic, diastolic blood pressure and fasting plasma glucose levels compared with subjects with both minor allele from either SNP. CONCLUSIONS: We observed that KLOTHO G395A polymorphism was associated with blood pressure and KLOTHO C1818T polymorphism was associated with glucose metabolism in Korean women. Further studies are needed to clarify this relationship.     

中老年患者KLOTHO基因G-395A多态性与心力衰竭和心肌纤维化的相关性

目的:观察分析中老年患者KLOTHO基因G-395A多态性与心力衰竭(HF)和心肌纤维化的相关性。方法:随机选择无血缘关系的中老年患者212例, 提取外周血白细胞基因组DNA, 采用单一等位基因特异性引物PCR技术检测KLOTHO基因G-395A位点多态性,分析其在不同年龄组的分布是否有统计学意义;并把中老年患者分为HF组和非HF组,分析KLOTHO基因G-395A多态性与HF的相关性及与HF各严重程度分级的相关性;同时采用ELISA方法检测上述212例患者血液标本血清中Ⅰ型前胶原羧基端肽（PⅠCP）,Ⅲ型前胶原氨基端肽（PⅢNP）的浓度,分析KLOTHO基因G-395A多态性与心肌纤维化的相关性。结果:①G-395A位点存在多态性,出现3种基因型。②该位点基因型在中老年患者中频率分布总体上没有显著差异（χ2=12.159 P=0.121）;进一步分析各年龄组两两之间与基因型频率分布均无显著差异。③中老年患者KLOTHO基因G-395A多态性与HF发病危险性呈显著相关（χ2=23.634 P=0.00）;进一步分析显示AG是GG易患HF的1.991倍;AA是GG易患HF的1.527倍;GG可能对HF是保护因素。而与HF分级差异比较没有统计学意义（P=0.202）。④Ⅰ、Ⅲ型胶原浓度及Ⅰ/Ⅲ比值与中老年患者G-395A的3种基因型比较没有显著差异,与基因型不相关。结论:在中老年患者中, KLOTHO基因启动子区G-395A呈现3种多态性,这3种多态性与HF发病危险性呈显著相关, 携带A等位基因发生HF的危险性明显高于携带G等位基因的患者,GG可能对HF是保护因素;而与HF分级差异比较及与心肌纤维化程度比较没有统计学意义。     

Association of G-33A polymorphism in the thrombomodulin gene with myocardial infarction in Koreans.

Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the TM promoter activity. These results indicated that G-33A polymorphism in TM might be a genetic risk factor for myocardial infarction.     

Synergistic effects between 561A > C and 98G > T polymorphisms of E-selectin gene and hypercholesterolemia in determining the susceptibility to coronary artery disease

Coronary artery disease (CAD) is a multifactorial disease that results from the interaction between genetic and traditional risk factors. The endothelium dysfunction plays a key role in the progression of atherosclerotic lesions. E-selectin is a marker of endothelium dysfunction. The aim of the present study was to find a relationship between 561A > C and 98G > T polymorphisms of E-selectin gene and CAD as well as interactions between these polymorphic variants and traditional risk factors of the disease in determining the susceptibility to CAD. The study population included 191 patients with angiographically documented CAD and 203 blood donors. The analysis of genetic polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. We found that the frequencies of 561C and 98T alleles of E-selectin gene and carriers of C and T alleles were similar in the entire groups as well as in the age-and sex-matched subgroups. We observed a strong significant correlation between those two polymorphisms; almost all subjects possessing one "proatherosclerotic" allele of E-selectin gene also had the second allele (r = 0.963, P < 0.0001). There were also synergistic effects between both polymorphisms and hypercholesterolemia (but not with smoking or overweight) in determining the susceptibility to CAD. The present study points to synergistic interactions between 561A > C or 98G > T polymorphisms of E-selectin gene and hypercholesterolemia that cause a significant increase in the susceptibility to CAD.     

Alzheimer’s disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes

Type 2 diabetes (T2D) and Alzheimer??s disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-??) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-?? gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-?? gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-?? gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D.     

Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population

BACKGROUND: The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to Graves' disease (GD) in Caucasians. The objective of this study was to investigate whether PTPN22 gene polymorphisms confer susceptibility to GD and Graves' ophthalmopathy (GO) in a Japanese population. METHODS: We performed a case-control study of PTPN22 gene polymorphisms in Japanese GD patients (n = 414) and healthy control subjects with no antithyroid autoantibodies or family history of autoimmune disorders (n = 231). The G-1123C polymorphism (rs2488457) in the promoter region, Arg620Trp (C1858T) polymorphism (rs2476601) in exon 14, IMS-JST146695 polymorphism (rs3789607) in intron 19, and SNP37 (rs3789604) downstream of the PTPN22 gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism using restriction enzymes and direct PCR sequencing methods. RESULTS: None of the GD patients or control subjects had the 1858T allele of the PTPN22 gene polymorphism. The AA-genotype and A-allele frequencies of SNP37 were significantly higher in GD patients than in control subjects (A-allele frequency: p = 0.0085, odds ratio = 1.45). The genotype frequencies and allele frequencies of the G-1123C and IMS-JST146695 polymorphisms did not differ between GD patients and control subjects. The -1123G/1858C/JST146695T/SNP37C haplotype frequency was significantly lower in GD patients than in control subjects. There were no associations between PTPN22 gene polymorphisms and GO. CONCLUSIONS: The results suggest that SNP37 of the PTPN22 gene is associated with susceptibility to GD in a Japanese population. Further studies including functional analyses are required.     

Analysis of MMP-7 and TIMP-2 gene polymorphisms in coronary artery disease and myocardial infarction: A Turkish case-control study

Matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) have a significant role in tissue remodeling related to cardiac function. In earlier studies, MMP-7 A-181G (rs11568818), C-153T (rs11568819), C-115T (rs17886546), and TIMP-2 G-418C (rs8179090) polymorphisms have been studied in various diseases. However, association between coronary artery disease (CAD) and these polymorphisms has been poorly studied. The goal of this study is to investigate the association of CAD and myocardial infarction (MI) with MMP-7 or TIMP-2 polymorphisms. This study included 122 CAD patients and 132 control individuals. DNA was extracted from whole blood. Polymerase chain reaction-restriction fragment length polymorphism and automated direct sequencing method were used for genotyping of these polymorphisms. No significant differences were found between MMP-7 A-181G, C-115T, and TIMP-2 G-418C polymorphism and CAD or MI in a Turkish population. Despite the fact that the genotypes of MMP-7 C-153T polymorphism had no significant differences among MI and control groups, allele frequencies of C-153T polymorphism were significantly different between the two groups. Our study is the first report to clarify the appreciable relationship between MMP-7 C-153T polymorphism and MI development in CAD patients. However, these findings also need to be confirmed in other populations so we can improve our knowledge about the genetic factors affecting the development of CAD.     

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

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

Association of peroxisome proliferator-activated receptorgamma gene Pro12Ala and C161T polymorphisms with metabolic syndrome.

BACKGROUND Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved mainly in adipocyte differentiation and has been suggested to play an important role in the pathogenesis of insulin resistance (IR) and atherosclerosis. The frequencies of 2 common polymorphisms of the PPARgamma gene, Pro12Ala single nucleotide polymorphism (SNP) in exon B and C161T SNP in exon 6, were investigated in 792 subjects and the correlations between the different genotypes, IR and metabolic syndrome (MS) were analyzed. METHODS AND RESULTS: Anthropometric measurements, fasting glucose, insulin and lipid profiles were measured in 792 people of the Han population in Beijing, China. Homeostatic model assessments and quantitative insulin sensitivity check indices were calculated. MS was diagnosed according to the IDF guidelines (2005) for a Chinese population. Polymerase chain reaction - restriction fragment length polymorphism were performed for DNA genotyping. For the C161T polymorphism, allele frequencies were 0.804 for the C allele and 0.196 for the T allele. For Pro12Ala, allele frequencies were 0.947 for proline and 0.053 for alanine. There was no Ala12Ala homozygote in the population. No differences were seen in the mean values of age, body mass index (BMI), blood pressure or fasting blood glucose level among different genotypes when analyzed as a whole. Subjects with an A or T allele had lower fasting insulin levels, HOMA-IR levels, and a lower level QUICKI trend. Further analysis by age was conducted, and A or T allele carriers in the <60 year group showed a trend of lower triglyceride and a higher high-density lipoprotein-cholesterol level, but this was not statistically significant. When subjects were divided into 4 groups according to the combination of genetic alleles of the 2 polymorphisms, the subjects with Pro12Ala and a T allele simultaneously showed a significantly higher BMI than those without the Ala allele. The presence of a T allele in the C161T polymorphism and Pro12Ala polymorphism seems to affect body weight, which is similar to the results found in previous studies. CONCLUSIONS: Both polymorphisms showed a significant association with IR, but failed to show an association with MS components. Those with an A allele of Pro12Ala and a T allele of the C161T polymorphism showed a higher BMI, which requires further investigation.     

Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors

OBJECTIVES: The aim of the study was to identify genes that confer susceptibility to coronary artery disease (CAD) in low- or high-risk men or women separately and thereby to assess the genetic risk of CAD in such individuals. BACKGROUND: The prevention of CAD would be facilitated by the identification of genes that confer susceptibility to this condition independently in low- or high-risk individuals, as defined by conventional risk factors. METHODS: The study population comprised 1661 unrelated Japanese individuals, including 1011 patients with CAD and 650 control subjects. Among all study subjects, 601 individuals (high-risk subjects) had hypertension, diabetes mellitus, and hypercholesterolemia, and 1060 individuals (low-risk subjects) had none of these risk factors for CAD. The genotypes for 37 polymorphisms of 31 candidate genes were determined by a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. RESULTS: Multivariate logistic regression analysis, with adjustment for age, body mass index, and the prevalence of smoking and hyperuricemia, revealed that the -219G-->T polymorphism of the apolipoprotein E gene in low-risk men, the -1171/5A-->6A polymorphism of the stromelysin-1 gene in low-risk women, the 1019C-->T polymorphism of the connexin 37 gene in high-risk men, and the 3932T-->C polymorphism of the apolipoprotein E gene in high-risk women were significantly associated with CAD. A stepwise forward selection procedure revealed that the effects of these polymorphisms on CAD were statistically independent of age or conventional risk factors. CONCLUSIONS: Genotyping of these polymorphisms may prove informative for assessment of the genetic risk of CAD in low- or high-risk men or women.     

Association of two apolipoprotein A-I gene MspI polymorphisms with lipid and blood pressure levels

INTRODUCTION: Two MspI polymorphisms in the ApoA-I gene (G-75A and C83T) have been shown to be associated with plasma HDL-cholesterol levels. METHODS: We used a PCR-based RFLP method to determine the association of these polymorphisms with lipid parameters in 271 non-diabetic, normotriglyceridaemic Chinese subjects, of whom 104 were patients with hypertension, with 10.2% having hypercholesterolaemia and the remainder were controls. RESULTS: As expected, the hypertensive group had higher blood pressure and indices of obesity, and a more adverse lipid profile. No differences in the ApoA-I G-75A genotype or allele frequency distributions between the controls and patients were identified. However, there was a significantly lower frequency of the CT genotype (p=0.012) and T allele (p=0.011) in the affected subjects with hypercholesterolaemia or hypertension. Similarly, blood pressure and triglyceride levels were significantly lower and HDL-cholesterol levels significantly higher in the subjects with the CT genotype compared to those with the CC genotype (p<0.05). However, the G-75A genotypes did not appear to influence the lipid or blood pressure levels. The -75A allele frequency was higher in our healthy controls than an equivalent Caucasian population (31.1% vs. 18.3%, p<0.001), whereas the 83T allele frequency was similar between the healthy Chinese and Caucasian groups. CONCLUSION: The 83T allele may be associated with a better lipid profile and blood pressure levels in this group of Chinese subjects.     

The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.

BACKGROUND: Most recently, evidence has been presented that the NADH/NADPH oxidase p22 phox C242T, but not the A640G gene polymorphism is associated with a reduced risk of coronary artery disease (CAD). METHODS AND RESULTS: We analysed the relationships of both p22 phox gene polymorphisms to CAD in 2205 male Caucasians whose coronary anatomy was defined by means of coronary angiography. In the total population and in high and low risk groups the relative frequencies of the C242T alleles were essentially the same in patients without or with CAD and in individuals without or with myocardial infarction. In contrast, the G allele of the A640G polymorphism was significantly more frequent in subjects without CAD than in patients with CAD (Odds ratio (OR) 0.74 (0.57-0.98); P = 0.038 in multiple logistic regression (MLR)). Correspondingly, the AA genotype of A640G was preferentially found in patients with CAD. These associations did not disappear when the analyses were corrected for multiple comparisons for other gene polymorphisms (ACE I/D gene variation, angiotensinogen T174M and M235T gene polymorphisms, AT1 receptor gene variation, phox C242T gene polymorphism, paraoxonase PON54 and PON191 gene variations) (2p = 0.01 in MLR for the presence of CAD; 2p = 0.039 in multiple regression for the extent of CAD). The association of the A640G gene variation with the presence and extent of CAD was not only identified in the total sample, but was even stronger in various high risk subpopulations of younger individuals (e.g. with hypertension with or without increased apolipoprotein B plasma levels). CONCLUSIONS: Our observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.     

Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population

The objective of this study was to analyze the influence of the polymorphisms G-6A of the angiotensinogen gene, insertion/deletion (I/D) of the angiotensin-converting enzyme, and C573T of the angiotensin II AT1 receptor gene on a healthy, middle-age population. A total of 370 (194 women) healthy normotensive Caucasian subjects, aged 25-50 yr old, were selected from the general population. A significant association was found between height and the C573T polymorphism in women (P < 0.001). After adjustment for age, this association remained significant (P < 0.002). Thus, the lowest height values were from subjects carrying TT genotype (CC, 1.627 +/- 0.008 m; CT, 1.595 +/- 0.006 m; TT, 1.586 +/- 0.010 m; P = 0.002). Likewise, the I/D polymorphism was associated with height (P = 0.002) in women. It remained significant after adjustment for age and the lowest height for the DD genotype (II, 1.629 +/- 0.011 m; ID, 1.603 +/- 0.006 m; DD, 1.591 +/- 0.007 m; P = 0.016). For both C573T and I/D polymorphisms, there was an allele dosage effect. Moreover, an additive and independent effect of the C573T polymorphism (P = 0.006) and the I/D polymorphism (P = 0.045) on height was observed. In contrast, no association with height was observed for the G-6A polymorphism. In conclusion, additive effects between polymorphisms of the renin-angiotensin system genes and height were observed in healthy women. These results should be studied by other groups in other populations and ethnic groups. Whether or not these associations need to be considered in the epidemiological studies analyzing the relationship between polymorphisms of the renin-angiotensin system genes and such height-influenced parameters as blood pressure merits further study.     

A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study.

We previously investigated the relation between hypertension and each of three major genetic polymorphisms in the renin-angiotensin (AGT)-aldosterone system (R-A-A), AGT M235T, angiotensin convert enzyme (ACE) I/D, and CYP11B2 -344C/T, by means of ambulatory blood pressure (ABP) monitoring in a general Japanese population (the Ohasama Study). A/C1166 gene polymorphism in the 3' untranslated region of the angiotensin II type 1 receptor (AT1) gene is the final remaining major target in R-A-A to be examined in the Ohasama Study population. In the present study, the AT1 A/C1166 polymorphism was genotyped by the TaqMan polymerase chain reaction (PCR) method or restriction fragment length polymorphism (RFLP) in 802 Japanese subjects aged 40 and over, who were previously genotyped for the AGT M235T, ACE D/I, CYP11B2 -344C/T polymorphisms. The AA genotype, AC genotype, and CC genotype were present in 678 (84.5%), 121 (15.1%), and 3 (0.4%) of subjects, respectively. Since the frequency of the C allele was quite low (0.079), the genotypes were classified according to the presence or absence of the C allele. Although daytime blood pressure (BP) was higher in subjects with the C allele, the difference was not statistically significant after adjusting for age, gender, body mass index, and smoking status. No significant difference was noted in the prevalence of cardiovascular diseases or nocturnal BP decline between the two groups. These results indicated that AT1 A/C1166 polymorphism was not associated with any clinical parameters associated with hypertension or atherosclerosis in the Japanese population.     

Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population

BACKGROUND: Genetic polymorphism in the gene for endothelial nitric oxide synthase (eNOS) has been identified as a potential risk factor for the development of premature coronary artery disease (CAD). We determined whether the eNOS 4ab, G894T, and T-786C polymorphisms are associated with premature coronary artery disease. DESIGN: A case-control study. METHODS: PCR-based assays were used to compare the frequency of eNOS gene polymorphisms in 573 Caucasian subjects aged under 50 years presenting with symptomatic CAD and documented by coronary angiography, with or without myocardial infarction, to that of 624 similarly aged community controls without a history of symptomatic CAD. RESULTS: We found no difference in the frequency of 4ab genotypes between cases and controls: in the CAD subjects, the 4aa, 4ab, and 4bb genotype frequencies were 1.9%, 24.3% and 73.8% respectively, compared to 2.2%, 25.5% and 72.3% respectively for the controls. There was also no significant difference between cases and controls in the frequency of any allele (4a/4b, 894G/894T, -786C/-786T), or genotype for any of the polymorphisms. Similarly, logistic regression analysis showed no evidence for an association of the polymorphisms with premature CAD or myocardial infarction or any indication of an interaction between the polymorphisms and other CAD risk factors, including smoking. CONCLUSIONS: In a large case-control study, and in contrast to some earlier positive findings by others, we have found no evidence for an association between several eNOS gene polymorphisms and premature CAD in an Australian Caucasian population.     

CYP2J2基因和EPHX2基因多态性与肺癌易感性研究

目的探讨CYP2J2基因启动子区G-50T多态性和EPHX2基因G860A多态性与肺癌发生的关系。方法经病理检查确诊为肺癌患者150例（肺癌组）,300名本院健康体检者作为对照组,检测其CYP2J2基因启动子区G-50T多态性和EPHX2基因G860A多态性,并进行统计学分析。结果肺癌组和对照组比较,CYP2J2启动子区G-50T多态性差异无统计学意义,而肺癌组患者EPHX2 860G等位基因频率显著高于对照组人群（96％比78．3％,P〈0．01）,多元回归分析方法显示,肺癌的发生与EPHX2 G860A多态性显著相关（校正OR值=0．164,95％CI 0．079～0．342,P〈0．001）。结论EPHX2 G860A多态件与肺痛密切相关．可作为肺癌高毹患者的预涮指标．     

The prevalence of C807T mutation of glycoprotein Ia gene among young male survivors of myocardial infarction: a relation with coronary angiography results

INTRODUCTION: The glycoprotein complex Ia/IIa (GP Ia/IIa) is a major collagen receptor on platelets and other cell types. Recently, linked polymorphisms within the coding region of the GP Ia gene (C807T and G873A) related to GP Ia/IIa surface expression have been identified. The 807T/873A allele is associated with high expression, whereas the 807C/873G allele is associated with low surface expression of GP Ia/IIa. Subsequently, the 807T allele was found to be associated with coronary artery disease (CAD) and cerebral infarction in younger patients. Moreover, platelet thrombus formation is significantly influenced by genetic variations of the GPIb alpha and GPIa receptors and is dependent on the blood flow rate. AIM: 1. To determine the frequency of C807T polymorphism of the GPIa gene in young survivors of myocardial infarction (MI) and 2. to evaluate the relationship between the intensity of CAD in the coronary angiography examination and the 807C/T genetic status of the patients. METHODS: 102 young male survivors of MI (YSMI) -- mean age 43, range 29-49 years, mean age at the time of the first episode 37+/-3 years -- were studied. Obesity was found in 15%, diabetes in 14%, hyperlipidemia in 87%, hypertension in 22% and smoking history in 90% of cases. Familial CAD and/or MI were confirmed in 50% of patients. The control group consisted of 106 healthy volunteers with a negative family history of CAD, both medical staff members and blood donors (mean age 40, range 18-42 years). The genetic study was performed using genomic DNA obtained from peripheral blood leukocytes. The C807T polymorphism of platelet glycoprotein Ia (GPIa) was investigated using the PCR method introduced by Santoso et al. RESULTS: Coronary angiography (Siemens Bicor system) revealed single-artery disease in 34%, two-artery disease in 36% and three-artery disease in 26% of patients. In two patients there were no signs of CAD. The C807T polymorphism of GPIa was found in 73.5% of investigated patients (heterozygotes CT 59.8%, homozygotes TT 13.7%). The CC genotype was confirmed in 26.5% of patients. A similar analysis performed in the group of healthy men showed C807T polymorphism of the GPIa gene in 73.6% (CT in 58.5% and TT in 15.1% of persons, ns). CC genotype was found in 26.4% of persons. Interestingly, the T genotype frequency was similar in patients with three- or two-artery disease in comparison with patients with single-vessel or without CAD (49.3% vs. 50.7%, respectively, ns). In 75 YSMI carrying C807T polymorphism of the GPIa gene additional genetic abnormalities were confirmed in 21 patients - BclI polymorphism of b-chain fibrinogen gene, G4070A and G1691A (FV Leiden) mutation of factor V gene and C677T polymorphism of methylenetetrahydrofolate reductase gene. Partial occurrence of combined polymorphisms was found. This was confirmed independently of the number of coronary arteries involved.CONCLUSIONS: Our results may question the potential role of C807T the GPIa anomaly as a single genetic abnormality predisposing young men to coronary artery disease.     

Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction

There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.     

Genetic variations of apolipoprotein A5 gene is associated with the risk of coronary artery disease among Chinese in Taiwan

Recently, a T/C polymorphism of the promoter region of the APOA5 gene at position -1131 and a G/T polymorphism at position 553 were found to be associated with increased levels of plasma triglyceride. Triglyceride plays a role in coronary artery disease (CAD), so this case-control study tested for a possible link between these two APOA5 polymorphisms, their common haplotypes and the risk of CAD. The subjects included 211 CAD patients and 677 unrelated controls. A significantly higher level of triglycerides and a lower level of high-density lipoprotein cholesterol (HDL-C) were noted for carriers with -1131C than for non-carriers (P<0.001 and 0.013, respectively) among controls. Plasma triglyceride levels were significantly higher (P=0.014) in controls with genotypes that contained the c.553T allele than in homozygotes for the G allele. Subjects homozygous for the wild-type haplotype had significantly lower triglyceride levels and higher HDL-C levels than subjects with all other haplotype pairs. The -1131C homozygous carriers and c.553T heterozygous carriers were found more frequently in 211 patients with CAD than in the 317 age/sex-matched controls (P=0.008 and 0.023, respectively) in univariate analysis. The significant association between c.553T allele carriers with CAD remained in multivariate regression analysis (OR, 1.79; CI, 1.07-3.00; P=0.028), after adjustments were made for other risk factors. Notably, haplotype analysis further verified that the APOA5 -1131C and c.553T bi-loci haplotype was significantly overpresented in CAD, as compared to the controls. These results indicate that the variants of APOA5 gene modulate plasma triglyceride and may use them to predict CAD susceptibility in Taiwanese Chinese.     

Klotho基因G-395A多态性与动脉硬化的相关性研究

目的研究重庆市汉族人群Klotho基因启动子区域G-395A单核苷酸多态性的分布,探讨该多态性位点与动脉硬化的相关性。方法232例健康体检者均进行臂踝脉搏波传导速度测定,并记录动脉硬化的传统危险因素,根据测定结果分为动脉硬化组(130例)和对照组(102例)。应用TaqMan探针等位基因特异性杂交分析法对Klotho基因G-395A多态性位点进行分析。结果G-395A多态性位点共检测出GG、GA、AA3种基因型,频率分别为60.3%、34.1%和5.6%,符合Hardy-Weinberg平衡。动脉硬化组-395A等位基因的频率显著低于对照组(33.1%vs48.0%,P=0.022)。logistic回归分析,调整传统危险因素后-395A与动脉硬化呈负相关(P=0.042,OR=0.537,95%CI:0.295~0.977)。结论Klotho基因-395A等位基因可能是动脉硬化的遗传学保护因素。