Association of Polymorphic Marker A1/A2 of Gene ITGB3 with Coronary Artery Disease and Myocardial Infarction

The distributions of the alleles and genotypes of polymorphic marker A1/A2 of gene ITGB3 encoding the 3 subunit of integrin IIb3 in groups of patients with coronary artery disease (CAD), including those who have had myocardial infarction (MI), and in the control group have been compared. Analysis using Fisher's test has not revealed significant differences between these groups with respect to the distributions of the alleles and genotypes of polymorphic marker A1/A2 of gene ITGB3. This indicates that this polymorphic marker is not associated with either CAD or MI in the Moscow population.     

Association of polymorphic marker G(-455)A of gene FGB with coronary artery disease

Patients with coronary artery disease (CAD), including those who have had myocardial infarction (MI), and control subjects have been compared with respect to the distributions of the alleles and genotypes of polymorphic marker G(-455)A of gene FGB encoding the fibrinogen beta-chain. The groups studied do not differ significantly with respect to the distributions of G(-455)A alleles and genotypes. This indicates that this marker is not associated with CAD in the Moscow population. Allele A of the G(-455)A polymorphic marker has been found to be associated with an increased fibrinogen content of blood plasma in women with CAD.     

Association of Polymorphic Marker G(−455)A of Gene FGB with Coronary Artery Disease

Patients with coronary artery disease (CAD), including those who have had myocardial infarction (MI), and control subjects have been compared with respect to the distributions of the alleles and genotypes of polymorphic marker G(–455)A of gene FGB encoding the fibrinogen -chain. The groups studied do not differ significantly with respect to the distributions of G(–455)A alleles and genotypes. This indicates that this marker is not associated with CAD in the Moscow population. Allele A of the G(–455)A polymorphic marker has been found to be associated with an increased fibrinogen content of blood plasma in women with CAD.     

Polymorphic gene markers of lipid metabolism are associated with diabetic nephropathy in patients with type 1 diabetes mellitus

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and n = 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker epsilon2/epsilon3/epsilon4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele epsilon3 and genotype epsilon3/epsilon3 of the polymorphic marker epsilon2/epsilon3/epsilon4 of APOE gene as well as in the carriers of allele 1 and APOB genotype/gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.     

A search for association between the polymorphic markers of PON1 and PON2 genes and diabetic nephropathy in patients with type I diabetes mellitus

Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes (PON1 and PON2) encoding enzymes of the body antioxidative defense were compared in type 1 diabetes mellitus patients with or without diabetic nephropathy. The patients with nonoverlapping ("polar") phenotypes constituted different groups. The first group contained patients with diabetic nephropathy (DN+, n = 62), clinical proteinuria (albuminuria above 300 mg per day), and at least 15-year disease duration. In control group, the patients had no diabetic nephropathy (DN-, n = 68), their albuminuria was below 200 mg per day, and disease duration was at least 20 years. Comparative analysis with exact Fisher's test revealed no significant differences in frequencies of alleles and genotypes of the PON1 gene polymorphic marker Gln192Arg and of PON2 gene polymorphic markers Ala148Gly and Cys311Ser. Our results suggest that the polymorphic markers studied are not associated with diabetic nephropathy among Russian patients in Moscow.     

Association of polymorphisms in the chemokine receptor CX3CR1 gene with coronary artery disease

Two chemokine receptor CX3CR1 gene variants, V249I and T280M, have been implicated in coronary artery diseases (CAD). Currently no consistent effect has been revealed and their role in cardiovascular disease is still conflicting. In the present study the association of CX3CR1 genotypes with CAD and myocardial infarction (MI) was investigated in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, including 3316 individuals in whom cardiovascular disease angiographically has been defined or ruled out. Similarly to previous studies, the alleles I249 and M280 were in strong linkage disequilibrium and formed an I₂₄₉M₂₈₀ haplotype. However, there was no relationship between CX3CR1 genotypes or corresponding haplotypes and the prevalence of CAD or MI. Adjusted for classical risk factors (age, sex, hypertension, dyslipidemia, diabetes mellitus and smoking), the odds ratio (OR) of V249I for CAD was 0.95 (95% confidence interval (CI) = 0.78–1.15, p = 0.61). The OR of T280M for CAD was 0.83 (95% CI = 0.66–1.04, p = 0.11). Furthermore, CX3CR1 variants were not associated with C-reactive protein levels, age at onset of CAD, severity of CAD and MI. In conclusion, present data of LURIC do not support the hypothesis that common variants of the CX3CR1 gene are associated with the presence of CAD or MI.     

Haplotype-based case-control study of CYP4A11 gene and myocardial infarction

CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P 相似文献   

Large scale association analysis identifies three susceptibility loci for coronary artery disease

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.     

The use of microsatellites for detecting DNA polymorphism, genotype identification and genetic diversity in wheat

A set of 20 wheat microsatellite markers was used with 55 elite wheat genotypes to examine their utility (1) in detecting DNA polymorphism, (2)in the identifying genotypes and (3) in estimating genetic diversity among wheat genotypes. The 55 elite genotypes of wheat used in this study originated in 29 countries representing six continents. A total of 155 alleles were detected at 21 loci using the above microsatellite primer pairs (only 1 primer amplified 2 loci; all other primers amplified 1 locus each). Of the 20 primers amplifying 21 loci, 17 primers and their corresponding 18 loci were assigned to 13 different chromosomes (6 chromosomes of the A genome, 5 chromosomes of the B genome and 2 chromosomes of the D genome). The number of alleles per locus ranged from 1 to 13, with an average of 7.4 alleles per locus. The values of average polymorphic information content (PIC) and the marker index (MI) for these markers were estimated to be 0.71 and 0.70, respectively. The (GT)_n microsatellites were found to be the most polymorphic. The genetic similarity (GS) coefficient for all possible 1485 pairs of genotypes ranged from 0.05 to 0.88 with an average of 0.23. The dendrogram, prepared on the basis of similarity matrix using the UPGMA algorithm, delineated the above genotypes into two major clusters (I and II), each with two subclusters (Ia, Ib and IIa, IIb). One of these subclusters (Ib) consisted of a solitary genotype (E3111) from Portugal, so that it was unique and diverse with respect to all other genotypes belonging to cluster I and placed in subcluster Ia. Using a set of only 12 primer pairs, we were able to distinguish a maximum of 48 of the above 55 wheat genotypes. The results demonstrate the utility of microsatellite markers for detecting polymorphism leading to genotype identification and for estimating genetic diversity. Received: 15 May 1999 / Accepted: 27 July 1999     

Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility

Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.     

Combined effect of hemostatic gene polymorphisms and the risk of myocardial infarction in patients with advanced coronary atherosclerosis

Background

Relative little attention has been devoted until now to the combined effects of gene polymorphisms of the hemostatic pathway as risk factors for Myocardial Infarction (MI), the main thrombotic complication of Coronary Artery Disease (CAD). The aim of this study was to evaluate the combined effect of ten common prothrombotic polymorphisms as a determinant of MI.

Methodology/Principal Findings

We studied a total of 804 subjects, 489 of whom with angiographically proven severe CAD, with or without MI (n = 307; n = 182; respectively). An additive model considering ten common polymorphisms [Prothrombin 20210G>A, PAI-1 4G/5G, Fibrinogen β -455G>A, FV Leiden and “R2”, FVII -402G>A and -323 del/ins, Platelet ADP Receptor P2Y12 -744T>C, Platelet Glycoproteins Ia (873G>A), and IIIa (1565T>C)] was tested. The prevalence of MI increased linearly with an increasing number of unfavorable alleles (χ² for trend = 10.68; P = 0.001). In a multiple logistic regression model, the number of unfavorable alleles remained significantly associated with MI after adjustment for classical risk factors. As compared to subjects with 3-7 alleles, those with few (≤2) alleles had a decreased MI risk (OR 0.34, 95%CIs 0.13–0.93), while those with more (≥8) alleles had an increased MI risk (OR 2.49, 95%CIs 1.03–6.01). The number of procoagulant alleles correlated directly (r = 0.49, P = 0.006) with endogenous thrombin potential.

Conclusions

The combination of prothrombotic polymorphisms may help to predict MI in patients with advanced CAD.     

中国人COL2A1基因座的扩增片段长度多态性

用聚合酶链式反应、高分辨聚丙烯酰胺凝胶水平电泳及银染技术对位于人类Ⅱ型胶原基因终止密码下游非转录区１．３ｋｂ处的可主数目串联重复育列进行了研究。制备了由人类不同基因型ＤＮＡ混合而成的人类等位基因型参考物，根据实验结果进行了命名。     

Plasminogen activator inhibitor 1 (PAI-1) 1334G/A genetic polymorphism in colorectal cancer

Plasminogen activator inhibitor 1 (PAI-1) content in colorectal cancer tissue extracts may be of strong prognostic value: high levels of PAI-1 in tumours predict poor prognosis. The gene encoding PAI-1 is highly polymorphic and PAI-1 gene variability could contribute to the level of PAI-1 biosynthesis. In the present work the distribution of genotypes and frequency of alleles of the 1334G/A polymorphism in 92 subjects with colorectal cancer in samples of cancer tissue and distant mucosa samples as well as in blood were investigated. Blood samples age matched healthy individuals (n = 110) served as control. The 1334G/A polymorphism was determined by PCR amplification using allele specific primers. No differences in the genotype distributions and allele frequencies between blood, distant mucosa samples and cancer tissue were detected. However, the distribution of the genotypes of the 1334G/A polymorphism in patients differed significantly (P <0.05) from those predicted by the Hardy-Weinberg equilibrium. There were significant differences in the frequencies of alleles between the colorectal cancer subjects and controls (P <0.05). The results support the hypothesis that the 1334G/A polymorphism may be associated with the incidence of colorectal cancer.     

Identification of functionally significant mutations in NAT2 gene using biological microchips

The product of gene NAT2 (N-acetyltransferase 2) is involved in the biotransformation system and participates in detoxication of some arylamine derivatives (in particular 2-aminofluorene, 4-aminobiphenyl and 4-naphthylamine) which are strongly mutagenic and carcinogenic. It also renders toxicological and pharmacological influence on a metabolism of medical products metabolized by the enzyme. We developed a microchip for detection of 16 functionally significant mutations coding 36 alleles of gene NAT2. Combinations of these alleles allow us to reveal more than 660 genotypes, which can be divided into four groups according acetylation phenotype: "fast" (R/R), "intermediate" (R/S), "slow" (S/S) and group with average or slow acetylating (R/S or S/S) alleles. The groups "R/S or S/S" include alleles, formed by a combination of 7 mutations (191G/A, 282C/T, 341T/C, 481C/T, 590G/A, 803A/G, 857G/A), theirs cis-trans position can be revealed by restriction analysis. In 37 of 71 DNA samples we unequivocally defined NAT2-genotypes, and other 34 samples have been characterized by more than two genotypes. 16 samples out of 34 had acetylation phenotype of group "R/S or S/S", which is characterized by the following combination of mutations: 282C/T, 341T/C, 481C/T, 590G/A and 803A/G. Thus, the developed biochip is a convenient screening method for primary detection of the majority of polymorphic replacements in gene NAT2.     

Polymorphic Gene Markers of Lipid Metabolism Are Associated with Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker ε2/ε3/ε4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele ε3 and genotype ε3/ε3 of the polymorphic marker ε2/ε 3/ε4 of APOE gene as well as in the carriers of allele I and APOB genotype I/I gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.__________Translated from Genetika, Vol. 41, No. 7, 2005, pp. 931–937.Original Russian Text Copyright © 2005 by Yakunina, Shestakova, Voron’ko, Vikulova, Savost’yanov, Chugunova, Shamkhalova, Dedov, Nosikov.     

Gene IL6 G(-174)C and gene IL10 G(-1082)A polymorphisms are associated with unfavourable outcomes in patients with acute coronary syndrome

We investigated the association of gene IL6 G(-174)C polymorphism and gene IL10 G(-1082)A polymorphism with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St -Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 9.10 +/- 5.03 months (the maximum term 18 months). In case of gene IL10 G(-1082)A polymorphism we determined that patients with CAD diagnose and A alleles gene IL10 had unfavorable outcome more often than patients with homozygous G alleles. Survival time from end point from carrier genotype GA and AA is 11.68 +/- 0.67 months against 12.69 +/- 0.65 months from carrier phenotype GG gene IL10 (chi2 = 4.13, p = 0.042). The group studied do not differ significantly with respect to the distributions of gene IL6 G(-174)C alleles and genotypes. However in case combined group studies of gene IL10 G(-1082)A polymorphism and IL6 G(-174)C polymorphism we determined that patients with CAD diagnose and carrier genotype GG gene IL6 and genotype GA and AA gene IL10 had unfavorable outcome more often (survival time 11.01 +/- 1.24 months) than patients with genotype CC and CG gene IL6 and genotype GG gene IL10 (survival time 13.28 +/- 0.83 months) chi2 = 10.23, p = 0.017. The obtained data allows assuming the important role of the IL6 and IL10 genes which are responsible for functioning of inflammation system, in the accelerated formation of failures at the patients who had a coronary syndrome.     

Association of deoxyribonuclease I genetic polymorphisms with myocardial infarction in Han Chinese

Deoxyribonuclease I gene exhibits polymorphisms, including a single nucleotide polymorphism (A2317G) and a 56 bp variable number of tandem repeat, designated as HumDN1. G2317 was regarded as an independent risk factor for Japanese myocardial infarction (MI) patients. We investigated the association between either A2317G or HumDN1 polymorphism of deoxyribonuclease I gene and MI in Han Chinese population. A2317G and HumDN1 polymorphisms in 278 MI patients and 297 unrelated controls were detected by PCR and PCR-restriction fragment length polymorphism. Plasma lipids were measured in fasting state by biochemical methods. A new HumDN1 genotype -HumDN1 4/6 was found in Han Chinese MI patients. Genotype distributions and allele frequencies of A2317G and HumDN1 did not differ between MI patients and control group (all P > 0.05). In addition, none of estimated haplotypes significantly increased or decreased the risk of MI. In analysis of covariance, plasma total cholesterol was observed to be associated with HumDN1 genotypes in MI patients (P = 0.02). Our data suggest HumDN1 genotypes are related to total cholesterol levels in Han Chinese MI patients, but deoxyribonuclease I gene polymorphisms are not associated with susceptibility to MI in Han Chinese.     

A Search for Association between the Polymorphic Markers of <Emphasis Type="Italic">PON1</Emphasis> and <Emphasis Type="Italic">PON2</Emphasis> Genes and Diabetic Nephropathy in Patients with Type I Diabetes Mellitus

Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes (PON1 and PON2) encoding enzymes of the organism antioxidant defense were compared in type 1 diabetes mellitus patients with or without diabetic nephropathy. The patients with nonoverlapping (“polar”) phenotypes constituted different groups. The first group contained patients with diabetic nephropathy (DN+, n = 62), clinical proteinuria (albuminuria above 300 mg per day), and at least 15-year disease duration. In control group, the patients had no diabetic nephropathy (DN−, n = 68), their albuminuria was below 200 mg per day, and disease duration was at least 20 years. Comparative analysis with exact Fisher’s test revealed no significant differences in frequencies of alleles and genotypes of the PON1 gene polymorphic marker Gln192Arg and of PON2 gene polymorphic markers Ala148Gly and Cys311Ser. Our results suggest that the polymorphic markers studied are not associated with diabetic nephropathy among Russian patients in Moscow.__________Translated from Genetika, Vol. 41, No. 6, 2005, pp. 844–849.Original Russian Text Copyright © 2005 by Voron’ko, Yakunina, Shestakova, Zotova, Chugunova, Shamkhalova, Vikulova, Debabov, Dedov, Nosikov.     

Determinants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans.

Homocysteine (Hcy)-thiolactonase (HTase) activity of the paraoxonase-1 (PON1) protein detoxifies Hcy-thiolactone in human blood and could thus delay the development of atherosclerosis. To gain insight into physiological role(s) of the PON1 protein, we studied HTase activities and PON1 genotypes in a group of 184 subjects, 32.6% of whom were healthy, 27.7% had angiographically proven coronary artery disease but did not have myocardial infarction (CAD), and 39.7% had myocardial infarction (MI). We found that the hydrolytic activities of the serum PON1 protein towards Hcy-thiolactone and the organophosphate paraoxon substrates were strongly correlated. PON1-192-RR and PON1-55-LL genotypes were associated with high HTase activity. HTase activity was negatively correlated with age (beta = -0.135, p =0.002), plasma total Hcy (in 192-QR subjects only; r = -0.46, p = 0.001), and positively correlated with total cholesterol (beta = 0.169, p<0.001), but not with HDL cholesterol. Mean HTase activities were similar in CAD subjects, MI subjects, and in healthy controls. However, the frequency of the PON1-192-RR genotype tended to be lower in CAD subjects than in controls (2% vs 10.0%, p = 0.057) and higher in MI subjects that in CAD subjects (10.9% vs 2.0%, p = 0.001). The R-allele was marginally associated with CAD (26.7% in controls vs 17.6% in CAD, p = 0.146) and significantly associated with MI (17.6% in CAD vs 31.5% in MI, p = 0.018). Multiple regression analysis suggests that PON1 genotype, total Hcy, total cholesterol, and age are major determinants of HTase activity in humans.