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PubMed2004

[New anti-cytokine strategy against patients with hypercytokinemia stratified by cytokine-related genetic polymorphisms].

The effects of genomic variability on susceptibility to not only hereditary diseases but also to common diseases and on the responsiveness to drugs have been demonstrated. Moreover, the effects of genetic polymorphism on the severity and outcome of critical illness which is caused by hypercytokinemia have been evaluated. We have measured cytokine blood levels in order to evaluate the severity of critical illness and efficacy of our treatment in clinical settings. We have found that hypercytokinemia in the carriers of high-risk genotype on cytokine-related polymorphisms was not responsible to the ordinary anti-cytokine therapy such as continuous hemodiafiltration using polymethyl methacrylate membrane hemofilter. Therefore, we should apply new stronger anti-cytokine strategies toward those high-risk genotype patients.

Cytokines↗
PubMed2002

[Genetic polymorphism of 6 short tandem repeat loci in Chinese Korean].

OBJECTIVE: To analyze genetic polymorphism of D16S539 D7S820 D13S317 CSF1PO TPOX and TH01 in Chinese Korean. METHODS: One hundred unrelated individuals were analyzed by PCR amplification fragment length polymorphism analysis. RESULTS: Six alleles and 18 genotypes of D16S539 locus, 7 alleles and 22 genotypes of D7S820 locus, 7 alleles and 23 genotypes of D13S317 locus, 6 alleles and 16 genotypes of CSF1PO locus, 6 alleles and 11 genotypes of TPOX locus, 5 alleles and 12 genotypes of TH01 locus. CONCLUSION: The genotype distribution of all the 6 short tandem repeat(STR) in Chinese Korean met Hardy-Weinberg equilibrium, and have higher heterozygosities. The data obtained can be used in human identity and paternity testing, and in other genetic researches and population investigation.

Alleles↗
PubMed2003

Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan.

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.

Adenocarcinoma↗
PubMed2005

[Genetic polymorphism of D1S1612 and D18S535 in Chinese Han population of Beijing].

To investigate the genetic polymorphism of D1S1612 and D18S535 in Han population of Beijing. Amp-FLP method was used. 9 alleles, 25 genotypes were observed for D1S1612 locus; and 9 alleles and 27 genotypes for D18S535 locus. All allele frequencies, heterozygosity (H), discrimination power (Dp), exclusion of paternity probability (PE) and polymorphism information content (PIC) were calculated. The allele distributions of the two loci were conformed to Hardy-Weinberg equilibrium (P>0.01). According to the results obtained in this study, it is suggested that both D1S1612 and D18S535 are useful genetic markers for individual identification and paternity testing in forensic science practice as well for genetic study.

Alleles↗
PubMed1999

Glutathione-S-transferase (GSTM1) genetic polymorphisms do not affect human breast cancer risk, regardless of dietary antioxidants.

Glutathione-S-transferases catalyze the detoxication of carcinogen metabolites and reactive oxygen species (ROS) produced through a number of mechanisms. Glutathione-S-transferase (GST) M1 is polymorphic, and the null allele results in a lack of enzyme activity. Because there are indications that ROS may be involved in breast carcinogenesis, we sought to determine whether the GSTM1 null allele was associated with increased breast cancer, particularly among women with lower consumption of dietary sources of alpha-tocopherol, carotenoids and ascorbic acid. In a study of diet and cancer in western New York, women with primary, incident, histologically confirmed breast cancer (n = 740) and community controls (n = 810) were interviewed and an extensive food-frequency questionnaire administered. A subset of these women provided a blood specimen. DNA was extracted and genotyping performed for GSTM1. Data were available for 279 cases and 340 controls. The null allele did not increase breast cancer risk, regardless of menopausal status. There were also no differences in associations between the polymorphism and risk among lower and higher consumers of dietary sources of antioxidants or smokers and nonsmokers. These results indicate that GSTM1 genetic polymorphisms are not associated with breast cancer risk, even in an environment low in antioxidant defenses.

Antioxidants↗
PubMed2025

A comprehensive evaluation of candidate genetic polymorphisms in a large histologically characterized MASLD cohort using a novel framework.

BACKGROUND: There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication. METHODS: We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094). RESULTS: Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409. CONCLUSIONS: Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.

Humans↗
PubMed2003

Physical activity modulates effects of some genetic polymorphisms affecting cardiovascular risk in men aged over 40 years.

BACKGROUND AND AIM: Several genetic polymorphisms have been found to be involved in cardiovascular risk, and many studies have documented the beneficial effect of systematic physical activity (PA) on the cardiovascular system. Our aim was to investigate the interactive effects of PA and genetic background on plasma lipids and homocysteine (tHcy) levels. METHODS AND RESULTS: Clinical and metabolic parameters, dietary intakes and some polymorphisms of the genes involved in cardiovascular risk (Apo E, fatty acid binding protein-2, Apo AII, hepatic lipase and methylene tetrahydrofolate reductase) were determined in 100 men aged over 40 years who cycle 120-150 Km/week and 100 age-matched sedentary controls. The physically active subjects had lower concentrations of plasma LDL cholesterol (LDL-C), triglyceride (TG), Apo B, glucose and tHcy, and higher concentrations of plasma HDL cholesterol (HDL-C) and Apo AI than the sedentary men; they also had larger LDL particle sizes (LDLs). The LDL-C and Apo B raising effect of the Apo E epsilon 4 allele detectable in the sedentary subjects was totally absent in the cyclists, in whom the LDL-C and Apo B lowering effect of the epsilon 2 allele was observed. PA blunted the TG-raising effect of the Apo AII-265TT genotype, and amplified the HDL-C raising effect of the HL-250AA genotype. PA had a small but significant lowering effect on plasma tHcy adjusted for folate levels in subjects with the 677TT genotype of the MTHFR gene. CONCLUSIONS: Extended high-intensity PA in men aged over 40 years may modify their metabolic cardiovascular risk factors even in the presence of some unfavourable genotypes.

Adult↗
PubMed2000

Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia.

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMTdeficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.

Antimetabolites, Antineoplastic↗
PubMed2003

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors.

BACKGROUND: Findings from previous studies regarding the association between the CYP17 genotype and breast cancer are inconsistent. We investigated the role of the MspAI genetic polymorphism in the 5' region of CYP17 on risk of breast cancer and as a modifier of reproductive risk factors. METHODS: Questionnaire and genotyping data were obtained from a population-based, case-control study of premenopausal (n = 182) and postmenopausal (n = 214) European-American Caucasian women in western New York. Cases and controls were frequency matched by age and by county of residence. Odds ratios and 95% confidence intervals were used to estimate relative risks. RESULTS: The CYP17 genotype was not associated with breast cancer risk; however, controls with the A2/A2 genotype (associated with higher estrogens) had earlier menarche and earlier first full-term pregnancy. Premenopausal women with A1/A1 genotypes, but not with A2 alleles, were at significantly decreased risk with late age at menarche (odds ratio = 0.37, 95% confidence interval = 0.14-0.99), and at increased risk with late age at first full-term pregnancy (odds ratio = 4.30, 95% confidence interval = 1.46-12.67) and with use of oral contraceptives (odds ratio = 3.24, 95% confidence interval = 1.08-9.73). Associations were weaker among postmenopausal women. CONCLUSION: These results suggest that the effects of factors that may alter breast cancer risk through a hormonal mechanism may be less important among premenopausal women with putative higher lifetime exposures to circulating estrogens related to the CYP17 A2 allele.

Adult↗
PubMed1980

Genetic polymorphism of human erythrocyte glyoxalase II.

A new method for the detection of glyoxalase II (hydroxyacylglutathione hydrolase) after starch gel electrophoresis is described. A survey of Asian-Pacific populations indicates that genetic polymorphism of glyoxalase II is extremely rare. Polymorphism was observed only in a Micronesian population from the island of Nauru, in which the frequency of the new variant allele HAGH2 was found to be .016. The electrophoretic pattern in heterozygotes was a double band, suggesting that the structure of glyoxalase II is monomeric.

Alleles↗
PubMed1990

A "new" genetic polymorphism of a human serum protein: inter-alpha-trypsin-inhibitor.

A new genetic polymorphism of a human serum glycoprotein, the inter-alpha-trypsin-inhibitor (ITI), has been demonstrated by population and family studies. Sera were examined after neuraminidase treatment by isoelectric focusing on agarose gels followed by immunoblotting or by immunofixation with specific ITI-antiserum. Using this method, three common ITI phenotypes 1, 1-2 and 2, as well as two further rare ITI types 1-3 and 2-3 were disclosed. Genetically, these phenotypes are controlled by three allelic genes that determine a total of six phenotypes. These alleles are designated ITI*1, ITI*2 and ITI*3. The homozygous form of the third allele ITI*3 has not been found, as yet. The frequencies of ITI were examined in two population samples from Southern Germany (n = 248) and from Tyrol, Austria (n = 124). The gene frequencies of the common alleles ITI*1 and ITI*2 were 0.575 and 0.417, respectively, in Southern Germany, and 0.577 and 0.423, respectively, in Tyrol, Austria. The third allele ITI*3 was found only in the sample from Southern Germany, thus far, and was calculated to be 0.008.

Alleles↗
PubMed2002

Genetic polymorphisms in microsomal epoxide hydrolase and susceptibility to adult acute myeloid leukaemia with defined cytogenetic abnormalities.

Acute myeloid leukaemia (AML) cases with different chromosomal abnormalities may reflect different aetiologies. Benzene exposure, from a number of sources including smoking, is one risk factor for AML. Individual susceptibility to benzene may depend on differences in expression of metabolizing enzymes. We tested the hypothesis that smoking as well as genetic polymorphisms in the microsomal epoxide hydrolase gene (HYL1), an enzyme involved in benzene metabolism, could be risk factors for AML with defined chromosomal abnormalities. Twenty-six AML cases with -7/del(7q) and 24 cases with t(8;21), as well as 43 cases with normal karyotype and 155 age-, sex- and residence-matched controls, were drawn from a large case-control study on adult acute leukaemia. Current smoking was significantly associated with the cytogenetic abnormalities t(8;21) or -7/del(7q) (OR = 4.9; 95%CI = 2.1-11.5) but not with a normal karyotype, relative to individuals who were not current smokers. A putative high activity HYL1 phenotype [exon 3, residue 113 (Tyr/Tyr) and exon 4, residue 139 (His/Arg or Arg/Arg)] was associated with a significantly increased AML risk in men with -7/del(7q) or t(8;21) (OR = 4.4; 95%CI 1.1-17.0) but not with a normal karyotype. This suggests that AML cases with defined chromosomal abnormalities could be related to specific carcinogen exposures and, furthermore, suggests that smoking and genetic polymorphisms in HYL1 could be risk factors for AML with -7/del(7q) or t(8;21).

Acute Disease↗
PubMed2004

[Genetic polymorphism of 3 STR loci on chromosome X and its forensic application in Chinese population].

To investigate the genetic polymorphisms of three short tandem repeats loci of chromosome X in Chinese Han population in Chengdu area and its use in forensic science. Three X-chromosome linked short tandem repeat loci were analyzed by PCR followed by polyacrylamide gel electrophoresis. Hardy-Weinberg equilibrium was tested and forensic interested value was calculated . The power of exclution of DXS6804, DXS9896 and GATA144D04 is 0.5990, 0.6220, 0.4280, respectively. The result showed that all the three STR loci were polymorphic among 100 unrelated females and 120 unrelated males from Chinese Han population. Chi(2) tests demonstrated that genotype frequencies in females did not depart from Hardy-Weinberg equilibrium. Three X-chromosome linked short tandem repeat loci have high polymorphism, they can be applied to forensic medicine and population genetics.

Alleles↗
PubMedDate not supplied

Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism.

It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2- to 3-fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low Km for acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this "null" variant have higher than normal blood acetaldehyde levels and exhibit an alcohol-flush reaction which appears to be a deterrent to heavy drinking and alcoholism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Oxidoreductases↗
PubMed1999

[Genetic polymorphisms of five STR loci in a Chinese Han population].

OBJECTIVE: To understand the allele structure and genetic polymorphism at five STR loci in Chinese Han population, and construct a preliminary database. METHODS: EDTA-blood specimens were collected from the unrelated individuals. The DNA samples were extracted with Chelex method and were amplified by PCR technique. The PCR products were analyzed using both the PAGE horizontal electrophoresis with discontinuous buffer system and the automated fluorescence detection approach. RESULTS: Four STRs consist of simple repeat motifs, while one STR contains a complex repeat structure. The STR polymorphisms at all of the five loci have been observed in Chinese Han population. CONCLUSION: The obtained data are beneficial to understanding the population genetics of the five STR loci in Chinese Han population. As a simple approach, the PAGE horizontal electrophoresis can be employed for typing the five STR markers.

Alleles↗
PubMed1997

Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity.

TPMT is a cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including medications such as mercaptopurine and thioguanine. TPMT activity exhibits autosomal codominant genetic polymorphism, and patients inheriting TPMT deficiency are at high risk of potentially fatal hematopoietic toxicity. The most prevalent mutant alleles associated with TPMT deficiency in humans have been cloned and characterized (TPMT*2 and TPMT*3A), but the mechanisms for loss of catalytic activity have not been elucidated. In the present study, we established that erythrocyte TPMT activity was significantly related to the amount of TPMT protein on Western blots of erythrocytes from patients with TPMT activities of 0.4-23 units/ml pRBC (rs = 0.99; P < 0.001). Similarly, heterologous expression of wild-type (TPMT*1) and mutant (TPMT*2 and TPMT*3A) human cDNAs in yeast and COS-1 cells demonstrated comparable levels of TPMT mRNA but significantly lower TPMT protein with the mutant cDNAs. Rates of protein synthesis were comparable for wild-type and mutant proteins expressed in yeast and with in vitro translation in rabbit reticulocyte lysates. In contrast, pulse-chase experiments revealed significantly shorter degradation half-lives for TPMT*2 and TPMT*3A ( approximately 0.25 hr) compared with wild-type TPMT*1 (18 hr). The degradation of mutant proteins was impaired by ATP depletion and in yeast with mutant proteasomes (pre-1 strain) but unaffected by the lysosomal inhibitor chloroquine. These studies establish enhanced degradation of TPMT proteins encoded by TPMT*2 and TPMT*3A as mechanisms for lower TPMT protein and catalytic activity inherited by the predominant mutant alleles at the human TPMT locus.

Alleles↗
PubMed2004

Implications of cytochrome P450 genetic polymorphisms on the toxicity of antitumor agents.

In the treatment of cancer, a narrow therapeutic window generally exists between toxicity and suboptimal therapy. In addition, interindividual variation in drug metabolism seriously complicates therapy. Genetic polymorphisms in phase 1 and phase 2 enzymes are present in the population and may explain part of the observed interindividual variation in drug pharmacokinetics. For the cytochrome P450 superfamily, information on variant alleles encoding enzymes with decreased activity is rapidly on the increase. The potential of applying pharmacogenetic screening before therapy in the treatment of cancer seems to be greatest for CYP2B6 (cyclophosphamide treatment), CYP2C8 (paclitaxel therapy), and CYP3A5; however, the drugs of interest still need to be identified for this latter enzyme.

Antineoplastic Agents↗
PubMed1987

Alpha-1-antitrypsin genetic polymorphism in South Africa.

The alpha 1-antitrypsin (AAT) or protease inhibitor (Pi) genetic polymorphism was studied in 144 white, 100 coloured, 104 Indian and 127 black (Northern Sotho) healthy individuals (controls), in the Pretoria area. Their Pi phenotype and gene frequency distributions are compared with world-wide data on other population groups. The severely deficient Pi phenotypes S, Z and SZ jointly attain frequencies of 0.3-0.4% in coloureds and whites; in blacks and Indians the corresponding frequencies are very much lower. The implication for preventive medicine and public health is that in South Africa the sequelae of Pi deficiencies such as cirrhosis of the liver and/or emphysema of the lung are of practical importance in whites and coloureds and much less so in blacks and Indians. In 176 white breast cancer patients studied, the Pi phenotype and gene frequency distributions were found to be similar to those of healthy controls (not statistically significant). Cohorts of other patients were also phenotyped because of their low alpha 1-globulin concentrations in routine serum protein electrophoresis and/or their specific disease condition (cirrhosis of the liver or emphysema of the lung) known to be associated with AAT deficiency. These results are discussed in terms of their significance for family follow-up, genetic counselling and a preventive service. The need to avoid atmospheric pollution, especially cigarette smoke, is emphasised as a major and cost-effective preventive measure.

Black People↗