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PubMed2006

[Study on genetic polymorphisms of CYP2F1 gene in Guangdong population of China].

OBJECTIVE: To investigate the genetic polymorphism of CYP2F1 gene, a member of CYP450 gene family in the healthy population and the patients with nasopharyngeal carcinoma (NPC) of Guangdong province, and furthermore analyze the relationship between CYP2F1 genetic polymorphism and the risk of developing NPC. METHODS: By direct gene sequencing, all of 10 exons of CYP2F1 gene were detected in 40 peripheral blood specimens of patients with primary NPC. For the genetic polymorphism with high allelic frequency, mismatch PCR-RFLP technique was developed to identify the different frequency between 368 NPC cases and 344 cancer-free controls. RESULTS: There were totally 35 SNPs identified in all of 10 exons and exon-intron junctions of CYP2F1 gene from 40 NPC patients, which included 10 missense mutations and 1 frame shift mutation. The most important mutation was C insertion located in 15-16 bp, which caused the frame shift. The allelic frequency of C insertion was 25%. However, there was no significant difference found between 368 NPC cases and 344 controls in allelic frequency of 15-16 bp C insertion mutation (P>0.05). CONCLUSION: A lot of genetic polymorphism of CYP2F1 gene is found in Guangdong population of China. However, no single genetic polymorphism associated with the individual susceptibility to NPC can be identified. The cooperated operations with multiple genetic polymorphisms of one or more genes may be critical factors contributing to the development and progression of NPC.

Asian People↗
PubMed2000

Genetic polymorphism of CYP2A6 in the German population.

Genetic polymorphism of drug metabolizing enzymes (DME) can lead to severe toxicity or therapeutic failure of pharmacotherapy. Additionally, genetically determined differences in the activity of the metabolic enzymes can increase an individual's susceptibility to certain types of chemically induced cancers and possibly other diseases. Cytochrome P450 is one of the most important metabolic systems of the organism involved in the oxidation of different xenobiotics. This contribution summarizes and updates the information concerning the genetic polymorphism of the CYP2A6 isoform of the cytochrome P450. A special emphasis is put upon the genotyping techniques of CYP2A6 with a comparative analysis of their predictable sensitivity and specificity given on the example of the German population.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer.

BACKGROUND & AIMS: Human pancreatic cancer might be associated with folate deficiency and impaired metabolism. We tested this hypothesis by examining the contribution of functional polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) to risk of cancer. METHODS: DNA from 163 pancreatic cancer patients and 337 control subjects was genotyped for MTHFR (677C > T and 1298A > C) and TS (5'-untranslated region tandem repeat and G/C). Association with risk of pancreatic cancer was estimated by logistic regression. All statistical tests were two-sided. RESULTS: We observed an increased risk of pancreatic cancer associated with the MTHFR 677CT (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.61-4.29; P = .0005) or 677TT (OR, 5.12; 95% CI, 2.94-9.10; P < .0001) genotype compared with the MTHFR CC genotype. An increased risk of pancreatic cancer was also associated with the TS 3Rc/3Rc genotype (OR, 2.19, 95% CI, 1.13-4.31; P = .022) compared with the TS 3Rg/3Rg genotype. Joint effect between MTHFR C677T polymorphism and smoking or drinking increased risk of pancreatic cancer in a super-multiplicative manner. The ORs for smoking, the polymorphism, and both factors combined were 0.70 (95% CI, 0.30-1.63), 2.17 (95% CI, 1.17-4.21), and 3.10 (95% CI, 1.54-6.51), respectively. This joint effect was much stronger in heavy smokers (OR, 6.69; 95% CI, 3.39-13.63; P < .0001). The ORs for drinking, the polymorphism, and both factors combined were 0.98 (95% CI, 0.40-2.30), 2.81 (95% CI, 1.65-4.98), and 4.39 (95% CI, 2.25-8.78), respectively. CONCLUSION: The MTHFR and TS polymorphisms are genetic determinants for developing pancreatic cancer.

Adult↗
PubMed2003

Prediction of stone disease by discriminant analysis and artificial neural networks in genetic polymorphisms: a new method.

OBJECTIVE: To use information from genetic polymorphisms and from patients (drinking/exercise habits) to identify their association with stone disease, the main analytical and predictive tools being discriminant analysis (DA) and artificial neural networks (ANNs). PATIENTS, SUBJECTS AND METHODS: Urinary stone disease is common in Taiwan; the formation of calcium oxalate stone is reportedly associated with genetic polymorphisms but there are many of these. Genotyping requires many individuals and markers because of the complexity of gene-gene and gene-environmental factor interactions. With the development of artificial intelligence, data-mining tools like ANNs can be used to derive more from patient data in predicting disease. Thus we compared 151 patients with calcium oxalate stones and 105 healthy controls for the presence of four genetic polymorphisms; cytochrome p450c17, E-cadherin, urokinase and vascular endothelial growth factor (VEGF). Information about environmental factors, e.g. water, milk and coffee consumption, and outdoor activities, was also collected. Stepwise DA and ANNs were used as classification methods to obtain an effective discriminant model. RESULTS: With only the genetic variables, DA successfully classified 64% of the participants, but when all related factors (gene and environmental factors) were considered simultaneously, stepwise DA was successful in classifying 74%. The results for DA were best when six variables (sex, VEGF, stone number, coffee, milk, outdoor activities), found by iterative selection, were used. The ANN successfully classified 89% of participants and was better than DA when considering all factors in the model. A sensitivity analysis of the input parameters for ANN was conducted after the ANN program was trained; the most important inputs affecting stone disease were genetic (VEGF), while the second and third were water and milk consumption. CONCLUSIONS: While data-mining tools such as DA and ANN both provide accurate results for assessing genetic markers of calcium stone disease, the ANN provides a better prediction than the DA, especially when considering all (genetic and environmental) related factors simultaneously. This model provides a new way to study stone disease in combination with genetic polymorphisms and environmental factors.

Adult↗
PubMed1993

Genetic polymorphism of human interleukin-1 alpha.

Interleukin-1 alpha (IL-1 alpha) has been implicated in the pathogenesis of infectious, autoimmune and inflammatory diseases. There is, however, very little information on the cis-acting sequences involved in IL-1 alpha regulation or whether there is any variation in the structure of the gene. It is known that intron 6 of IL-1 alpha shows a 5 x 46 bp tandem repeat in the genomic sequence. We have studied this region of the gene. Amplification by polymerase chain reaction showed different sized products from different individuals, most being of higher molecular weight than the expected size of 620 bp. Sequencing demonstrated that the polymorphism was due to a variable number of repeats of the 46 bp sequence. This was confirmed by restriction fragment length analysis of genomic DNA. Altogether, 72 unrelated individuals were tested and 6 alleles ranging from 5 to 18 repeats were found, the most frequent allele (62%) containing 9 repeats. This polymorphism may be of interest in gene function, since each repeat contains three potential binding sites for transcriptional factors: an SP1 site, a viral enhancer element and a glucocorticoid-responsive element. The latter, at least, demonstrates site-specific protein binding by electromobility shift assay. The functional significance of the polymorphism and its allelic frequency in inflammatory and autoimmune diseases are currently under investigation.

Base Sequence↗
PubMed2004

First report of a genetic polymorphism of the cytochrome P450 3A43 (CYP3A43) gene: identification of a loss-of-function variant.

In the present study, we report the first investigation of polymorphisms in the human CYP3A43 gene. A screening for sequence variations in the 5'-flanking and protein coding regions of the CYP3A43 gene was performed by a Polymerase Chain Reaction - Single Strand Conformational Polymorphism (PCR-SSCP) strategy, using DNA samples from 48 unrelated French individuals. Three polymorphisms in the coding region were identified, comprising two nucleotide substitutions, one silent (c.1047C>T) and one missense mutation (c.1018C>G/P340A), and a frame shift mutation (c.74delA), leading to a premature stop codon and, presumably, to a severely truncated protein. In order to evaluate the extent of the frame shift mutation in a larger population, 352 individuals were further genotyped. Thirty-four samples (4.83%) were found to be heterozygous and one homozygous (0.14%) for the nucleotide deletion, which suggests that, although the potential significance of this polymorphism remains to be further evaluated, some individuals are deficient for CYP3A43 activity.

Alleles↗
PubMed2002

Genetic polymorphism in myeloperoxidase but not GSTM1 is associated with risk of lung squamous cell carcinoma in a Chinese population.

Myeloperoxidase (MPO), an enzyme derived from neutrophils, metabolically activates a wide range of carcinogens, whereas glutathione S-transferase M1 (GSTM1) detoxifies various electrophilic metabolites. A -463G-->A polymorphism in the promoter region of the MPO gene diminishes the expression of MPO and has been consistently shown to be associated with reduced risk of lung cancer in different ethnic populations. In our study, we have assessed the role of this polymorphism in lung cancer risk in a Chinese population. Genotypes of MPO and GSTM1 were determined by PCR-SSCP and multiplex PCR in 314 patients with lung cancer and 320 frequency-matched controls. The allele frequency for MPO -463A was found to be 0.155 in controls and 0.114 in cases. Subjects with the MPO -463GG genotype were at an increased risk of squamous cell carcinoma (SCC) of the lung compared to those having at least one -463A variant allele (adjusted odds ratio [OR] 2.35; 95% confidence interval [CI] 1.40-3.94). Stratified analysis suggested an interaction between heavy smoking (> or =26 pack-years) and the MPO-463GG genotype. The adjusted OR of lung SCC for those having MPO-463GG genotype and smoked > or =26 pack-years was 20.50 (95% CI 5.58-75.33) compared to 6.22 (95% CI 1.72-22.47) for those smoked > or =26 pack-years but having at least one variant A allele (p = 0.023, test for homogeneity). This effect of the MPO polymorphism was not observed in lung adenocarcinoma. GSTM1 deletion was quite common in both controls (49.4%) and cases (50.3%) but was not associated with risk of lung cancer alone or in combination with the MPO polymorphism. Our results confirm the previous reports showing that the variant A allele of MPO has a protective effect against risk of lung cancer.

Alleles↗
PubMed1997

Human erythrocyte protein L-isoaspartyl methyltransferase: heritability of basal activity and genetic polymorphism for thermal stability.

Protein L-isoaspartyl methyltransferase (PIMT) is believed to play an important role in the disposition of age-damaged proteins by catalyzing the repair of abnormal isoaspartyl linkages resulting from the spontaneous deamidation of asparaginyl residues or isomerization of aspartyl residues. As a step toward testing the hypothesis that human disease- or age-related pathology might be associated with a deficiency in PIMT, we investigated basal activity and thermal stability of PIMT in erythrocyte lysates from 299 U.S. family members. Thermal stability was measured because it is a sensitive measure of variation in amino acid sequence. Basal activity was normally distributed with a mean+/-SD of 558+/-43 units/ml erythrocytes. Statistical analysis of the data revealed that basal PIMT activity exhibited a high degree of heritability. Enzyme thermal stability showed a skewed bimodal frequency distribution, and segregation analysis of family member pedigrees was consistent with Mendelian inheritance of two major alleles. No DNA was available from the family samples, so we tested two additional population samples for a known Ile/Val polymorphism at codon 119 and for PIMT activity and thermal stability, using blood donated by 25 Norwegians and by 20 Koreans. Single-stranded conformational polymorphism analysis using polymerase chain reaction revealed a 100% correlation between thermal stability grouping and this polymorphism. The high thermal stability samples were all homozygous Ile, the low thermal stability samples were all homozygous Val, and the intermediate thermal stability samples were all heterozygous. Furthermore, this polymorphism was responsible, in part, for the variation observed in basal erythrocyte PIMT activity. These results will help provide a foundation for future studies aimed at correlating levels of PIMT activity, or other properties of this enzyme, with human disease.

Aging↗
PubMed1990

T-cell receptor genes in tassel-eared squirrels (Sciurus aberti). I. Genetic polymorphism and divergence in the Abert and Kaibab subspecies.

The role of environmental factors in the evolution and maintenance of diversity of antigen receptor gene families which participate in the immune response in mammals is inadequately understood. In order to elucidate the impact of these factors, we have undertaken the analysis of these gene families in the tassel-eared squirrel (Sciurus aberti) which has been separated into discrete subspecies by geographic barriers and whose food resources can be quantitated for estimating environmental quality. In this communication we describe the initial analysis of the complexity and polymorphism of sequences related to T-cell receptor (Tcr) alpha and beta chain genes in two subspecies, Sciurus aberti aberti (Abert) and Sciurus aberti kaibabensis (Kaibab) which have identical habitats and are separated by the Grand Canyon in Arizona, USA. Genomic blot analysis of 60 Abert and 62 Kaibab individuals collected over a 3-year period was performed with mouse Tcrb and Tcra cDNA probes. Sequences homologous to Tcrb-C, Tcrb-J1, and Tcrb-J2 genes were observed in all individuals from both subspecies; although Tcrb-J1 fragments were monomorphic. Tcrb-C and Tcrb-J2 fragments were polymorphic with both species- and subspecies-specific sequences. A single, monomorphic Tcra-C fragment was observed in addition to multiple Tcra-V fragments homologous to the mouse Tcra-V1 subfamily. Abert samples exhibited greater numbers of Tcra-V1 fragments as well as greater polymorphism than Kaibab samples. Heterozygosity estimates of Tcrb-C and Tcra-V1 sequences were determined for annually collected samples and compared with the yearly estimates of availability of hypogeous fungi, one of the major diet items of tassel-eared squirrels. In the Kaibab annual collections, Tcra-V1 heterozygosity declined with the decline in food resource, whereas heterozygosity of Tcrb-C sequences was inversely related to food resource. Similarly, a reduction in food resource for Abert squirrels in 1985 coincided with an increase in Tcrb-C heterozygosity in the same year. These results suggest that the diversity of gene families which participate in the immune response in mammals may be affected by environmental factors.

Animals↗
PubMed2005

Association of genetic polymorphism in GH gene with milk production traits in Beijing Holstein cows.

Associations were analysed between polymorphisms of the growth hormone gene (GH-MspI) (localized in intron 3) and milk production traits of Beijing Holstein cows (a total of 543 cows). Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method was used for identification of various genotypes. Frequencies of genotypes were 0.77, 0.21 and 0.02 for A/A, A/B and B/B, respectively. The frequency of the GH A allele is 0.875. The results of the least squares means show that in all three lactations, the GH A/A cows yielded more milk (P less than 0.01 for lactation I and P less than 0.05 for lactations II and III), whereas A/B cows showed higher milk fat content than A/A individuals (P less than 0.05 for lactations I and II, and P less than 0.01 for lactation III). The A/A cows yielded more fat than A/B individuals (P less than 0.01 only in lactation I). The A/A cows yielded more milk protein than A/B individuals (P less than 0.01 for lactations I, II, and III). The A/A cows produced milk of higher protein content than of A/B individuals (P less than 0.05 only in lactation II).

Animals↗
PubMed2003

Determination of -3858G-->A and -164C-->A genetic polymorphisms of CYP1A2 in blood and saliva by rapid allelic discrimination: large difference in the prevalence of the -3858G-->A mutation between Caucasians and Asians.

INTRODUCTION: Two mutations in CYP1A2, -164C-->A (allele CYP1A2*F) and -3858G-->A (allele CYP1A2*C), affecting the inducibility of the enzyme, have been published. The aim of this study was to develop a high throughput allelic discrimination assay for these mutations in both saliva and blood and to determine their frequency in Caucasians. METHODS: An allelic discrimination assay, based on the fluorogenic 5'-nuclease activity (TaqMan), was developed for the two mutations. Genomic DNA extracted from 17 saliva and 100 blood samples from Caucasians was analysed. RESULTS AND CONCLUSIONS: For the -164C-->A mutation, we found an allelic frequency of 68% in the Caucasian population, comparable with data published for Asians and Caucasians. For the -3858G-->A mutation, the allele frequency was only 2% in Caucasians, a much lower value than the approximately 25% reported in Asians (P<0.001). The presented allelic discrimination allows fast and accurate detection of these two mutations. Genotype calls were 100% identical for DNA from saliva and blood. Saliva is easily accessible and represents an excellent alternative to the traditionally used venous blood for genotyping.

Asian People↗
PubMed2005

Genetic polymorphisms and linkage disequilibrium of sulfotransferase SULT1A1 and SULT1A2 in a Korean population: comparison of other ethnic groups.

AIMS: To determine the allele frequencies of sulfotransferases (SULTs) 1A1 and 1A2 and their linkage disequilibrium in a Korean population and compare them with those of other ethnic groups. METHODS: Genotypes of the SULT1A1*1, *2, and *3 and SULT1A2*1, *2, and *3 allelic variants were determined in 234 Korean subjects using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. RESULTS: Allele frequencies for SULT1A1*1 and *2 were 0.876 [95% confidence interval (CI), 0.843-0.905] and 0.124 (95% CI, 0.096-0.157), respectively. Similarly, those for SULT1A2*1 and *2 were 0.885 (95% CI, 0.852-0.912) and 0.115 (95% CI, 0.088-0.150), respectively. However, no subject with SULT1A1*3 or SULT1A2*3 was detected. These genotype distributions are similar to those of Asian populations including the Chinese and Japanese, but quite different from other ethnic groups such as African-Americans and Caucasians. The expected allelic frequencies of SULT1A1 and SULT1A2 at Hardy-Weinberg equilibrium are quite similar to the observed distributions in the population. SULT1A1*2 and SULT1A2*2, the most common variant alleles of these two genes, are strongly and positively linked in the Korean population (D' = 0.8919, chi2 = 343.24, P = 0.0034). CONCLUSIONS: SULT1A1*2 and SULT1A2*2 are the major allelic variants in the Korean population, whereas the SULT1A1*3 and SULT1A2*3 alleles were not found. SULT1A1*2 and SULT1A2*2 are strongly linked.

Arylsulfotransferase↗
PubMed2006

Population research of genetic polymorphism at amino acid position 631 in chicken Mx protein with differential antiviral activity.

A single amino acid substitution between Asn and Ser at position 631 in the chicken Mx protein has been reported to determine resistant and sensitive antiviral activity. In this study, we investigate whether various kinds of chicken breeds and jungle fowls carry the resistant or sensitive Mx allelic gene by using the mismatched PCR-restriction fragment length polymorphism (RFLP) technique. In total, 271 samples from 36 strains of 17 chicken breeds and from 3 kinds of jungle fowls were examined. The rates of the resistant Mx gene and sensitive gene were 59.2% and 40.8%, respectively. Only a Red jungle fowl captured in Laos carried the resistant Mx gene, and the other three Red jungle fowls from Indonesia and Gray and Green jungle fowls all had the sensitive Mx gene. These results were confirmed by the determination of amino acid sequences in the GTPase effector domain of jungle fowls.

Alleles↗
PubMed2004

Chromosome and DNA damage analysis in individuals occupationally exposed to pesticides with relation to genetic polymorphism for CYP 1A1 gene in Ecuador.

DNA damage was measured by using the alkaline comet assay and the chromosomal aberration (CA) test using peripheral blood samples from 45 pesticide sprayers from Cayambe, Ecuador. From a total of approximately 200 nuclei scored for each donor with the comet assay, a highly significant increase in DNA migration was observed when compared with a similar unexposed control population. Additionally, in the CA test, the exposed individuals were found to be significantly different when compared to the control population. Polymorphisms for the CYP 1A1 (Msp I and Ile/Val) in exposed individuals were analyzed by PCR-RFLP and allele-specific PCR techniques. No association was found between the polymorphisms and higher levels of DNA damage as assessed by the comet assay.

Chromosome Aberrations↗
PubMed2006

IL-4 receptor genetic polymorphisms and asthma in Asian populations.

BACKGROUND: IL-4 receptor alpha chain is crucial for the binding and signaling of IL-4, which mediates isotype switching and IgE production. The gene of IL-4 receptor alpha chain is a candidate gene for asthma and atopy. OBJECTIVES: To determine whether Ile50Val and Q576R polymorphisms of IL-4 receptor alpha chain gene were associated with asthma and higher level of total IgE in Chinese, Malay and Indian populations. METHODS: About 303 physician-diagnosed asthmatic subjects (145 Chinese, 73 Malay, 85 Indian) and 355 unselected blood donors (157 Chinese, 98 Malay, 100 Indian) were recruited. Total serum IgE level was measured by ELISA. Genotypes of Ile50/Val and Q576R were determined by PCR and restriction enzyme length polymorphism (RFLP). RESULTS: Ile50Val heterozygote is less frequent in asthmatics than in controls in Malay population (P=0.007). No difference was found in Chinese and Indian population. Ile50/Ile50 was more prevalent in higher total serum IgE group (IgE>100IU/ml) in Malay. The prevalence of Ile50/R576 haplotype was lower in asthmatics than controls in Chinese (P=0.046); while the prevalence of Ile50/Q576 haplotype was lower in asthmatics than in controls in Malay (P=0.048). The frequencies of the two single nucleotide polymorphisms (SNPs) and haplotypes vary among ethnicities (P<0.05). CONCLUSION: IL-4RA gene polymorphisms and its haplotypes showed ethnic variations. The association between IL-4RA gene polymorphisms, its haplotypes and asthma differed from ethnicities.

Adult↗