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PubMed2005

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. METHODS: DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects. RESULTS: Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA. CONCLUSIONS: These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease. CLINICAL RELEVANCE: Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.

Aortic Aneurysm, Abdominal↗

PubMed2005

DNA polymorphisms and haplotypes in the 5'-upstream region of the ABO blood group gene.

We investigated the polymorphisms in the 5'-upstream region between nucleotide position (nt) -9600 and nt-4105 of the ABO blood group gene using PCR and direct sequencing methods. We found 16 single nucleotide polymorphisms, two insertion-deletion polymorphisms and two sequence polymorphisms. One of the insertion-deletion polymorphisms was found at nts from -9605 to -9204, and the alleles of that locus were named ABORR*L (non-deletion) and ABORR*S (52-base-deletion). There were two haplotypes constructed from 14 polymorphisms in the region between nt-9600 and nt-7565; they were tentatively named ABORR*L-associated and ABORR*S-associated haplotypes. The ABORR*L-associated haplotype may link with ABO*O(A) (also known as ABO*O201), and the ABORR*S-associated haplotype links with the other common alleles. This indicates the existence of two major lineages of the Japanese ABO alleles in the 5'-upstream region from nt-7565. In contrast to these findings, we observed six haplotypes in the region between nt-6371 and nt-4105, and we assume that the sequence in that region is variable as compared with those in the other 5'-upstream regions. We examined the generation of two sequence polymorphisms found in the present study. In the both cases, the formation of a hairpin loop caused by palindrome in a single-stranded DNA molecule may play an important role in generating the polymorphism.

5' Flanking Region↗

PubMed2006

Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence.

The paper focuses on such candidate gene polymorphisms that alter alcoholism-related intermediate phenotypes including: dopaminergic system polymorphic variants (DRD2 -141C Ins/Del in promoter region, exon 8 and DRD2 TaqI A and DAT 40bp VNTR genes polymorphisms) that cause predisposition to severe alcoholism (haplotype Ins/G/A2); COMT Val158Met gene polymorphism related to differences in executive cognitive function and 5-HTT gene promoter polymorphism, which alters stress response and affects anxiety and dysphoria. The transmission disequilibrium test (TDT) was used in the study. One hundred Polish families with alcohol dependence were recruited. The control subjects for the case-control study were 196 ethnically and gender matched healthy individuals. It was found that DRD2 TaqIA and DAT gene polymorphisms contained statistically significant differences in allele transmission. In the homogenous subgroups of patients with early onset and with withdrawal complications a statistically significant preferential A2 allele transmission was found in DRD2 TaqIA gene polymorphism. The alleles and genotypes distribution of the investigated polymorphisms did not differ significantly between the alcoholics and the controls in the case-control study. The results confirmed the fact that the candidate genes (DRD2 and DAT) are partially responsible for the development of alcohol dependence. The results are also in agreement with the hypothesis that there are various subtypes of alcohol dependence, which differ depending on their genetic background. Meanwhile, the currently available pharmacological therapies for alcoholism treatment are effective in some alcoholics but not for all of them. Some progress has been made in elucidating pharmacogenomic responses to drugs, particularly in the context of Clonninger and Lesch typology classification system for alcoholics.

Adult↗

PubMed2005

The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy.

Genetic factors could be implicated in the pathogenesis of severe diabetic retinopathy (DR). Recently, we reported a strong association between the eNOS4b/a endothelial nitric oxide synthase (eNOS) polymorphism and severe DR. To examine whether T-786C and C774T eNOS polymorphisms are involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped. The distribution of T-786C and C774T eNOS polymorphisms was in Hardy-Weinberg equilibrium and did not differ between the study and control groups. However, in case patients (n=126), T-786C and C774T polymorphisms influenced the onset pattern of severe DR (P=0.0169 and P=0.0257, respectively). The C-786C genotype was associated with early-onset severe DR (duration of diabetes: 15.2+/-5.9 vs. 19.4+/-6.3 years, P=0.0105), and the homozygous T774T genotype was associated with late-onset severe DR (24.3+/-7.0 vs. 18.4+/-6.2 years, P=0.0067). In the case of patients with high glycosylated hemoglobin levels (HbA1c >8%, n=88), the association between the T-786C polymorphism and early-onset severe DR was stronger (P=0.0068). Case patients carrying the C-786C genotype had higher HbA1c values (9.61+/-1.89%) than those carrying the T-786T genotype (8.93+/-1.47%, P=0.0173). Multivariate analysis showed that T-786C polymorphism was the best independent factor for onset pattern of severe DR (P<0.001). These findings, supported by previous associations between eNOS4b/a polymorphism and DR, suggest that T-786C and C774T eNOS polymorphisms affect the onset pattern of severe DR.

Adult↗

PubMed2004

Polymorphisms affecting gene regulation and mRNA processing: broad implications for pharmacogenetics.

Functional polymorphisms that alter gene expression and mRNA processing appear to play a critical role in shaping human phenotypic variability. Intensive studies on polymorphisms affecting drug response have revealed multiple modes of altered gene function, frequently involving cis-acting regulatory sequence variants. Experimental and in silico methods have advanced the search for such polymorphisms, but considerable challenges remain. Here, a survey of polymorphisms in drug-related genes indicates that: (a) a substantial proportion of genetic variability still remains unaccounted for; (b) a majority of these genes harbors known regulatory polymorphisms; and (c) a portion of polymorphisms affect splicing and mRNA turnover. Pharmacogenetic optimiziation of individual drug therapy may require a complete understanding of all functional sequence variants in key genes. This review surveys known noncoding polymorphisms in genes encoding cytochrome P450s and other drug-metabolizing enzymes, drug transporters, and drug targets and receptors. Current methods and challenges associated with the identification and characterization of functional polymorphisms are also discussed.

Animals↗

PubMed2005

Glucocorticoid receptor polymorphisms and post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity. Two common glucocorticoid receptor (GR) polymorphisms (N363S and BclI) appear to contribute to the population variance in GC sensitivity. There is some evidence that there may be a genetic predisposition to PTSD. Hence we studied 118 Vietnam war veterans with PTSD for (i) GR polymorphisms, particularly the N363S and the BclI polymorphisms which are thought to be GC sensitising, and (ii) two measures of GC sensitivity, the low-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5+/-19.2 nmol/L, N=75) and controls (348.6+/-23.0 nmol/L, N=33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6+/-3.2 vs. 40.8+/-4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the BclI GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls (945+/-122, N=106 vs. 730+/-236, N=28, P=0.42). PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S. Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the BclI polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores. In conclusion, the N363S and BclI GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the BclI GG genotype, CAPS scores and basal cortisol levels were negatively correlated.

Adult↗

PubMed2006

Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease.

INTRODUCTION: Endothelium-derived nitric oxide (NO) is synthesized from l-arginine by endothelial nitric oxide synthase (eNOS) encoded by the eNOS3 gene on chromosome 7. The effects of the eNOS polymorphisms with the risk of coronary artery disease are conflicting. In this study, we investigated the association of the eNOS genotypes with coronary artery disease in Koreans. MATERIALS AND METHODS: A case-control study was performed to evaluate the association between the eNOS -786T>C, 4a4b, or 894G>T polymorphism and coronary artery disease. 147 consecutive patients with coronary artery disease and 222 healthy controls were recruited. The genotypes of eNOS -786T>C and 894G>T polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes of a 27 bp insertion/deletion in intron 4 (eNOS 4a4b) were determined by the banding pattern on gel electrophoresis. RESULTS: The eNOS -786T>C (odds ratio [OR]; 1.61, 95% confidence interval [CI]; 0.97-2.69), 894G>T (OR; 1.12, 95% CI; 0.65-1.92) and 4a4b (OR; 1.44, 95% CI; 0.87-2.39) polymorphisms were not an independent predisposition factor to coronary artery disease. However, a subgroup analysis adjusted with various cardiovascular risk factors confirmed positive association of the -786T>C polymorphism in CAD patients with hypertension and a smoking history and also a significant association of the intron 4 genotypes with a smoking history, but no significance has been found in the eNOS polymorphisms of 894G>T upon any risk adjustment. In this study we also found that the distribution of heterozygotes (-786TC, 894GT, and 4a4b) and variant homozygotes for the -786C, 894T, and intron 4a alleles of eNOS in Koreans were significantly lower than in Caucasian populations. CONCLUSIONS: The present study demonstrates that polymorphisms of the eNOS -786T>C and 4a4b are associated with coronary artery disease with adjustments for cardiovascular risk factors in the Koreans.

Case-Control Studies↗

PubMed2005

A case-control study of methylenetetrahydrofolate reductase polymorphisms in cervical carcinogenesis.

OBJECTIVES: Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are thought to be associated with a varying risk of cervical dysplasia. The purpose of this trial was to study the role of the two common functional MHTFR polymorphisms in a large multiracial population at risk for cervical dysplasia and cancer. METHODS: This is a nested case-control study of 376 subjects obtained from cohorts enrolled in an ongoing prospective cervical carcinogenesis protocol. Cases included invasive cancers (n = 51), and high (n = 50) and low (n = 50) grade dysplasia. There were 225 normal controls. Functional MTHFR 677C-->T and 1298A-->C genotypes were identified. Follow-up cytology data were reviewed for the control subjects from the time of study entry until August 2004. RESULTS: There is a significant racial difference in allele frequency of the 677C-->T polymorphism (P < 0.005). African-American women had an extremely low prevalence of the 677T allele (8%). There was no significant difference in the frequency of the 677T allele between cases and controls. There is no racial difference in allele frequency of the 1298A-->C polymorphism. Also, no significant difference was found between cases and controls. Of the 51 cancers, no case was homozygous for both aberrant polymorphisms (677T, 1298C), and only 3 cases were heterozygous for both. Follow-up data were available for 129 of 225 control subjects (57%). Only 15 (12%) have had a subsequent abnormal pap, and there was no association with the 677C-->T polymorphism. CONCLUSIONS: We confirm a significant difference in the 677T allele frequencies among racial groups. However, there is no association of either the 677C-->T or 1298A-->C polymorphisms in cervical carcinogenesis. There is no role of the combined polymorphism effect in cervical cancer or evidence of prediction for future Pap abnormalities.

Adolescent↗

PubMed2002

Detection of polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the microsomal epoxide hydrolase gene using fluorescence PCR method combined with melting curves analysis.

An association between exon 3 polymorphisms of the gene encoding microsomal epoxide hydrolase (mEH) and susceptibility to the development of chronic obstructive pulmonary disease (COPD) has been described. We have developed two methods for detecting polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the mEH gene based on different melting temperatures (T(m)) of fluorescent-labeled oligonucleotide hybridization probes using single-step assays that combine fluorescence PCR and melting curve analysis (LightCycler methodology). DNA was extracted from blood in 79 COPD patients and 146 healthy controls. Results were compared with those obtained by restriction fragment length polymorphism (RFLP) analysis to detect Tyr113His variants and a single-strand conformation polymorphism (SSCP) assay for His139Arg detection. The T(m) of the exon 3 polymorphisms were 61.3 degrees C for Tyr113 (wild type) and 67.5 degrees C for His113 (mutant). The T(m) values of the exon 4 polymorphisms were 67.5 degrees C for His139 (wild type) and 59.2 degrees C for Arg139 (mutant). The within- and between-run melting peaks for the same allele differed by less than 0.5 degrees C for both the exon 3 and the exon 4 polymorphisms. Thus, melting analysis allowed easy and unambiguous assignment of genotyping by means of the respective melting curves. The proportion of individuals who were homozygous mutant for exon 3 was significantly higher in the COPD group than in the control group (p=0.004). LightCycler fluorescence genotyping of exon 4 polymorphisms correlated perfectly with SSCP results. RFLP assay classified 2 patients as homozygous mutant while LightCycler analysis genotyped them as heterozygous. DNA analysis by PCR and sequencing confirmed the LightCycler result. These high-speed (about 40 min for 32 samples), highly sensitive, and specific small-volume assays with low labor requirements hold great promise as tools for rapid detection of COPD susceptibility.

Adult↗

PubMed2002

Differential effect of two common polymorphisms in the cholesteryl ester transfer protein gene on low-density lipoprotein particle size.

This study was performed to determine the relationship between the two common polymorphisms of cholesteryl ester transfer protein (CETP) gene and LDL size in Japanese individuals. The LDL size was determined by gradient gel electrophoresis in 136 patients undergoing routine check-ups. The presence of two polymorphisms (I405V and Taq1B) was determined using PCR-based methods. The VV genotype for the I405V polymorphism was associated with both a lower plasma CETP concentration and a higher plasma HDL-C concentration. Further, the LDL size in patients with the VV genotype was significantly smaller than that in patients with the II+IV genotype (26.0 +/- 0.8 vs. 26.3 +/- 0.7 nm, P<0.05). Although the B2B2 genotype for the Taq1B polymorphism was also associated with both a lower plasma CETP concentration and a higher plasma HDL-C concentration, it had no effect on the LDL size (26.2 +/- 0.7 vs. 26.3 +/- 0.8 nm, P=0.73). Stepwise multiple regression analysis revealed that the VV genotype, as well as plasma TG concentration, age, HbA1c concentration, and BMI, were determinants of LDL size, while no significant relationships were seen between any of the Taq1B polymorphisms and LDL size. These data suggest that the I405V polymorphism but not the Taq1B polymorphism may be responsible for the distribution of LDL size. This may explain the differential effects of these two polymorphisms on the risk of CHD.

Adult↗

PubMed1998

The codon 55 polymorphism in the paraoxonase 1 gene is not associated with the risk of coronary heart disease in Asian Indians and Chinese.

Recently several but not all studies have implicated the codon 192 polymorphism in the paraoxonase 1 (PON1) gene with the risk of coronary heart disease (CHD). These findings suggest that this polymorphism is not functional but rather may be in linkage disequilibrium with a functional mutation in the PON1 or a nearby gene. In this investigation, we have evaluated the role of another common polymorphism in the PON1 gene at codon 55 with the risk of CHD in a biracial sample of Asian Indians and Chinese. We observed a significant inter-racial variability in the allelic distribution as the frequency of the less common allele, codon 55/L, was significantly higher in Indians than Chinese (0.202 versus 0.036; P < 0.0001). However, despite this inter-racial difference the codon 55 polymorphism was neither associated with CHD risk nor with plasma lipoprotein-lipids variation in both racial groups. We also used two site haplotype data (codons 55 and 192) to assess the combined contribution of the two polymorphisms to the risk of CHD. There was a strong linkage disequilibrium between the two polymorphic sites in both racial groups (P < 0.0001). While the haplotype data revealed no association with CHD in Chinese, the frequency of the BL haplotype was significantly higher (0.430 versus 0.311; P = 0.004) and the frequency of the AL haplotype was significantly lower (0.368 versus 0.483; P = 0.006) in Indian patients than controls. Since the B allele of the codon 192 polymorphism was shown to be an independent risk factor for CHD in Indians in our previous study, the positive association of the BL haplotype with CHD appears to be mediated by the B allele with no independent contribution from the codon 55 polymorphism.

Adult↗

PubMed2006

A systematic review of vitamin D receptor gene polymorphisms and prostate cancer risk.

PURPOSE: Polymorphisms in the vitamin D receptor gene have been hypothesized to alter the risk of prostate cancer. However, studies investigating the associations between specific vitamin D receptor polymorphisms and prostate cancer risk have yielded inconsistent results. MATERIALS AND METHODS: We performed a meta-analysis of 26 studies evaluating the association between vitamin D receptor TaqI, poly(A), BsmI, ApaI, and/or FokI polymorphisms, and prostate cancer risk. RESULTS: The studies were heterogeneous in terms of study design, selection of cases and controls, and racial composition. Random effects models were used to estimate the pooled OR and 95% CI of each vitamin D receptor polymorphism under codominant, additive, dominant and recessive genetic models. Overall we did not find evidence to support an association between any of the vitamin D receptor polymorphisms and the risk of prostate cancer. For TaqI, which is the most studied vitamin D receptor polymorphism with 18 studies (total of 2,727 cases and 3,685 controls), the pooled OR was 1.00 (95% CI 0.85 to 1.18) for the Tt vs TT genotypes, 0.94 (95% CI 0.78 to 1.13) for the tt vs TT genotypes and 0.89 (95% CI 0.71 to 1.10) for the recessive model (tt vs Tt plus TT). ORs for the poly(A) microsatellite, BsmI, ApaI and FokI polymorphisms were similar. CONCLUSIONS: The results of this meta-analysis suggest that the vitamin D receptor TaqI, poly(A), BsmI, ApaI and FokI polymorphisms are not related to prostate cancer risk.

Humans↗

PubMed2001

Influence of polymorphisms of the human glutathione transferases and cytochrome P450 2E1 enzyme on the metabolism and toxicity of ethylene oxide and acrylonitrile.

A cohort of 59 persons with industrial handling of low levels of acrylonitrile is being studied as part of a medical surveillance programme. Previously, an extended haemoglobin adduct monitoring (N-(cyanoethyl)valine and N-(hydroxyethyl)-valine) was performed regarding the glutathione transferases hGSTM1 and hGSTT1 polymorphisms but no influence of hGSTM1 or hGSTT1 polymorphisms on specific adduct levels was found. A compilation of case reports of human accidental poisonings had pointed to significant individual differences in human acrylonitrile metabolism and toxicity. Therefore, a re-evaluation of the industrial cohort included known polymorphisms of the glutathione transferases hGSTM3 and hGSTP1 as well as of the cytochrome P450 CYP2E1. A detailed statistical analysis revealed that exposed carriers of the allelic variants of hGSTP1, hGSTP1*B/hGSTP1*C, characterized by a single nucleotide polymorphism at nucleotide 313 which results in a change from Ile to Val at codon 104, had higher levels of the acrylonitrile-specific haemoglobin adduct N-(cyanoethyl)valine compared to the carriers of the codon 113 alleles hGSTP1*A and hGSTP1*D. The single nucleotide polymorphism at codon 113 of hGSTP1 (hGSTP1*A/hGSTP1*B versus hGSTP1*C/hGSTP1*D) did not show an effect, and also no influence was seen on specific haemoglobin adduct levels of the polymorphisms of hGSTM3 or CYP2E1. The data, therefore, point to a possible influence of a human enzyme polymorphism of the GSTP1 gene at codon 104 on the detoxication of acrylonitrile which calls for experimental toxicological investigation. The study also confirmed the impact of GSTT1 polymorphism on background N-(hydroxyethyl)-valine adduct levels in haemoglobin which are caused by endogenous ethylene oxide.

Acrylonitrile↗

PubMed1997

Polymorphisms in the p53 gene in thyroid tumours and blood samples of children from areas in Belarus.

We present changes in the p53 gene in a group of 70 thyroid tumours and 40 blood samples obtained from children from Belarus. Three thyroid tumours show a polymorphism in exon 6 (codon 213) and 5 tumours show a polymorphism in intron 6, 37 bp upstream to the 5'-end of exon 7. Only one patient has a mutation in exon 7 (codon 258) resulting in an amino acid substitution in the protein p53. The distribution of polymorphisms in the 40 blood samples was as follows: three patients had a polymorphism in exon 6 and two persons had a polymorphism in intron 6. One polymorphism in intron 6 was also found in the group of 30 healthy children from Belarus. The fact that the differences in the sequence in p53 found in the tumours was also seen in the blood of these patients demonstrates that they are polymorphisms not induced by radiation exposure. It is difficult to conclude, if the polymorphisms found by us could be associated with the predisposition to radiation-induced cancer.

Adolescent↗

PubMed2001

The Sma I polymorphism in the von Willebrand factor gene associated with acute ischemic stroke.

The von Willebrand factor (vWF) is a highly multimerized glycoprotein that promotes platelet adhesion and aggregation at a high shear rate, and also acts as a carrier of coagulation factor VIII. vWF has been identified as a risk factor for recurrent myocardial infarction in the general population. It has been reported that two polymorphisms of vWF gene promoter and the Thr789Ala polymorphism in vWF gene are associated with arterial thrombosis. The Sma I polymorphism is located in intron 2 of vWF gene. The relevance of this polymorphism to thrombotic disease was investigated by genotypic identification in two case-control studies: 107 patients with acute ischemic stroke, 49 patients with acute myocardial infarction (AMI), and 113 health controls age- and race-matched for each patient. Twenty-eight (26.2%) of the 107 patients with acute ischemic stroke, 8 (16.3%) of 49 patients with AMI, and 11 (9.7%) of 113 controls were found to be homozygous for CC genotype, respectively. The prevalence of the CC genotype in acute ischemic stroke was significantly higher than that of the normal controls (odds ratio [OR]=3.29, 95% confidence interval [CI]=1.54-7.01,.01>P>.001). However, the prevalence of the CC genotype in AMI was not significantly different from that of the normal controls (OR=1.81, 95% CI=0.68-4.82,.30>P>.20). Plasma vWF:Ag was also determined by enzyme-linked immunosorbent assay (ELISA) on the frozen plasma of 122 subjects. The mean plasma vWF:Ag levels of the controls, patients with acute ischemic stroke, and AMI were 0.468, 0.584, and 0.783 U/ml, respectively. The mean level of plasma vWF:Ag did not differ significantly between controls and patients with acute ischemic stroke (P=.195), but had significantly difference between controls and patients with AMI (P=.001). No association was found between the Sma I polymorphism and vWF plasma levels in controls, patients with acute ischemic stroke, or the AMI group (one-way ANOVA, P=.323, P=.315, P=.96). Results show that the Sma I polymorphism is strongly associated with increased risk of acute ischemic stroke, however, no association was observed between this polymorphism and AMI. This polymorphism of vWF may represent a newly identified risk factor for acute ischemic stroke in Chinese. Whether it is the real functional variant associated with acute ischemic stroke remains to be elucidated.

Acute Disease↗

PubMed1996

A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis.

Plasma plasminogen activator inhibitor-1 (PAI-1) level was observed to be associated with sequence variations at the PAI-1 locus. Therefore, PAI-1 gene promoter was screened for possibly new polymorphisms and to investigate the contribution of these sequence variations to PAI-1 levels in patients with deep vein thrombosis (DVT). DNA was isolated from blood of 83 consecutive unrelated patients (42 +/- 11 years old) and from 50 apparently healthy subjects of similar age and gender distribution. Six fragments covering DNA sequence- 1523 base pairs (bp) upstream from the start of PAI-1 gene transcription to +90 bp in the first exon, were amplified by polymerase chain reaction and analyzed by single-strand conformation polymorphisms. Two polymorphisms were found: a previously described 4G/5G deletion/insertion polymorphism -675bp upstream from the start of transcription and a novel G/A single base substitution polymorphism further upstream at -844 bp. The two polymorphisms were in strong linkage disequilibrium. Significant differences between patients and controls were observed neither for the frequencies of the 4G/5G alleles (0.60/0.40 and 0.59/0.41, respectively) nor for the frequencies of the G/A alleles (0.33/0.67 and 0.41/0.59, respectively). The distribution of both polymorphisms was similar in idiopathic and secondary DVT as well as in first and recurrent DVT. In patients association between the 4G/5G genotypes and PAI activity was observed, with the highest values in the 4G/4G genotype (13.3 U/mL), median values in the 4G/5G genotype (9.8 U/mL) and the lowest values in the 5G/5G genotype (2.0 U/mL). Despite the lack of association between the G/A genotypes and plasma PAI-1 levels, electrophoretic mobility shift assay showed specific binding of a nuclear protein from human vascular endothelial cells extracts to both the G and the A variant, suggesting functional importance of this novel G/A polymorphism in regulating the expression of PAI-1 gene.

Adult↗

PubMed2000

PCR-detected genome polymorphism in malignant cell growth.

In this chapter, we analyze the problem of genetic polymorphism in tumorigenesis, which determines basic capacities of tumors. The study of genome polymorphism with modified PCR methods allows the detection of various forms of polymorphism in tumor cells. This method has made it possible to determine association of DNA polymorphism with conditions of oncogenes, antioncogenes, and genes of apoptosis and with their allelic states. A special type of nonspecific DNA polymorphism that resulted from an increase in the mutation number in the cancer cell genome was discovered. This phenomenon was called the microsatellite mutator phenotype. Because the type of DNA polymorphism correlates with various biological capacities of malignant tumors and has an important prognostic significance, the analysis of DNA polymorphism in benign and malignant tumors of different histogenesis will play an important role both in theoretical studies of cancer and in oncological practice. A modified B1-PCR was used to study the genome polymorphism in the mouse tumor cells. The gain of the band 470 bp and the loss of the band 600 bp were revealed in the hepatoma cell line MH-22a as compared with liver cells of C3HA mice. The differentiation of teratocarcinoma EC F9 cells to endoderm-like cells was not accompanied by any changes in the B1-AF DNA fingerprint.

Animals↗

PubMed1998

Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers.

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated the possible relationships between DNA polymorphisms in the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) genes and CSF concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). The DAT polymorphism was not significantly associated with any of the monoamine metabolites, but a tendency for relationship with 5-HIAA was found in women. For both of the two SERT polymorphisms investigated, a functional promoter polymorphism and an intronic polymorphism without known function, significant relationships were found with CSF MHPG levels. No relationship was found between the SERT polymorphisms and CSF HVA and 5-HIAA. The NET polymorphism was associated with CSF MHPG levels but not HVA and 5-HIAA concentrations. The results suggest that SERT and NET genotypes may participate differentially in the regulation of the norepinephrine turnover rate under presumed steady-state conditions in the central nervous system. As only limited data so far indicate interactions between the serotonin and norepinephrine systems in the brain, and the NET polymorphism investigated is not known to be of functional significance, the results should be interpreted with caution until replicated.

Adult↗