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PubMed2005

No apparent association between genetic polymorphisms (-102 C>T) and (-9 T>C) in the human manganese superoxide dismutase gene and gastric cancer(1).

BACKGROUND: Manganese superoxide dismutase (MnSOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk. This one base pair transition (-9 T>C) leads to a Val to Ala amino acid change in the mitochondrial targeting sequence. In addition, the MnSOD promoter contains an activator protein-2 (AP-2) binding site that modifies transcription of MnSOD. Mutations have been identified in the proximal region of the promoter in human tumor cell lines. One of these mutations (-102 C>T) has been shown to change the binding pattern of AP-2, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the (-9 T>C) and (-102 C>T) polymorphisms with gastric cancer in a population-based case-control study conducted in Warsaw, Poland. MATERIALS AND METHODS: DNA was obtained from a population based case-control study of stomach cancer conducted in Warsaw, Poland, between 1994 and 1996. The MnSOD -9 T>C genotype was determined by PCR-RFLP assay. The MnSOD -102 C>T genotype was determined using a TaqMan allele discrimination assay. RESULTS: The frequency of the -102 C>T polymorphism was 41% (38/91) in gastric cancer cases and 38% (50/130) in the controls (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.6-2.1). The frequency of the -9 T>C polymorphism was 44% (202/464) in cases and 56% (262/464) in controls (OR 1.1; 95% CI 0.9-1.37). The lack of association was observed in both non-smokers (OR 1.5; 95% CI 0.7-2.34) and smokers (OR 1.1; 95% CI 0.7-1.7). Furthermore, the association was not significant when smokers were segregated by extent of smoking history. CONCLUSION: The association of the manganese superoxide dismutase polymorphisms at -102 C>T and the -9 T>C were not found to be associated with gastric cancer in a Polish case-control study.

Adenocarcinoma↗
PubMed1979

Synthesis of highly diversified carrier ampholytes. Evaluation of the resolving power of isoelectric focusing in the Pi system (alpha-1-antitrypsin genetic polymorphism).

The use of condensing reagents such as epoxypropanol, diepoxyoctane, acrylamide and N,N'-methylenebisacrylamide in the synthesis of carrier ampholytes increased the diversity of amphoteric components. The quality of these synthetic carrier ampholytes has been tested in the separation of variants of alpha-1-anti-trypsin, a genetic polymorphism called the Pi system. A resolving power of the order of 0.005 pH unit was obtained.

Ampholyte Mixtures↗
PubMed1998

[Genetic polymorphism of the CYP2C subfamily].

Cytochromes P450 (CYP) are a superfamily of hemoproteins that metabolize various foreign compounds. The human CYP2C subfamily is one of the subfamilies of the CYP2 family and it consists of four members of CYP isoforms, CYP2C8, CYP2C9, CYP2C18 and CYP2C19. A well-characterized genetic polymorphism occurs in CYP2C19, which is associated with the 4'-hydroxylation of S-mephenytoin. There are two phenotypes, extensive metabolizers and poor metabolizers (PM) of mephenytoin. The frequency of PM in the Japanese population is 20%, while only 3% of Caucasians are PM of mephenytoin. Two defective alleles, designated as CYP2C19*2 and CYP2C19*3, have been described, and the latter mutation has been detected only in Oriental populations. Recently, an allelic variant of CYP2C9 that causes substitution of Leu359 for Ile359 has been shown to be associated with the decreased metabolic clearance of various therapeutic agents including warfarin, tolbutamide and phenytoin. The frequency of this variant allele in the Japanese population is 2%, while those of the Caucasians are 6-9%. Although the role of CYP2C18 in the drug metabolism remains obscure, we have recently found that defective alleles of CYP2C19*3 and CYP2C18m1 are completely linked, suggesting that PM of CYP2C19 with CYP2C19*3 alleles is a PM of CYP2C18 and vice versa.

Alleles↗
PubMed1983

New genetic polymorphism recognized in the prealbumin region of chicken egg yolk.

Two-dimensional electrophoretic analysis of water-soluble proteins of chicken egg yolk was done by a first-dimension separation in agarose gel (pH 8.6) followed by a second-dimension separation in horizontal polyacrylamide gel (pH 9.0). Genetic polymorphism of a protein, tentatively designated as Pr M prealbumin, was observed. The analysis of family data suggests that the Pr M prealbumin is controlled by two alleles, Pr M+ and Pr M-, at a single autosomal locus. The Pr M+ allele appears to be dominant to the Pr M- allele.

Alleles↗
PubMed2002

[Genetic polymorphisms of drug metabolizing enzymes].

Multiple forms of CYP exist in humans. P450s comprise a superfamily of enzymes. These P450s play important roles in the oxidation of structurally diverse endobiotics and xenobiotic chemicals including anticancer drugs and carcinogens. The genes encoding most of the CYP1, CYP2, and CYP3 families show genetic polymorphism. In this article, we describe recent findings that these polymorphic enzymes can abolish or quantitatively or qualitatively alter drug metabolism in humans.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Serum myeloperoxidase concentration in a healthy population: biological variations, familial resemblance and new genetic polymorphisms.

Myeloperoxidase (MPO) has been involved in the pathogenesis of several diseases through excessive production of reactive oxygen species (ROS) as well as through its genetic polymorphism. The aims of this study were to identify the factors affecting MPO serum concentration, to study the familial resemblance of MPO levels and to investigate the association between newly described MPO polymorphisms as well as the G-463A one and MPO levels in a healthy population. MPO serum concentrations were measured by an enzymatic immuno-assay (EIA) in 82 healthy families of the STANISLAS Cohort and MPO genotype, determination was performed using PCR-restriction fragment length polymorphism or allele specific oligonucleotide assay. MPO concentrations were significantly higher in parents than in offspring. The factors affecting MPO levels were age, the number of white cells, smoking in fathers and oral contraceptive intake in mothers. They explain from 12.4% up to 35.9% of MPO variability in men and women, respectively. Family correlations of MPO concentrations were of similar magnitude. The -129A allele of a newly described G-129A substitution was significantly associated with decreased MPO levels, whereas the -463A allele was suggested to be associated with increased levels of lipid variables. In this study, we identified factors affecting MPO serum concentrations and showed that molecular variations of the gene have only a weak influence on MPO variability. In contrast, the association between the G-463A polymorphism and lipid levels would suggest a possible implication of MPO in the risk of cardiovascular diseases. These results have to be confirmed and further investigations will be conducted in that way.

Adolescent↗
PubMed2003

Interleukin-6 genetic polymorphisms are not related to Helicobacter pylori-associated gastroduodenal diseases.

BACKGROUND: Polymorphisms in the promoter region of the proinflammatory cytokine, interleukin (IL)-6 have been related to several chronic inflammatory diseases. Inter-individual variation in the severity of gastric inflammation may be important in determining the clinical outcome of an Helicobacter pylori infection and relate to polymorphisms in this region. MATERIALS AND METHODS: We studied H. pylori-infected patients with duodenal ulcer or gastric cancer. In addition six gastric cancer cell lines, AGS, SNU-668, MKN-1, MKN-7, MKN28 and KATOIII, were cocultured with both cag pathogenicity island-positive and -negative H. pylori. Single nucleotide polymorphisms at positions -174, -572, and -597 in the IL-6 promoter region were identified by PCR-RFLP. The IL-6 production from the cancer cells was determined by ELISA. RESULTS: Sixty patients with gastric cancer and 60 with duodenal ulcer were studied. The alleles at positions -174 and -597 were closely linked (-174G/-597G or -174C/-597A) regardless of the ethnic group or disease presentation. There was no difference in the allele frequency at any of the sites among patient groups. H. pylori-induced IL-6 production from the gastric cancer cell lines was also independent of the IL-6 polymorphisms or the presence of the cag pathogenicity island. CONCLUSIONS: The genetic polymorphisms in IL-6 can be attributable to ethnicity and appear to be independent of the clinical outcome of an H. pylori infection.

Adult↗
PubMed2004

Metabolic susceptibility genes and prostate cancer risk in a southern European population: the role of glutathione S-transferases GSTM1, GSTM3, and GSTT1 genetic polymorphisms.

BACKGROUND: Glutathione S-transferase (GST) metabolic enzymes may be involved in the development of human cancer. Genetic polymorphisms have been reported in GSTM1, GSTM3, and GSTT1 with functional alterations and influencing cancer risk. METHODS: We analyzed DNA samples from 335 (670 alleles) unrelated individuals, 185 community control subjects, and 150 prostate cancer (PC) patients, for GSTM1, GSTM3, and GSTT1 genotypes using polymerase chain reaction (PCR). RESULTS: The analysis of the frequencies from the 670 alleles indicates that men carrying two B-alleles (GSTM3) have increased risk for PC (OR = 5.50, 95% confidence interval (CI) 1.2-25.8; P = 0.016). Multivariate logistic regression analysis confirmed this association (OR = 5.2, 95% CI 1.1-25.0; P = 0.036). No increased PC risk was observed for men carrying any of the GSTM1 or GSTT1 genotypes (OR = 1.20, 95% CI 0.75-1.90; P = 0.420 for GSTM1 null and OR = 0.87, 95% CI 0.50-1.51; P = 0.550 for GSTM1 null). However, GSTT1 null was overrepresented in men with advanced PC disease (P = 0.038). CONCLUSIONS: Our results indicate that polymorphism in the GSTM3 may be an important biomarker for PC risk, especially in the definition of the genetic risk profile of populations of southern Europe.

Aged↗
PubMed2003

Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers.

Alcoholic beverages are causally related to cancer of the oral cavity, pharynx, larynx and esophagus. Ethanol is oxidized to acetaldehyde and then to acetate by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), both of which have genetic polymorphisms. A review of case-control studies of the effects of ALDH2, ADH2 and ADH3 genotypes shows consistently positive associations between inactive heterozygous ALDH2 and the less-active ADH2 genotypes and the risk for esophageal cancer in East Asian heavy drinkers and this enzyme-related vulnerability may extend to light-to-moderate drinkers. Some studies suggest similar associations with the risk for head and neck cancer in moderate-to-heavy-drinking Japanese. An established carcinogen in experimental animals, acetaldehyde can interact with human DNA. ALDH2-associated cancer susceptibility fits into a scenario in which acetaldehyde plays a critical role in the development of human cancer. Alcohol flushing and drinking behavior may partly explain this carcinogenic effect in carriers of less-active ADH2 genotypes. Whether the ADH3 genotype influences head and neck cancer risk in Western nations is controversial. Professional and public education about risky conditions connected to the ALDH2 and ADH2 genotypes and environmental factors is important in a new strategic approach to the prevention of alcohol-related cancers in East Asians. The use of simple tests to identify inactive ALDH2 on the basis of alcohol flushing responses could benefit many people, by helping them to identify their own cancer risks. Such testing could also help clinicians diagnose esophageal cancer earlier, through the use of endoscopic screening in the high-risk population.

Alcohol Dehydrogenase↗
PubMed1985

The genetic polymorphism of alpha 2-HS glycoprotein: study by ultrathin-layer isoelectric focusing and immunoblot.

The genetic polymorphism of human alpha 2-HS glycoprotein was studied by ultrathin-layer isoelectric focusing in a pH range 4.2-4.9 followed by immunoblotting using antisera specific for the protein. Three common phenotypes, HSGA1-1, HSGA2-2, and HSGA1-2, were easily recognized using this technique. Each homozygous phenotype was constituted by five major bands with different pI's, and the heterozygous phenotype represented an exact combination of each of them. After removal of sialic acid, each homozygous pattern was resumed in a single band, which differed in charge between HSGA1 and HSGA2. Asialo-heterozygous HSG1-2 combined the two bands characteristic of each allele product. Family studies are in agreement with an autosomal codominant transmission of the two alleles. Population studies indicate that the frequency of the HSGA1 and 2 alleles are .65 and .35, respectively.

Blood Proteins↗
PubMed1997

Association between genetic polymorphisms of the cytochromes P-450 (1A1, 2D6, and 2E1) and the susceptibility to pancreatic cancer.

OBJECTIVES: Metabolic activation is a prerequisite for the carcinogenic effect of many carcinogens, and considerable interindividual variation exists in the metabolic capacity to activate the carcinogens. The cytochromes P-450 (CYPs) are responsible for the activation mechanism, and polymorphisms of the CYPs (CYP1A1, CYP2D6, and possibly CYP2E1) are known to be related to increased susceptibility to smoking related Kreyberg type I lung cancer. The aim of this study is to clarify the relationship of genetic polymorphisms of the CYPs to susceptibility to pancreatic cancer, another smoking-related cancer. METHODS: We analyzed 45 samples from patients with pancreatic cancer and 53 samples from controls. DNA was isolated from blood samples and the CYP1A1, 2D6 and 2E1 genes were amplified by PCR. Analyzing the genotypes of the CYPs by allele-specific PCR or RFLP analysis, we assessed the allele frequencies for each mutation of the CYPs among the patients with pancreatic cancer and the controls. RESULTS: The allele frequencies for the mutation in the 3'-flanking region of the CYP1A1 among the cases and the controls were 0.31 and 0.36, respectively. The allele frequencies for the exon 7 mutation of the CYP1A1 were 0.16 and 0.23, respectively, but with no statistical significance. The frequencies for the mutant c2 allele of the CYP2E1 were 0.19 and 0.30, respectively, but with no statistical significance. Two persons homozygous for a gene deletion of the CYP2D6 were observed among control subjects; other mutations were not observed among either the patients or controls. CONCLUSION: We could not find any evidence that polymorphisms of the CYPs are associated with increased susceptibility to pancreatic cancer.

Adult↗
PubMed2006

[An analysis for genetic polymorphism of twelve Y short tandem repeat loci in Chaoshan populations].

OBJECTIVE: To study the genetic polymorphism of twelve short tandem repeat loci of Y chromosome in Chaoshan Han populations. METHODS: Twelve Y short tandem repeat loci, of which the template DNAs were extracted from blood samples of 121 unrelated Chaoshan Han individuals, were amplified by using the PowerPlex Y system. The PCR products were genotyped with ABI PRISM 3100 genetic analyzer. RESULTS: From the loci DYS19, DYS437, DYS389I, DYS389II, DYS438, DYS439, DYS393, DYS391, DYS390, and DYS392, 4-7 alleles were checked out; from the loci DYS385, 35 alleles were observed. The overall observed haplotype diversity reached 0.9976. DYS391 was the locus with the lowest gene diversity (0.4445), while DYS385 had the highest gene diversity (0.9525). CONCLUSION: The 12 Y-STR loci are highly polymorphic and suitable to forensic casework, population genetics and anthropology studies.

China↗
PubMed1983

Genetic polymorphism of the vitamin D binding protein (Gc protein) in pig plasma determined by agarose isoelectrofocusing.

Genetic polymorphism of the pig plasma vitamin D binding protein Gc was demonstrated by agarose isoelectrofocusing followed by either autoradiography or immunofixation with specific human Gc antiserum. Three different types F, FS and S were observed. Family data supported the genetic theory that the Gc types are controlled by two autosomal codominant alleles GcF and GcS. Both alleles are present in Yorkshire and Duroc. In Danish Landrace and Hampshire only the GcF allele was observed.

Alleles↗
PubMed2006

Association study of genetic polymorphisms of SLC2A10 gene and type 2 diabetes in the Taiwanese population.

AIMS/HYPOTHESIS: The gene encoding solute carrier family 2, facilitated glucose transporter, member 10 (SLC2A10, previously known as glucose transporter 10 [GLUT10]) is a promising candidate gene for type 2 diabetes since it is highly expressed in liver and pancreas and is located on human chromosome region 20q12-q13.1, a region previously shown to harbour type 2 diabetes susceptibility genes. We investigated whether the SLC2A10 gene could be a type 2 diabetes susceptibility gene in the Taiwanese population. SUBJECTS AND METHODS: Sequencing of SLC2A10 gene from 48 diabetic subjects detected short tandem repeat polymorphisms in the promoter region, but did not detect any other sequence variants or new single-nucleotide polymorphisms (SNPs) other than those already in the SNPper database ( http://snpper.chip.org ) (30 June 2005). RESULTS: Using these genetic polymorphisms, we divided the SLC2A10 gene into four distinct linkage disequilibrium blocks and performed a case-control association study in a group of type 2 diabetes subjects (n = 375) and normoglycaemic individuals (n=377). The HapD (A-G-T-C) haplotype in block 3, a rare haplotype, which consisted of four SNPs (rs3092412, rs2235491, rs2425904 and rs1059217), was modestly associated with type 2 diabetes with a haplotype score of -2.95567 (p = 0.012 with the haplotype-specific test). CONCLUSIONS/INTERPRETATION: Our results suggest that SLC2A10 genetic variations do not appear to be major determinants for type 2 diabetes susceptibility in the Taiwanese population.

Aged↗
PubMed2005

Circadian variability of pharmacokinetics of 5-fluorouracil and CLOCK T3111C genetic polymorphism in patients with esophageal carcinoma.

The variations of plasma concentrations of 5-fluorouracil (5-FU) were investigated in 30 esophageal cancer patients treated with repetitive protracted venous infusion (PVI) of 5-FU-based chemoradiotherapy, and in an attempt to find a new possible candidate that explains their variations, CLOCK T3111C genetic polymorphism was examined. The patients have received 2 courses of chemoradiotherapy consisting of 2 cycles of 5-day PVI of 5-FU (400 mg/m/d) with cisplatin and concurrent radiation. The plasma concentrations of 5-FU were determined at 5 PM on day 3 and 5 AM on day 4 after the beginning of each 5-FU infusion. The CLOCK T3111C genotype was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) and by direct sequencing. Plasma concentrations were measured in 239 samples. In the first course, the plasma concentrations of 5-FU at 5 AM were significantly lower than those at 5 PM in the first cycle, whereas a similar tendency was observed in the second cycle, although not significantly (Wilcoxon signed-rank test). The plasma concentrations of 5-FU at 5 PM and 5 AM in the second cycle were both significantly higher than those in the first cycle, and their coefficient of variation in the former was also significantly smaller than that in the latter. These phenomena in the first course were also observed in the second one. These results revealed the elevation of plasma drug concentration and its reduced circadian variation during repetitive PVI of 5-FU. In 5-FU-based chemotherapy, its administration schedule should be made in consideration of these phenomena. The CLOCK T3111C genotype did not have a significant impact on the variation of the plasma concentrations of 5-FU in this study population. Further studies are needed to clarify the mechanism of these phenomena and to identify an easy-to-assess marker of circadian rhythms for use in individualizing delivery of 5-FU.

Aged↗
PubMed2005

Lipoprotein metabolism of pregnant women is associated with both their genetic polymorphisms and those of their newborn children.

To explore whether the placenta contributes to the lipoprotein metabolism of pregnant women, we took advantage of the fact that placental proteins are encoded from the fetal genome and examined the associations between lipids of 525 pregnant women and the presence, in their newborns, of genetic polymorphisms of LPL and apolipoprotein E (APOE), two genes expressed in placenta. After adjustment for maternal polymorphisms, newborn LPL*S447X was associated with lower triglycerides (-21 +/- 9 mg/dl), lower LDL-cholesterol (LDL-C; -12 +/- 5 mg/dl), lower apoB (-14 +/- 4 mg/dl), higher HDL-C (5 +/- 2 mg/dl), and higher apoA-I (9 +/- 4 mg/dl) in their mothers; newborn LPL*N291S was associated with higher maternal triglycerides (114 +/- 31 mg/dl); and newborn APOE*E2 (compared to E3E3) was associated with higher maternal LDL-C (14 +/- 6 mg/dl) and higher maternal apoB (14 +/- 5 mg/dl). These associations (all P < 0.05) were independent of polymorphisms carried by the mothers and of lipid concentrations in newborns and were similar in amplitude to the associations between maternal polymorphisms and maternal lipids. Such findings support the active role of placental LPL and APOE in the metabolism of maternal lipoproteins and suggest that fetal genes may modulate the risk for problems related to maternal dyslipidemia (preeclampsia, pancreatitis, and future cardiovascular disease).

Adult↗
PubMed2002

Renin-angiotensin system genetic polymorphisms and cerebral white matter lesions in essential hypertension.

It has been reported that both the DD genotype of the angiotensin converting enzyme (ACE) gene and the presence of cerebral white matter lesions (WML) may represent risk factors for the development of stroke. The present study investigates a possible association between 3 different genetic polymorphisms of the renin-angiotensin system and the presence of WML in 60 never-treated essential hypertensive patients (36 men, 24 women), aged 50 to 60 years, without clinical evidence of target organ damage. All patients underwent brain magnetic resonance imaging to establish the presence or absence of WML. The insertion/deletion (I/D) ACE gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 receptor gene polymorphisms were determined by standard polymerase chain reaction. Twenty-five hypertensive patients (41.6%) were found to have WML on brain magnetic resonance imaging. No significant association between the M235T angiotensinogen or A1166C angiotensin II type 1 receptor genotypes and the presence of WML was found. However, the frequency of the DD genotype in patients with WML (64%) was significantly higher than that observed in patients without WML (28.6%; P=0.022). The DD genotype odds ratio for the presence of WML was 4.44 (95% confidence interval: 1.48 to 13.3). Likewise, the proportion of the D allele in patients with WML (74%) was significantly higher (P=0.014) than that observed in patients without WML (51.4%). We conclude that the presence of the DD genotype and/or the D allele of the ACE gene may be a predisposing factor for developing WML in essential hypertensive patients. However, because of the small sample size, these results require confirmation in a larger study.

Aged↗
PubMed2001

Theoretical 3D model of histamine N-methyltransferase: insights into the effects of a genetic polymorphism on enzymatic activity and thermal stability.

Histamine N-methyltransferase (HNMT) catalyzes the N-methylation of histamine in mammals. The experimentally determined HNMT three-dimensional (3D) structure is not available. However, there is a common genetic polymorphism for human HNMT (Thr105Ile) that reduces enzymatic activity and is a risk factor for asthma. To obtain insights into mechanisms responsible for the effects of that polymorphism on enzymatic activity and thermal stability, we predicted the 3D structure of HNMT using the threading method and molecular dynamics simulations in water. Herein, we report a theoretical 3D model of human HNMT which reveals that polymorphic residue Thr105Ile is located in the turn between a beta strand and an alpha helix on the protein surface away from the active site of HNMT. Ile105 energetically destabilizes folded HNMT because of its low Chou-Fasman score for forming a turn conformation and the exposure of its hydrophobic side chain to aqueous solution. It thus promotes the formation of misfolded proteins that are prone to the clearance by proteasomes. This information explains, for the first time, how genetic polymorphisms can cause enhanced protein degradation and why the thermal stability of allozyme Ile105 is lower than that of Thr105. It also supports the hypothesis that the experimental observation of a significantly lower level of HNMT enzymatic activity for allozyme Ile105 than that with Thr105 is due to a decreased concentration of allozyme Ile105, but not an alternation of the active-site topology of HNMT caused by the difference at residue 105.

Computer Simulation↗