基质金属蛋白酶9基因-1562C/T多态性与新疆维吾尔族心肌梗死的相关性研究

目的 探讨新疆维吾尔族人群基质金属蛋白酶9(matrix metalloproteinase 9,MMP9)基因启动子区-1562C/T多态性与心肌梗死(myocardialinfarction,MI)发病的相关性.方法 选择经皮冠状动脉造影检查确诊的维吾尔族心肌梗死患者347例(MI组),以同期冠脉造影阴性、排除冠心病诊断的403例维吾尔族患者为对照组.采用聚合酶链反应-限制性片段长度多态性方法对所有纳入对象MMP9基因-1562C/T多态性进行分析,比较两组间MMP9基因多态性频率分布的差异,并结合造影情况,探讨MMP9基因多态性与MI发病及冠脉狭窄程度的关系.结果 MI组CT+TT基因型频率(27.67%)明显高于对照组(14.14%),两组差异具有统计学意义(χ2=20.99,P＜0.01),T等位基因频率在MI组和对照组分别为15.71%、7.56%(χ2=24.57,P＜0.01).Logistic回归分析显示,携带-1562T等位基因的个体发生MI的风险大约升高2倍(OR=2.009,95%CI:1.250～3.230);携带T等位基因合并糖尿病的个体发生MI的风险明显升高(OR=3.714,95%CI:1.299～10.773).MMP9基因-1562C/T多态性分布与MI冠脉狭窄程度差异无统计学意义.结论 MMP9基因-1562C/T多态性可能与新疆维吾尔族人群MI茇病具有相关性;-1562T等位基因可能是MI遗传易感性的基因标记之一;-1562T等位基因与糖尿病在MI发生中具有协同作用.MMP9基因-1562C/T多态性与MI冠脉狭窄程度无关.

Abstract：

Objective To investigate the association between matrix metalloproteinase 9 gene (MMP9)- 1562C/T polymorphism and myocardial infarction (MI) in Uighur population of Xinjiang.Methods A total of 347 patients with MI evidenced by coronary arteriography, and 403 controls free from coronary artery disease with normal angiograms were recruited for the study. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) was used to detect the -1562C/T functional promoter polymorphism of the MMP9 gene. The relationship between the polymorphism and the severity of coronary arterial stenosis was analyzed. Results The results showed that the frequency of CT and TT genotypes in patients with MI (27. 67%) was significantly higher than that in controls (14. 14%). The frequencies of the - 1562T allele were 15. 71% and 7. 56% in the MI group and the control group respectively (2 = 24.57, P＜0.01). Logistic regression analysis indicated that the T allele carriers (CT+TT) had significantly increased risk of MI compared with the CC carriers (OR=2. 009, 95%CI: 1. 250-3. 230). Individuals carrying the -1562T allele with diabetes mellitus were at an increased risk of MI (OR=3. 714, 95% CI: 1. 299-10. 773). The frequencies of CT and TT genotypes were not significantly different among MI patients with one, two and three or more significantly diseased vessels (χ2 =0. 491, P=0. 782). Conclusion The - 1562C/T polymorphism in the MMP9 gene promoter is associated with the susceptibility to MI in the Uighur population of Xinjiang. The T allele might be a risk factor of MI. And there was a coordinated effect between the -1562T allele and diabetes mellitus in the development of MI.The -1562C/T polymorphism may not be a predictor of the severity of coronary atherosclerosis.     

Association of the gene polymorphisms of platelet glycoprotein Ia and IIb/IIIa with myocardial infarction and extent of coronary artery disease in the Korean population

Platelet membrane receptor glycoproteins (GP) are essential for the platelet activation process, and the genetic polymorphisms in the genes that encode platelet glycoproteins have been proposed to influence the risk of acute coronary syndrome and atherosclerosis. In this study, we investigated the role of GPIa, HPA-1 and HPA-3 polymorphisms as putative risk factors for myocardial infarction (MI) and the extent of coronary artery disease. We selected 1,073 subjects who underwent coronary angiography; 242 had normal or minimal coronary atherosclerosis, and 831 patients had significant coronary artery disease (CAD). The genotype was determined by the methods of single base extension for C807T/G873A polymorphisms of GPIa, and restriction fragment length polymorphism for HPA-1 and HPA-3. The C807T and G873A polymorphisms of GPIa showed complete linkage in the Korean population. For HPA-1 gene polymorphism, only the HPA-1a/a (PlA1/A1) genotype was observed in 192 selected subjects from our study population. The distribution of GPIa (C807T/G873A) and HPA-3 genotypes did not differ significantly between normal subjects and CAD subjects. No significant association between MI and both gene polymorphisms was present. However, for the subgroup analysis of young male patients whose age was less than 56 years, the genotype frequency of HPA-3b/b was significantly lower in patients with MI compared to patients without a history of MI (7.5% vs. 20.0%, p=0.04). The odds ratio for HPA-3 b homozygosity versus the HPA-3a carrier was 0.32 (95% CI, 0.10- 0.99, p=0.04). Conclusively, HPA-3 polymorphism was associated with MI in Korean individuals younger than 56 years of age, but other polymorphisms of GP, which we studied, were not associated with both the extent of coronary atherosclerosis or MI.     

5-羟色胺转运体基因启动子连锁多态区多态性与早发心肌梗死及血小板膜糖蛋白Ⅰb的关系

目的 研究中国北方汉族人群5-羟色胺转运体基因启动子连锁多态区(5-hydroxytryptamine transporter gene linked polymorphic region,5-HTTLPR)缺失/插人多态性与早发心肌梗死及血小板膜糖蛋白I b(gIycoprotein I b,GP I b)的关系.方法 采用性别、年龄配对方法 ,选择150例早发心肌梗死患者和150例冠状动脉造影阴性对照者作为研究对象.采用聚合酶链反应技术检测受试对象5-HTTLPR多态性位点的基因型和等位基因分布,全血流式细胞术检测血小板膜GPIb阳性百分率及平均荧光强度.结果 5-HTTLPR基因型LL型、LS型和SS型在心肌梗死组分布频率分别为32%,47%,21%,在对照组为17%,43%和39%(P＜0.01).L等位基因频率在心肌梗死组明显高于对照组(56%vs 39%,P＜0.01).心肌梗死组和对照组内不同基因型的血小板膜GPIb指标比较,LL基因型的血小板膜GP I b阳性百分率及荧光强度均低于同组LS型和SS型(均P＜0.01),多因素Logistic回归分析结果 提示5-HTTLPR的LL基因型与早发心肌梗死发病独立相关(OR=1.961,P=0.037).结论 5-HTTLPR的LL纯合子血小板活化程度增高,LL基因型可能与中国北方汉族人群早发心肌梗死的发病相关联.     

Interleukin-6 gene polymorphism is an age-dependent risk factor for myocardial infarction in men

Several studies show that inflammatory components may contribute to atherosclerosis and increase the risk for myocardial infarction (MI). Interleukin-6 (IL-6) is a key pro-inflammatory and immune-modulatory cytokine of relevance for cardiovascular diseases. In this case-control study, 200 patients with MI and 257 healthy controls were genotyped for the polymorphism present in -174 promoter region of the IL-6 gene. Plasma concentrations of IL-6 and C-reactive protein (CRP) in a group of patients and controls were measured. The -174 C allele was associated with an increased risk of developing MI (OR = 2.886, c.i. = 1.801-4.624, P = 0.0001) in older patients, while no association was found in younger ones. The IL-6 plasma levels were higher in patients with MI carrying the CC genotype than in GG patients (CC carriers, IL-6 = 2.97 pg mL(-1) vs. GG carriers = 1.81 pg mL(-1), P = 0.016). A positive correlation of IL-6 levels with those of CRP in serum from patients with MI was also found. Data from this study suggest that the C allele of the promoter polymorphism in the IL-6 gene is a risk factor for MI in the elderly, and the production of the IL-6 is differentially affected by different genotypes of the IL-6 -174 promoter polymorphism.     

PON1 polymorphism, diabetes mellitus, obesity, and risk of myocardial infarction: Modifying effect of diabetes mellitus and obesity on the association between PON1 polymorphism and myocardial infarction.

PURPOSE: Previous studies on PON1 gene polymorphism and the risk of coronary atherosclerotic diseases have been inconsistent. This may be in part due to population difference in prevalence of high oxidative stress and its modifying effect on the association. Diabetes and obesity are two major risk factors of myocardial infarction (MI) and associated with high oxidative stress. We investigated the association between PON1 Q192R polymorphism and the risk of myocardial infarction (MI) and in particular, whether the association can be modified by diabetes mellitus (DM) and obesity. METHODS: We conducted a case-control study, including 154 MI cases and 154 controls enrolled in Beijing, China. Epidemiological and clinical data and PON1 Q192R genotype were obtained from each subject. RESULTS: Without considering the modifying effect of DM and obesity, PON1 Q192R polymorphism was not associated with MI. When simultaneously examining the joint association of this polymorphism, DM, and obesity with MI, as compared to subjects with QQ genotypes and without DM and obesity, subjects with QR/RR genotypes and with either DM or obesity had significantly higher risk of MI (OR = 3.6, 95% CI: 1.5-8.7). CONCLUSION: Our data suggest that PON1 Q192R polymorphism was not independently associated with MI but further increased the risk of MI among the subjects with DM, obesity, or both, the conditions associated with high oxidative stress.     

Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia

Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation‐associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti‐inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population‐based case‐control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20–0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ≤ 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia. © 2013 Wiley Periodicals, Inc.     

ALOX5AP基因SG13S114A/T多态性与颈动脉粥样硬化斑块稳定性的相关性

目的 探讨花生四烯酸5-脂氧合酶激活蛋白(arachidonate 5-lipoxygenase acttvating protein,ALOX5AP)基因SG13S114 A/T的多态性与颈动脉粥样硬化斑块稳定程度的关系.方法 应用聚合酶链反应-限制性片段长度多态性分析法检测132例颈动脉易损斑块及152例稳定斑块的急性脑梗死者ALOX5AP基因SG13S114 A/T基因型,比较两组间该位点多态性的差异.结果 易损斑块组ALOX5AP基因SG13S114 AA基因型和A等位基因频率高于稳定斑块组,两组差异有统计学意义(P＜0.01),其中男性和女性上述基因型和等位基因频率的比较,易损斑块组均高于稳定斑块组,两组差异有统计学意义(P＜0.01).结论 ALOX5AP基因SG13S114 A/T多态性可能与动脉粥样斑块的稳定性有关,其中SG13S114 A等位基因可能是易损斑块的风险因素.     

Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis.

Wide inter-individual variation of expression of compound metabolic enzymes is determined by polymorphism and may predispose the development of diseases provoked by environmental factors. The combined analysis of phase II detoxification system genes: arylamine N-acetyltransferase 2 (NAT2), and glutathione S-transferases (GST) M1 and T1 was carried out in patients with minimal/mild (group I; n = 36) and moderate/severe endometriosis (group II; n = 29) and controls (n = 72) of French origin, using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The results show a significant difference between patients and controls with regard to NAT2 gene polymorphism (P < 0.05). This is mainly due to the high percentage of slow acetylator genotypes (SA) in patients compared with controls (60.0 versus 38.9%; P < 0.02) with a distinct preponderance in subjects with minimal/mild endometriosis (69.4%, P < 0.005) where there is a significantly elevated frequency of slow allele S1 (NAT2*5) (P = 0.05). Significantly increased proportions of GSTM1-deficient genotypes were found in both groups of patients, in comparison with the controls (75.0 and 79.3% versus 45.8%; P < 0. 0001). A preponderance of GSTT1-negative subjects among patients was also detected, but did not appear significant. We suggest the involvement of both NAT2 and GSTM1 detoxification system genes in the pathogenesis of endometriosis and the possible impact of NAT2 gene polymorphism in the development of different forms of this disease.     

A DNA polymorphism at the angiotensin II type 1 receptor (AT1R) locus and myocardial infarction

Two hundred and thirty-five survivors of myocardial infarction (MI) were compared to 384 controls with respect to distribution of genotypes and gene frequencies in the A1166C polymorphism at the angiotensin II type 1 receptor (AT1R) locus. No differences in allele frequencies or genotype distribution were observed when all patients were compared with all controls. When comparing CC homozygotes with the combined group of CA heterozygotes and AA homozygotes (CA/AA), a difference in borderline significance between the MI group and controls was observed (p = 0.05). In males alone, this difference was much more pronounced because of the larger proportion of males with the CC genotype in MI cases than in male controls (p = 0.01). No significant differences were observed between female cases and controls. No interaction between the insertion/deletion (I/D) polymorphism at the angiotensin I-converting enzyme (ACE) locus and the polymorphism at the AT1R locus was detected. When subdividing the subjects into a "low-risk" and a "high-risk" group, based on levels of apolipoprotein B (apoB) and body mass index (BMI), and whether or not the person used lipid-lowering drugs, the frequency of CC homozygotes in male cases of the "low-risk" group differed significantly compared to the frequency in male controls of the "low-risk" group (p < 0.001). No differences were observed in females, but the number of "low-risk" group female cases was low (n = 3). Thus, CC homozygosity appears to be associated with MI in Norwegian males, especially among those with a "low-risk" phenotype.     

5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease

We first hypothesized in 2000 that a polymorphism of the human gene encoding the enzyme 5-lipoxygenase (5-LOX) might be associated with Alzheimer's disease. Only a little progress has been made in directly testing our proposal. However, additional important new data lead us to hypothesize that genetic variability not only in the 5-LOX gene, i.e., ALOX5, but also in polymorphism of the five-lipoxygenase activating protein (FLAP) gene, i.e., ALOX5AP, may be associated with Alzheimer's pathology. Studies in mice followed by several extensive clinical studies have identified ALOX5 and ALOX5AP polymorphisms as strong risk factors for atherosclerosis and cerebrovascular pathologies. New data point to a significant aggregation of vascular risk factors and risk of Alzheimer's disease. Preliminary findings in postmortem brain of Alzheimer's patients identified elevated 5-LOX immunostaining in this disease. We suggest that our hypothesis of a link between the ALOX5 and ALOX5AP gene polymorphisms and Alzheimer's disease could be tested in a clinical setting and in animal models, i.e., transgenic mice could be produced by crossing the available 5-LOX-deficient mice with the available transgenic mice models of Alzheimer's disease.     

No association between dinucleotide repeat polymorphism in intron 1 of the epidermal growth factor receptor gene EGFR and risk of lung cancer

The tyrosine kinase receptor EGFR pathway is one of the oncogenic signaling cascades involved in lung cancer, mediating the epidermal growth factor receptor gene EGFR. First-intron polymorphisms with greater numbers of CA dinucleotide repeats tend to downregulate EGFR expression, which suggests that this polymorphism may modulate susceptibility to lung cancer. The present hospital-based case-control study evaluated the possible association of CA repeat polymorphism in the EGFR gene with risk of lung cancer in a Korean population. A bimodal pattern appeared, with a frequency of 57.1% for 20 CA repeats and 18.6% for 16 CA repeats. There was, however, no significant difference in distribution of allele genotypes between all lung cancer cases and the controls, nor among histological types for the cases.     

Taq1B polymorphism of CETP gene on lipid abnormalities in patients with type II diabetes mellitus

The most common alterations in lipid and lipoprotein metabolism in type 2 diabetes involve an elevation in both plasma triglyceride and VLDL concentrations, a dense LDL phenotype and low levels of HDL cholesterol. The inverse relationship between the level of HDL cholesterol and the risk of cardiovascular disease is commonly explained by the crucial role of HDL in reverse cholesterol transport. Cholesterol ester transfer protein (CETP) has a central role in the metabolism of HDL and may therefore alter the susceptibility to atherosclerotic vascular disease. To evaluate the effect of Taq1B polymorphism of intron 1 of CETP gene on serum lipid concentrations in Turkish type 2 diabetic patients, we investigated Taq1B polymorphism and serum lipid levels in 116 controls and in 164 diabetic patients. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine the CETP Taq1B polymorphism. Serum lipid levels were measured enzymatically. Statistical analyses was performed by SPSS. In control group: subjects with B2B2 genotype have high HDL-cholesterol levels (p=0.029) and B1B1 genotypes have high triglyceride levels (p=0.07). Diabetic patients with and without MI with B2B2 genotype have high HDL-cholesterol levels. Taq B1B1 genotype has higher in diabetic patients with myocardial infarction (MI) than diabetic patients without myocardial infarction (42.1% and 32.7%; chi2=1.42, p=0.23). The present study demonstrates that the CETP Taq1B gene polymorphism is an association with low HDL cholesterol levels in patients with type II diabetes mellitus and healthy controls in Turkey. We also showed that CATE Taq1B gene polymorphism may be related to myocardial infarction in type II diabetic patients.     

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT)13, (GT)20, and (GT)24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14+ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P=0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14+ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats.     

Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients

In this study we examined a possible association between a 27 base pair (bp)-repeat polymorphism in intron 4 of the ecNOS gene and myocardial infarction (MI) in a subgroup of the Turkish population. We compared MI and control groups for the frequencies of the ecNOS alleles and their genotypes. The frequency of the ecNOS 4a/a and 4a/b genotypes was found to be significantly higher in the MI group than in the control group. Interestingly, the frequency of the ecNOS 4a/b polymorphism was found to be significantly higher in the selected MI group (patients with no known secondary risk factors) than in the control and non-selected MI group. We found that the patients with MI had the frequency of the a/a genotype 4.3%, of the a/b genotype 26.6% and the b/b genotype 69.1%. The controls, however, showed only 0.6% for a/a, 18.0% for a/b and 81.4% for the b/b genotype (P < 0.001; chi2 = 13.626). In this study, we show that myocardial infarction is associated with one subtype of ecNOS gene polymorphism.     

Addressing the link between paraoxonase-1 gene variants and the incidence of early onset myocardial infarction

Introduction

The enzyme paraoxonase-1 (PON1) represents an endogenous defense mechanism against vascular oxidative stress, thereby contributing to the prevention of atherosclerosis. Several polymorphisms have been reported in the PON1 gene, including Q192R. PON1 phenotype is commonly expressed as the paraoxonase/arylesterase ratio (PON/ARE). The major aim of this study was to investigate the association between PON1 Q192R polymorphism, PON1 phenotypes and the incidence of early-onset acute myocardial infarction (AMI) in Egyptians.

Material and methods

The study subjects consisted of 102 AMI patients and 72 age-matched healthy controls. Genotyping and enzyme activities were determined using PCR-RFLP and kinetic spectrophotometric assays, respectively.

Results

The genotype distribution for the PON1 gene was significantly different between AMI patients (QQ = 38.24%, QR = 49.02%, RR = 12.75%) and controls (QQ = 66.67%, QR = 25%, RR = 8.33%). Allele frequencies were also significantly different between patients (Q = 62.75%, R = 37.25%) and controls (Q = 79.17%, R = 20.83%). The genotypes QR and RR showed higher risk for AMI compared to the homozygous QQ (odds ratio (OR) = 3.231, p < 0.001). The average PON/ARE ratio in MI patients (1.187 ±0.1) did not differ significantly from controls (1.118 ±0.26). However, it showed a significant difference among different genotypes in both AMI patients (QQ = 0.91 ±0.11, QR = 1.09 ±0.11 and RR = 2.65 ±0.4) (p = 0.0002) and controls (QQ = 0.68 ±0.1, QR = 1.07 ±0.11 and RR = 4.89 ±2.84) (p < 0.0001).

Conclusions

PON1 192R allele represents an independent risk factor for early-onset AMI in Egyptians, and PON1 Q192R polymorphism modulates the paraoxonase phenotype.