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At least 433 records · Page 24Linked to original sources
PubMed2003

The role of -850 tumor necrosis factor-alpha and apolipoprotein E genetic polymorphism in patients with Down's syndrome-related dementia.

Down's syndrome (DS) is a disease with a complex etiology. It is likely that other factors besides genes located on chromosome 21 may play a role in clinical features of affected patients. Tumor necrosis factor-alpha (TNF-alpha) (6p21.3) and apolipoprotein E (APOE) (19q13.2) are candidate genes as they interact with the brain deposition of Abeta, one of the neuropathological hallmarks in DS. We examined 136 DS patients and 113 controls for -850 TNF-alpha and APOE polymorphisms. The -850T frequency in DS was significantly higher than in controls (P<0.005, OR 2.05, 95% CI 1.22-3.49) while the APOE E4 allele was negatively selected in patients compared to normal subjects (P<0.005, OR 0.38, 95% CI 0.20-0.71). Our findings suggest that the -850T allele, which is more common among patients at high risk of dementia such as those with DS, might eventually play a role in the development of dementia; no inference on the role of the allele APOE E4 in DS-related dementia may be derived from our results.

Adolescent↗
PubMed2004

Meta-analyses of the association between genetic polymorphisms of neurotrophic factors and schizophrenia.

Based on the neurodevelopmental hypothesis of schizophrenia, neurotrophic factors (NTFs) may be involved in its pathogenesis. Previous association studies between schizophrenia and neurotrophic factors have shown inconsistent results, which might be due to the heterogeneity and small sample size of the studies. To reach a conclusive understanding of the association, we used a meta-analytic method to study the association of schizophrenia with the polymorphisms in two candidate genes, ciliary neurotrophic factor (CNTF) and neurotrophin 3 (NT3). In our study, two meta-analyses were performed. One included eight studies examining the association of schizophrenia with the A3 allele in a dinucleotide repeat polymorphism of the NT3 gene promoter (N=1938). The other was employed in nine studies examining the association with a null mutation of the CNTF gene (N=2393). Neither of these analyses provided evidence for association. However, our sub-analyses showed a trend of association between the NT3 polymorphism and schizophrenics in Japanese, as well as an association between the CNTF null mutation and schizophrenics without psychiatric family history. These results suggested that the variations at the NT3 and the CNTF genes do not influence the schizophrenia risk, but a role in the susceptibility of subgroups of the patients cannot be excluded.

Alleles↗
PubMed2004

Genetic polymorphisms and activity of PON1 in a Mexican population.

Human paraoxonase (PON1) plays a role in detoxification of organophosphorus (OP) compounds by hydrolyzing the bioactive oxons, and in reducing oxidative low-density lipoproteins, which may protect against atherosclerosis. Some PON1 polymorphisms have been found to be responsible for variations in catalytic activity and expression and have been associated with susceptibility to OP poisoning and vascular diseases. Both situations are of public health relevance in Mexico. Therefore, the aim of this study was to evaluate PON1 phenotype and the frequencies of polymorphisms PON1 -162, -108, 55, and 192 in a Mexican population. The studied population consisted of unrelated individuals (n = 214) of either gender, 18-52 years old. Serum PON1 activity was assayed using phenylacetate and paraoxon as substrates. PON1 variants, -162, 55, and 192, were determined by real-time PCR using the TaqMan System, and PON1 -108 genotype by PCR-RFLP. We found a wide interindividual variability of PON1 activity with a unimodal distribution; the range of enzymatic activity toward phenylacetate was 84.72 to 422.0 U/mL, and 88.37 to 1645.6 U/L toward paraoxon. All four PON1 polymorphisms showed strong linkage disequilibrium (D% >90). PON1 polymorphisms -108, 55, and 192 were independently associated with arylesterase activity; whereas the activity toward paraoxon was related only with PON1 192 polymorphism, suggesting that this polymorphism is determinant to infer PON1 activity. A better understanding of the phenotype and genotypes of PON1 in Mexican populations will facilitate further epidemiological studies involving PON1 variability in OP poisoning and in the development of atherosclerosis.

Adult↗
PubMed2006

Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel.

INTRODUCTION: There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel. MATERIALS AND METHODS: Patients (n=120) undergoing percutaneous coronary intervention who received aspirin for > or =1 week but not clopidogrel were included. Blood samples were drawn at baseline and 20-24h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or =70% and 0.5 mg/mL arachidonic acid-induced aggregation > or =20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or =10% in response to 5 and 20 microM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y(12) gene and the 1622A>G polymorphism of the P2Y(1) gene were genotyped by polymerase chain reaction. RESULTS: There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2) carriers (P=0.065). CONCLUSIONS: We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y(12) or P2Y(1) and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations.

Aged↗
PubMed2005

Association of the genetic polymorphisms of the renin-angiotensin system with kidney graft long-term outcome: preliminary results.

Recent studies have demonstrated some association between the renin-angiotensin system (RAS) activity and the development and progression of different entities as diabetes mellitus (DM) or chronic allograft nephropathy. To investigate these associations, we studied some gene polymorphisms of RAS in a group of renal transplant recipients. We retrospectively analyzed 42 patients who underwent a primary renal transplantation for 2 years. A subgroup of 23 patients (55%) was diagnosed with postransplant DM in accordance with American Diabetes Association 2001 criteria. We studied two RAS gene polymorphisms: the angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen (AGTM235T). Genotyping was performed by DNA purification and amplification with a polymerase chain reaction technique. The distributions of genotypes were ACE DD, ID, II: 33%, 48%, 19%; and AGT TT, MT, MM: 15%, 45%, 40%, respectively. We observed a progressive loss in renal function measured by creatinine clearance (Cockroft) in D-allele carriers (DD+ID) between the first and the second transplantation year: 65.3 +/- 4.3 vs 59.8 +/- 4.6 mL/min (P = 0.02); that was not seen in II patients: 68.8 +/- 4.6 vs 68.4 +/- 4 mL/min (P = 0.87). Fifty percent of D-allele carriers developed DM vs 25% of non-D-allele carriers (P = 0.19). Eighty-three percent of homozygous patients for the AGT-TT allele developed DM vs 35% of non TT patients (P = 0.04). There were no significant differences regarding recipient demographic characteristics, type of donor, number and severity of acute rejections, and immunosuppressant treatment between the groups. In conclusion, ACE D-allele seems to be associated with a poorer kidney graft long-term outcome. ACE D and AGT T alleles may be implicated in glucose metabolism disorders after transplantation.

DNA↗
PubMed2004

Genetic polymorphisms of GSTM1, p21, p53 and HPV infection with cervical cancer in Korean women.

OBJECTIVES: The aim of this study was to determine whether GSTM1 or GSTT1 might be associated with risk of cervical cancer development in Korean women. The multiplicative interaction of GSTM1 and GSTT1 genotype with p21, p53 polymorphism, and HPV genotype was also investigated. METHODS: From 1997 to 1999, uterine cervical carcinoma was diagnosed in 215 Korean women at the Department of Obstetrics and Gynecology of Seoul National University Hospital. None of the women in the control groups (n = 98) had any evidence of cervical lesions, which were confirmed by Pap smear. Finally, 81 cases and 86 controls were genotyped for p21, p53, and GSTM1 and T1 and HPV infection. A multiplex PCR method was used for the genotyping of GSTM1 and GSTT1; direct sequencing for p53 codon 72, high-risk HPV, and PCR-RFLP (BsmAI) for p21 codon. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. RESULTS: Although the GSTM1 and GSTT1 genotype was not significantly associated with cervical cancer development for all women, the GSTM1 null genotype was significantly associated with an increased risk of cervical cancer development in women with high-risk HPV infection (OR = 2.9, 95% CI: 1.0-8.2). Although the frequency of overall GSTT1 null genotype was significantly lower in cervical carcinoma patients with high-risk HPV infection (OR = 0.3, 95% CI: 0.1-1.0), almost 2-fold increased risk was observed among women with GSTT1 null and Arg/Arg genotype (OR = 1.9, 95% CI: 0.7-5.4). Although the cervical cancer risk was 3.3-fold increased in women with null and Arg/Arg genotype compared to women with GSTM1 present and p21 Ser-containing genotype, there was no significant multiplicative interaction between GSTM1 and p21 (P for interaction = 0.785) or p53 (P for interaction = 0.815). CONCLUSIONS: These findings suggest that the risk of cervical cancer may be related to GSTM1 genotype in women with high-risk HPV infection and that there is a possible gene-gene interaction in the incidence of cervical cancer.

Female↗
PubMed1998

Platelet glycoprotein IIb/IIIa genetic polymorphism is associated with plasma fibrinogen levels in myocardial infarction patients. The REGICOR Investigators.

Fibrinogen is the major ligand of platelet glycoprotein IIb/IIIa platelet receptor. Genes coding for platelet fibrinogen receptor glycoprotein IIb/IIIa are polymorphic. The PLA alloantigen has two antigenic determinants, PLA1 and PLA2, located in a 17-23 kD fragment of glycoprotein IIIa. We analyzed whether PLA genotype has any effect on plasma fibrinogen concentration and investigated if the effect has different magnitude in myocardial infarction patients compared with subjects free of angina or myocardial infarction. One hundred sixteen consecutive patients who suffered a myocardial infarction and 136 subjects recruited by random sampling from the local census were included in the study. PLA genotype distribution and allele frequencies in patients did not significantly differ from those in the control group. Mean fibrinogen concentration tended to be higher in controls with genotype PLA1PLA1 than in those with genotype PLA1PLA2 or PLA2PLA2, and in patients this difference reached statistical significance (p < 0.001). We conclude that the PLA polymorphism may be in linkage disequilibrium with another functional mutation in or near the promoter area of the fibrinogen gene or even in another gene, which controls the production or the clearance of fibrinogen.

Chi-Square Distribution↗
PubMed1996

Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism.

Steady-state serum concentration to dose ratios of the neuroleptic agent perphenazine were related to CYP2D6 metabolizer status for 96 psychiatric inpatients: 88 extensive metabolizers and eight poor metabolizers. The median concentration per dose of the poor metabolizer group (0.195 nmol/L per milligram) was about twice the median (0.098 nmol/L per milligram) of the 56 extensive metabolizers without interacting medicine (p < 0.01). The rest of the extensive metabolizers (n = 32), who were comedicated with drugs that compete with perphenazine for metabolism by CYP2D6, had an intermediate median value of 0.140 nmol/L per milligram. The range of concentration/dose values for the total extensive metabolizer group extended from 0.025 to 0.688 nmol/L per milligram, that is, an almost thirtyfold variation. The concentration/dose range of the eight poor metabolizer subjects was 0.096 to 0.750 nmol/L per milligram. Serum levels not corrected for dose overlapped to a large degree among the groups, with a total range from 0.5 to 12 nmol/L. This study points toward a limited information value of CYP2D6 genotyping in the context of therapeutic drug monitoring of perphenazine.

Adolescent↗
PubMed1998

Genetic polymorphism of the hepatic cytochrome P450 2C19 in north Indian subjects.

One hundred unrelated healthy North Indian subjects were phenotyped with respect to their ability to metabolize omeprazole to 5-hydroxyomeprazole. Each volunteer was requested to ingest 20 mg (57.9 mumol) omeprazole. Urine was collected for a period of 8 hours and the amount of 5-hydroxyomeprazole excreted was estimated by HPLC. Histogram, probit, and normal test variable plots showed the antimode value for the log hydroxylation index of omeprazole to be 1.7. Of 100 North Indian subjects, 11 demonstrated log hydroxylation index values more than 1.7. Thus it is inferred that the frequency of occurrence of poor metabolizers of omeprazole in North Indian subjects is 11% (95% confidence interval, 5% to 17%). From the Hardy-Weinberg Law it was computed that the frequency of occurrence of the mutant allele of hepatic CYP2C19 in the North Indian subjects was 0.33.

Adult↗
PubMed1998

In search of a biological pattern for human longevity: impact of apo A-IV genetic polymorphisms on lipoproteins and the hyper-Lp(a) in centenarians.

We studied centenarians to investigate the biological basis of human longevity focusing on the apolipoprotein A-IV and lipoprotein(a), potentially involved in the susceptibility to atherogenic mechanisms. We analyzed two restriction polymorphisms, HinfI347 (alleles +, -) and Fnu4HI360 (alleles 1, 2), and a VNTR (alleles 3, 4) at the 3' region of the apo A-IV gene. The allele frequencies, the lipoprotein concentrations and their association in centenarians and adults have been compared. In centenarians, the HinfI genotype distribution is different (P < 0.05) and the (+13) haplotype is prevalent (0.54 vs. 0.39), with a greater association of (+3), indicating the selection of a favourable allele. The lipoprotein modulation by the apo A-IV polymorphisms is suggested by significant associations in adults ((+/+) homozygotes have lower LDL-cholesterol and apo B than heterozygotes; (1/1) homozygotes have higher TG and apo B than heterozygotes), that in centenarians still exists as a trend. Centenarians show peculiar lipoprotein features: lower LDL-cholesterol (mean 103 vs. 115 mg/dl; P < 0.02), and higher lipoprotein(a) (median 17.5 vs. 4.5; P < 0.002). Large part of them (47%), especially the Hinf(+/+) and the (+13) homozygotes, have a lipoprotein(a) > 20 mg/dl, value considered as the threshold for atherogenic risk, surprisingly compatible with healthy longevity.

Adult↗
PubMed2000

Genetic polymorphism of heparan sulfate proteoglycan (perlecan, HSPG2), lipid profiles and coronary artery disease in the Australian population.

Perlecan is one of the three major classes of heparan sulfate proteoglycans (HSPGs) within the cardiovascular system; it interacts with lipid metabolism by binding to lipoprotein lipase (LpL) and apolipoprotein B (apo B) and may be related to vascular disease. We explored interactions between an HSPG2 polymorphism (BamHI marker), and apo B and coronary artery disease (CAD) in patients undergoing coronary angiography. The frequencies of the HSPG2 BamHI +/+, +/-, and -/- genotypes were 4.7, 31.7 and 63.6%, respectively, with a '+' allele frequency of 20.6%. The genotype distribution was in Hardy-Weinberg equilibrium (chi(2)=0.669, P0.05). The +/+homozygotes had the lowest apo B levels (0.74+/-0.06 g/l, n=36) compared to +/- (0.89+/-0.03 g/l, n=241) and -/- (0.93+/-0.02 g/l, n=480) genotypes. Although plasma apo B concentration was the strongest lipid risk factor for significant CAD, the HSPG2 genotypes were not independently associated with the presence of CAD (P=0.640 in males; P=0.224 in females), with significant CAD (P=0.764; P=0.110) or with the number of significantly stenosed coronary arteries (P=0.945; P=0. 335). In Australian Caucasians undergoing coronary angiography the HSPG2 BamHI polymorphism is associated with lower circulating apo B but not with the occurrence or severity of CAD. This may be due to HSPG2-mediated alterations in the HSPG2-apo B-LpL system and requires further exploration.

Australia↗
PubMed2001

A new multiplex PCR strategy for the simultaneous determination of four genetic polymorphisms affecting HIV-1 disease progression.

The CCR5 Delta32, CCR2 64I, SDF1 3'A, and CCR5 promoter 59029 polymorphisms have been suggested to influence HIV-1 disease progression. Furthermore, the CCR5 Delta32 and the CCR2 64I polymorphisms have been associated with various other diseases. The purpose of the present study was to develop a multiplex assay for the simultaneous determination of these four polymorphisms. Results obtained with the multiplex assay were compared to results obtained by conventional RFLP-PCR and no differences were observed. The multiplex assay offers a quick tool for the determination of the CCR5 Delta32, CCR2 64I, SDF1 3'A, and CCR5 promoter 59029 A/G polymorphisms.

Chemokine CXCL12↗
PubMed1990

Functional consequences of the genetic polymorphism of the third component of complement.

The third component of complement, the central protein of the complement cascade, occurs in two principal allotypes, C3S and C3F. An excess frequency of the F allotype has been implicated in a number of disease states, including some forms of glomerulonephritis. These associations have been explained by functional differences between C3S and C3F. We examined several complement functions, using purified preparations of C3S or C3F. The C3S allotype was 1.3 times more efficient than C3F in a hemolytic assay employing sensitized sheep erythrocytes; this difference was shown to arise from a slightly more efficient deposition of C3F on the cell surface. These differences are trivial and of much less magnitude than the functional differences between C4A and C4B. There were no differences between allotypes in their ability to be converted to inactive C3b (C3bi) by complement factors H and I or by CR1 and factor I. No significant differences were seen between the allotypes and their ability to support solubilization of preformed immune complexes.

Animals↗
PubMed2000

[Aplasia after azathioprine administration: role of the thiopurine methyltransferase genetic polymorphism].

BACKGROUND: Azathioprine is an immunosuppressor drug widely used in the treatment of autoimmune diseases. Adverse effects during treatment are related to the activity of thiopurine methyltransferase (TPMT), an enzyme which plays a role in azathioprine metabolism. The presence of the allelic variants of the TPMT gene allows us to classify patients into three different groups: high, moderate and low risk of myelosuppression after receiving standard doses of azathioprine. PATIENTS AND METHODS: Study of the allelic variants of the TPMT gene in the positions 460 and 719 with PCR methods in a patient with Crohn's disease, who developed aplasia after receiving azathioprine. The study was extended to his relatives. RESULTS: The patient under study carried the most frequent variant allele of the TPMT gene associated with low enzymatic activity. The mother and one sister of the patient were also carriers of this allelic variant. CONCLUSIONS: Genotyping the allelic variants of the TPMT gene is a useful method to identify patients at moderate or high risk of myelosuppression after administration of azathioprine.

Adult↗
PubMed2001

Association between genetic polymorphisms and biomarkers in styrene-exposed workers.

A comprehensive approach to evaluate genotoxic effects induced by styrene exposure was employed in 44 hand-lamination workers in comparison with 18 unexposed controls. The acquired data on single-strand breaks in DNA (SSBs), frequency of chromosomal aberrations and HPRT mutant frequency in peripheral blood lymphocytes were compared to the results on genotyping of some of the xenobiotic-metabolising enzymes (CYP1A1, CYP2E1, epoxide hydrolase and GSTM1, GSTP1 and GSTT1). Multifactorial regression analysis indicated that SSB in DNA were significantly associated with styrene exposure and with heterozygosity in CYP2E1 (5'-flanking region and intron 6; r(2)=0.614). The frequency of chromosomal aberrations (CA), as analysed by linear multiple regression analysis, significantly correlated with years of employment (P=0.004) and with combinations of epoxide hydrolase (EPHX) genotypes (exon 3, Tyr/His and exon 4, His/Arg), where individuals with low and medium activity EPHX genotypes exhibited higher frequencies of CA than those with high activity genotypes (P=0.044, r(2)=0.563). Moderately higher HPRT mutant frequencies were detected in styrene-exposed individuals (20.2 +/- 25.8 x 10(-6)) as compared to controls (13.3 +/- 6.3 x 10(-6)), but this difference was not significant. ANOVA (in the whole set of data) revealed that mutant frequencies at the HPRT gene were significantly associated with years of employment (F=6.9, P=0.0001), styrene in blood (F=10.1, P=0.0001), and heterozygosity in CYP2E1 (intron 6; F=13.5, P=0.0008) and GSTP1 (exon 5; F=3.6, P=0.038). In conclusion, our present data suggest that analysed biomarkers of DNA damage may be modulated by polymorphic CYP2E1, EPHX and GSTP1. In our study, styrene-specific DNA and haemoglobin adducts are under investigation. Completing these data with the results of genotyping of metabolising enzymes may provide a useful tool for individual genotoxic risk assessment.

Adult↗