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The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma.

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy+/-surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Genetic polymorphism of the alpha 2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans.

It is likely that a number of independent heritable traits, each encoded by a singular gene, contribute to pathologic elevations in blood pressure in humans. Genetic polymorphisms of individual genes may result in intermediate phenotypes which, by themselves, do not raise blood pressure, but, coupled with environmental or epistatic forces, contribute to the prevalence of human hypertension. The gene for the alpha 2-adrenergic receptor encoded by chromosome 10 (C10 A2AR) is polymorphic, and Southern blotting with a cDNA probe following restriction enzyme digest of this gene results in fragments of either 6.3 kb or 6.7 kb in size. We reported an association between homozygosity for the 6.3 kb allele and hypertension in blacks. Blacks with hypertension also have an increased risk for thrombotic stroke, increased baroreceptor sensitivity, and decreased sodium excretion. We noted that the C10 A2AR, which modulates norepinephrine release in blood-pressure-regulating regions of the brain, is also expressed on platelets and in the kidney. We postulated that functional changes associated with the C10 A2AR gene polymorphism could be responsible for increased baroreceptor sensitivity, epinephrine-mediated platelet aggregation, and decreased sodium excretion in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

Urinary PAH metabolites influenced by genetic polymorphisms of GSTM1 in male hospital incinerator workers.

Hospital waste incinerator workers are exposed to various pyrolysis products including polycyclic aromatic hydrocarbons (PAHs). We evaluated their exposure by assessing urinary 1-hydroxypyrene glucuronide (1-OHPG), as an internal dose of PAH exposure. The potential effect of genetic polymorphisms of GSTM1/T1 involved in PAH metabolisms was also investigated. Pre- and post-shift samples were collected from 28 hospital incinerator workers. Urinary 1-OHPG was assayed by synchronous fluorescence spectroscopy (SFS) after immunoaffinity purification with the monoclonal antibody 8E11. Genotypes of GSTM1/T1 were assessed by PCR-based methods. Information on smoking habits and use of personal protective equipment were collected by means of a self-administered questionnaire. The Mann-Whitney test was used to compare group means of these biomarkers. Urinary 1-OHPG levels were similar in pre- and post-shift urine samples. The arithmetic mean concentrations of urinary 1-OHPG were 0.16 +/- 0.04 micromol/mol creatinine pre-shift and 0.19 +/- 0.09 micromol/mol creatinine post-shift, but urinary 1-OHPG levels were significantly higher in individuals with the GSTM1 null genotype than with the GSTM1 present genotype (p=0.05, by Mann-Whitney test). Our results suggest that the urinary 1-OHPG levels in hospital waste incinerator workers may be modified by the GSTM1 genotype, but these findings remain to be confirmed in future studies involving larger sample sizes.

Adult↗

Genetic polymorphism of IgG in the mink. IV. Identification and genetic control of L3 allotype of the light chains.

A new allotype of the mink light chains, designated L3, was identified. This allotype is inherited as a Mendelian character at a frequency of 0.46 in the mink population. Data were obtained indicating that L3 is independent of the C gamma-heavy chain allotypes of mink immunoglobulins. The gene L3 is closely linked to a gene encoding L1, another light chain allotype. Alloantigens L1 and L3 are presumably markers of the light chains of two different subtypes. In contrast to L1, which occurs in many mammalian species, L3 is species-specific, i.e., it is a case of light chain polymorphism representative of the whole mink species.

Animals↗

[Relationship between genetic polymorphisms of metabolizing enzymes and prostate cancer].

OBJECTIVES: To study the possible relationship between CYP1A1, NAT2 genetic polymorphisms and the susceptibility of prostate cancer. METHODS: Forty-eight patients with prostate cancer and 112 healthy cases were selected as the control randomly. NAT2 and CYP1A1 gene polymorphisms were analysed with the methods of PCR-RFLP, ASA and real-time fluorescence Light-Cycler. The difference of frequency between the patients and the controls was compared. RESULTS: Among prostate cancer patients and their matched controls, the frequencies of alleles and genotypes were significantly different with Ile-Val gene Polymorphisms (P < 0.05), in which the frequency of the allele G and GG genotypes were significantly higher than those in their matched controls with an odds ratio of 1.59 and 3.06(P < 0.05), respectively; No significant differences of the frequencies of the MspI alleles and genotypes were found between the patients with prostate cancer and the matched controls(P > 0.05). No significant differences of NAT2 slow acetylator genotype frequency were found between the controls and prostate cancer patients (P > 0.05). CONCLUSIONS: The CYP1A1 Ile-Val gene polymorphisms might be associated with the occurrence of prostate cancer, while MspI gene polymorphisms and NAT2 slow acetylator genotype might not be associated with the occurrence of prostate cancer.

Adult↗

Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism.

Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine-derived 6-thioguanine nucleotides (6-TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6-TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine-induced myelosuppression.

Adult↗

Response of parathyroid glands to calcitriol in culture: Is this response mediated by the genetic polymorphisms in vitamin D receptor?

BACKGROUND: Recently, we have developed a model of parathyroid tissue culture that allows the study of the response of the parathyroid glands to long-term effectors, such as calcitriol, and that is also useful to study the likely effect of the genetic polymorphisms in the functionality of the glands. The aim of this study was to evaluate the response to calcitriol of cultured parathyroid tissue from patients with secondary hyperparathyroidism (HPT) and the possible effect of vitamin D receptor (VDR) gene polymorphisms on this response. METHODS: Parathyroid glands (N = 37) from 34 parathyroidectomized patients (17 men, 17 women) were used. Several gland fragments were cultured for 60 hours in the presence of calcitriol 10(-9) mol/L or 10(-8) mol/L. DNA from each fragment was extracted to normalize the hormone secretion levels and to genotype the restriction sites ApaI, BsmI, TaqI, and FokI in the VDR gene. RESULTS: The percentages of secretion observed in the response to calcitriol were: 69%+/- 28% (range, 3-100) and 46%+/- 19% (range, 8-78) for calcitriol 10(-9) mol/L and 10(-8) mol/L, respectively (P = 0.004). None of the polymorphisms showed statistical differences in response to calcitriol with any of the concentrations used. CONCLUSION: Parathyroid glands cultured in vitro from patients with secondary HPT are able to respond to calcitriol decreasing PTH synthesis. These results, however, do not support the current hypothesis that VDR polymorphisms are involved in the modulation of the parathyroid gland response.

Adult↗

Genetic polymorphism H131R of Fcgamma receptor type IIA (FcgammaRIIA) in a healthy Finnish population and in patients with or without platelet-associated IgG.

Patients (n=113) with histories of thrombocytopenia and with different profiles for platelet-associated IgG (PA-IgG) were subdivided according to the genetic polymorphism H131R in the Fcgamma receptor type IIA (FcgammaRIIA). PA-IgG was measured by the direct platelet immunofluorescence test (PIFT), and GP IIbIIIa and/or GP Ib-specific PA-IgG was investigated by a modified version of the direct monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. As a control, the distribution of FcgammaRIIA polymorphism H131R was determined among 93 healthy Finnish blood donors. The frequencies for H131 and R131 were 0.56 and 0.44 (CI: 0.37-0.51), respectively, which did not differ significantly from those in other Caucasian populations. The distribution of the genotypes HH131, HR131 and RR131 in the patients and controls did not differ significantly. In the HH131 group, the PA-IgG was higher than in the RR131 group (p=0.082). Female patients with the genotype RR131 seemed to be younger than those with HH131 (p=0.065). Among the female patients, a significantly greater number were under 40 yr old in the RR131 group than in the HH131 group (p=0.0060). Within the RR131 group, the female patients were far younger than the male patients (median 29 vs. 61 yr; p=0.0021). The results point to the heterogeneity of immune thrombocytopenia, which may partly explain the poor predictive value of PA-IgG studies.

Adult↗

Role of genetic polymorphism in the SA gene on the blood pressure and prognosis of renal function in patients with immunoglobulin A nephropathy.

The SA gene has been shown to be much more highly expressed in the kidneys of spontaneously hypertensive rats than in the corresponding wild-type strain. Genetic polymorphism of this gene has been shown to play a role in human hypertension, although the details of this association remain controversial. We investigated the possible associations between SA gene polymorphism and both hypertension and the prognosis of renal function in patients with immunoglobulin A nephropathy (IgAN). Genomic DNA was isolated from the peripheral blood of 367 individuals, including 274 patients with histologically proven IgAN and 100 controls without any history of renal disease. The SA genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) with Pst I. The frequencies of genotypes and alleles were not different between the patients with IgAN and those without renal disease. In the group without renal disease, the SA gene polymorphism was not associated with hypertension. However, in the patients with IgAN the A1 allele frequency was significantly higher in the hypertensives than in the normotensives. The renal survival of the patients with the A2 allele tended to be better than that of those without the A2 allele. The findings thus suggest that SA gene polymorphism may be associated with the renal prognosis of IgAN through its effect on blood pressure. Further, they suggest that the sensitivity to this gene polymorphism increases in patients with renal injury.

Aged↗

Chromosomal aberrations in workers exposed to low levels of benzene: association with genetic polymorphisms.

Benzene and its metabolites damage human lymphocytes, resulting in chromosomal aberrations and aneuploidy. Polymorphisms in the genes for benzene-metabolizing enzymes have been implicated in benzene-associated haematotoxicity. In this study, we examined the specificity of benzene-induced aneuploidy and the influence of genetic polymorphisms (GSTM1, GSTT1, GSTP1, NAT2, NQO1 and CYP2E1) on chromosomal aberrations. In total, 82 benzene-exposed workers from a coke oven plant and 76 matched controls were examined. The benzene concentration in the work-place air ranged from 0.014-0.743 p.p.m. (geometric mean 0.557 p.p.m.). Benzene exposure was associated with significant increases in both monosomy and trisomy of chromosomes 8 and 21. Translocations between chromosomes 8 and 21 [t(8:21)] were eight-fold more frequent in the high-level exposure group compared to the control group. Multiple regression analysis indicated that the frequencies of chromosome aberrations were significantly associated with benzene exposure and polymorphisms in the metabolic enzyme genes. A particular subset of genotypes, which included the GSTM1-null and GSTT1-null genotypes, the slow acetylator type of NAT2, a variant of the NQO1 genotype and the CYP2E1 DraI and RsaI genotypes, were either separately, or in combination, associated with increased frequencies of aneuploidy among the benzene-exposed individuals after adjustments for age, alcohol consumption and smoking. These results suggest that polymorphisms in the genes for benzene-metabolizing enzymes influence the susceptibility of individuals to chromosomal aberrations in relation to benzene exposure.

Aneuploidy↗

[A study on genetic polymorphism of rRNA gene pattern of Vibrio cholerae O139 in China].

OBJECTIVE: To investigated the genetic polymorphism of the isolated strains using ribotyping method. METHODS: One hundred twenty-two strains of V. cholerae O139 isolated from different areas of China from 1993 to 1999 were selected and characterized with ribotyping, including 16s rDNA and 23s rDNA probes. RESULTS: One hundred twenty-two strains were differentiated into 10 different ribotypes (RT1-RT10) on the basis of rRNA gene probes hybridization (with Bgl I digestion), which consisted of 7 - 9 bands between 12 and 1.5 kb in size. RT1 and RT3, as two predominant ribotypes, comprised most number of the strains which spread to the extensive range. Nine strains, which are negative to ctxAB, zot and RS individually, belong to 4 special ribotypes. The dendrogram revealing genetic relationship among different clones of V. cholerae O139 showed that the clones belonging to RT1 and RT2 had genetic similarity on high degree, although they were isolated from different regions. The two predominant ribotypes (RT1 and RT3) were distant in genetic relationship. CONCLUSION: Results showed the clonal diversity and the wide area distribution of V. cholerae O139 strains in China, suggesting the multiple origins of O139 epidemics.

Phylogeny↗

Genetic polymorphism of the sixth component (C6) of rat complement.

The complement protein C6 has been shown to be genetically polymorphic in the rat. Isoelectric focusing of plasma samples from 19 inbred strains demonstrated two electrophoretically distinguishable migration patterns, each consisting of three bands. Breeding studies with the use of the BN and DA strains showed that the C6 patterns were inherited in a manner consistent with the co-dominant autosomal expression of two alleles (C6 A and C6 B). The distribution of the C6 alleles in a backcross mating was compared with eight independently segregating marker genes: RT1.A, RT2, Gdc -1, Igk-1, Hbb, Svp-1, Fh-1, and Es-6. There was no detectable linkage between C6 and any of these eight loci.

Animals↗

High degree of genetic polymorphism in apolipoprotein(a) associated with plasma lipoprotein(a) levels in Japanese and Chinese populations.

We have developed a sensitive, high-resolutin method for the analysis of the apolipoprotein(a) [apo(a)] isoforms using sodium dodecyl sulfate (SDS)-agarose/gradient polyacrylamide gel electrophoresis. In an analysis of the genetic polymorphism of apo(a) isoforms and their relationship with plasma lipoprotein(a) [Lp(a)] levels in Japanese and Chinese, this method identified 25 different apo(a) isoforms and detected one or two apo(a) isoforms in more than 99.5% of the individuals tested. The apparent molecular weights of the apo(a) isoforms ranged from 370 kDa to 950 kDa, and 22 of the 25 different apo(a) isoforms had a higher molecular weight than of apo B-100. Studies on Japanese families confirmed the autosomal codominant segregation of apo(a) isoforms and the existence of a null allele at the apo(a) locus. The observed frequency distribution of apo(a) isoform phenotypes fit the expectations of the Hardy-Weinberg equilibrium in both the Japanese and Chinese populations. Our data indicate the existence of at least 26 alleles, including a null allele, at the apo(a) locus. The frequency distribution patterns of the apo(a) isoform alleles in Japanese and Chinese were similar to each other and also similar to that of apo(a) gene sizes reported in Caucasian American individuals. The average heterozygosity at the apo(a) locus was 92% in Japanese and 93% in Chinese. A highly significant inverse correlation was observed between plasma Lp(a) levels and the size of apo(a) isoforms in both the Japanese (r = 0.677, P = 0.0001) and the Chinese (r = -0.703, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

Genetic polymorphism of MHC class III and GLO in Chinese Yao nationality.

Yao nationality is one of the minority nationalities living mainly in South China (Guangxi Province). The purpose of this study was to provide data of MHC class III and GLO in Chinese Yao nationality and the different genetic background of Yao and Han nationality, the latter representing the major nationality in China. The genetic polymorphism of MHC class III and GLO in Chinese Yao nationality was determined. Previously the Japanese were considered to have the lowest C2*C frequencies (0.9386), but now we ascertained that the Yao have the lowest C2*C frequencies (0.9336). The data concerning gene frequencies of Yao are presented. They were also compared with the available data of Han.

China↗

[Genetic polymorphism of steroidogenic enzymes and steroid receptor level in tumors of the reproductive system].

The strategy of therapy and prognosis of reproductive system neoplasia generally depend on the steroid receptor status of tumor. The causes of formation of steroid receptor-free tumors are to be investigated. The genetic polymorphism of CYP19 (aromatase), CYP17 (17-hydroxylase; 17,20-lyase), CYP1B1 (4-estrogen hydroxylase) and COMT (catechol-O-methyl transferase) was studied in a total of 254 patients with breast and endometrial cancer, with particular reference to the association of certain polymorphisms and receptor status of tumor. It was found that the lack of estrogen receptor (ER) in breast tumor was due to a deficit in the A3A6 allele (p(0.01), while the absence of progesterone receptors was associated with a lower incidence of the A1A1 and A1A2 variants (p = 0.022) of tetranucleotide repeats in the CYP19 gene. In the same patients, receptor-negative tumors occurred more often (p = 0.032) than in combinations of higher level of 4-hydroxylase estradiol of S-allele in position 48 (Gly/Arg) of the CYP1B1 gene. Moreover, endometrial carcinoma patients tended to reveal (p = 0.058) an increased ratio of A6A7-CYP19 to allele A1-containing variant. No other distinctions between R(+) and R(-) tumors were identified. It is suggested that peculiar polymorphisms of steroidogenic enzymes may moderately influence the genesis of R(-) neoplasms which may be associated with either the rate of estrogen biosynthesis or, as in the case of CYP1B1, with formation of genotoxic derivatives of estrogens. The latter point is to be investigated further.

Adult↗

Cytokines, their genetic polymorphisms, and outcome after abdominal aortic aneurysm repair.

BACKGROUND: Excessive cytokine production has been implicated in the development of organ failure. Polymorphic sites in cytokine genes have been shown to affect levels of production in vitro and may influence cytokine production in vivo. The aims of this study were to determine if cytokines or their genetic polymorphisms were related to outcome after abdominal aortic aneurysm (AAA) repair. METHODS: A prospective study of 135 patients undergoing open AAA repair. Plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-10 were measured 24 h post-operatively and genotypes for the TNF-alpha -308, IL-1beta+3953, IL-6 -174, IL-10 -1082 and IL-10 -592 polymorphisms were determined for each patient. RESULTS: After elective AAA high levels of IL-10 were associated with both prolonged critical care (P<0.001) and hospital stay (P=0.001). The presence of a G allele at the IL-6 -174 locus was associated with a higher incidence of organ failure (P=0.04) and an A allele at TNF-alpha -308 with prolonged critical care stay (P=0.03). After ruptured AAA the development of multi-organ failure was associated with high levels of IL-6 (P=0.01) and TNF-alpha (P=0.04). High TNF-alpha levels were also associated with mortality (P=0.01). CONCLUSION: Post-operative cytokine levels are related to outcome after AAA repair. Cytokine gene polymorphisms may provide a method for determining which patients are at high risk of complications.

Aged↗

Genetic polymorphism of thiopurine S-methyltransferase in Argentina.

BACKGROUND: Thiopurine methyltransferase (TPMT) catalyses the S-methylation of 6-thiopurine drugs, which are commonly used in the treatment of autoimmune diseases, leukaemia and organ transplantation. TPMT activity is polymorphic as a result of gene mutations. Ethnic variations in phenotype and genotype have been identified in previous population studies, but no information was available within Latin-American populations. AIM: To establish the genetic polymorphism of TPMT in an Argentine population. METHODS: TPMT enzymatic activity of 147 healthy Argentine subjects was measured using a high-performance liquid chromatography method. The genotyping assay for nine defective alleles (TPMT*2 - *8) was based on restriction fragment length polymorphism polymerase chain reaction and allele-specific polymerase chain reaction methods. RESULTS: All subjects had detectable TPMT activity. Twelve individuals with low to intermediate activity were heterozygous for one of the mutant alleles: nine were TPMT*1/*3A, two TPMT*1/*2 and one TPMT*1/*4. All examined subjects with normal activity had wild-type genotype (TPMT*1/*1). CONCLUSION: Variant TPMT alleles were present in 8.2% of the examined subjects, which is in accordance with other studies. The frequency of TPMT*3A, TPMT*2 and TPMT*4 was 3.1%, 0.7% and 0.3%, respectively. TPMT*3A was the most prevalent allele, which is in accordance with results from Caucasian populations. This study provides the first analysis of TPMT activity and allele frequency distribution in Argentina, South America.

Adolescent↗

Effects of genetic polymorphisms of metabolic enzymes on cytokinesis-block micronucleus in peripheral blood lymphocyte among coke-oven workers.

Exploring the associations between genetic polymorphisms of metabolic enzymes and susceptibility to polycyclic aromatic hydrocarbon (PAH)-induced chromosomal damage is of great significance for understanding PAH carcinogenesis. Cytochrome P450, glutathione S-transferase, microsomal epoxide hydrolase, NAD(P)H:quinone oxidoreductase, and N-acetyltransferase are PAH-metabolizing enzymes. In this study, we genotyped for the polymorphisms of these genes and assessed their effects on cytokinesis-block micronucleus (CBMN) frequencies in peripheral blood lymphocytes among 141 coke-oven workers and 66 non-coke-oven worker controls. The geometric means of urinary 1-hydroxypyrene levels in coke-oven workers and the controls were 12.0 and 0.7 micromol/mol creatinine, respectively (P < 0.01). The CBMN frequency (number of micronuclei per 1,000 binucleated lymphocytes) was significantly higher in coke-oven workers (9.5 +/- 6.6 per thousand) than in the controls (4.0 +/- 3.6 per thousand; P < 0.01). Among the coke-oven workers, age was positively associated with CBMN frequency; the mEH His113 variant genotype exhibited significantly lower CBMN frequency (8.5 +/- 6.5 per thousand) than did the Tyr113/Tyr113 genotype (11.3 +/- 6.4 per thousand; P < 0.01); the low mEH activity phenotype exhibited a lower CBMN frequency (8.6 +/- 6.8 per thousand) than did the high mEH activity phenotype (13.2 +/- 6.7 per thousand; P = 0.01); the GSTP1 Val105/Val105 genotype exhibited a higher CBMN frequency (15.0 +/- 5.8 per thousand) than did the GSTP1 Ile105/Ile105 or Ile105/Val105 genotypes (9.3 +/- 6.5 per thousand; P < 0.01); the joint effect of high mEH activity phenotype and GSTM1 null genotype on CBMN frequencies was also found. Gene-environment interactions between occupational PAH exposure and polymorphisms of mEH and/or GSTM1 were also evident. These results indicate that the mEH, GSTP1, and GSTM1 polymorphisms may play a role in sensitivity or genetic susceptibility to the genotoxic effects of PAH exposure in the coke-oven workers.

Acyltransferases↗