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PubMed1992

P-domains as shuffled cysteine-rich modules in integumentary mucin C.1 (FIM-C.1) from Xenopus laevis. Polydispersity and genetic polymorphism.

A new frog integumentary mucin (FIM-C.1) has been discovered by molecular cloning. This mucin contains at least six typical P-domains as cysteine-rich modules. Shuffled P-domains have previously been detected in FIM-A.1, and they also form the basis of various P-domain peptides, which presumably have growth-modulating activities. Furthermore, FIM-C.1 contains at least three threonine-rich clusters, which consist of semi-repetitive cassettes. Various polydisperse transcripts have been characterized. They originate from two genes only and differ by deletions/insertions that are congruent with the semi-repetitive cassettes. Thus, polydispersities are probably generated by alternative splicing. Southern analysis revealed genetic polymorphism between different individuals. Furthermore, a specific antiserum was generated against a synthetic peptide deduced from the COOH-terminal end of FIM-C.1 and used for Western analysis.

Amino Acid Sequence↗
PubMed2004

Host genetic polymorphisms in human immunodeficiency virus-related neurologic disease.

The objective of this study was to determine whether host genetic polymorphisms influence the risk of developing human immunodeficiency virus (HIV) encephalitis and vacuolar myelopathy. Allelic association studies were carried out with common polymorphisms in candidate genes that are postulated to play a role in the pathogenesis of HIV-related neurologic complications. The authors studied brains and spinal cords from 270 patients who died of acquired immunodeficiency syndrome (AIDS) from 1989 to 1996. All had complete gross and microscopic pathologic evaluations, and the presence of microglial nodules, multinucleated giant cells, myelin pallor, and vacuolar myelopathy was assessed by an experienced neuropathologist who was blinded to the genotype. DNA was extracted from frozen brain samples, and determination of the presence of the APOE4, TNF-2, IL-1B*2, ILIRN*2 polymorphisms was determined by polymerase chain reaction (PCR) and restricted fragment length polymorphism (RFLP) mapping. The authors did not detect a consistent association between inheritance of candidate polymorphic alleles and the pathologic findings of HIV encephalitis or vacuolar myelopathy. Allelic association studies with candidate genes are powerful techniques that have the potential to contribute to understanding the pathophysiology of HIV-related neurodegeneration. This preliminary study, although including a substantial number of patients, was not sufficiently powered to exclude a modest but clinically significant effects. Future studies will require much larger sample sizes and technical advances to allow screening at larger number of candidate loci.

AIDS Dementia Complex↗
PubMed2003

Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development.

OBJECTIVE: We examined the potential association between alcohol consumption and genetic polymorphisms in the alcohol metabolizing enzymes, CYP2E1 and ALDH2, in individual susceptibility to breast cancer in a Korean study population. METHODS: Three hundred and forty-six histologically confirmed breast cancer patients and 377 controls with no present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2001. The CYP2E1 RsaI polymorphism was determined by a real time PCR method, and the ALDH2 Glu487 Lys polymorphism was determined by a PCR method with confronting two-pair primers (PCR-CTPP). RESULTS: The drinking women had a 1.4-fold risk for breast cancer (95% CI = 0.99-2.11) compared to never drinkers after adjustment for age and family history of breast cancer. No statistically significant overall differences were seen in the genotype frequencies between breast cancer cases and controls. However, the "ever"-drinking women with the CYP2E1 c2 allele containing genotypes had a 1.9-fold risk (95% CI = 0.99-3.83) for developing breast cancer compared to non-drinkers with the CYP2E1 c1/c1 genotype (P for interaction = 0.043). CONCLUSION: This study therefore suggests that the CYP2E1 c2 allele may influence the individual susceptibility to breast cancer in alcohol-consuming women.

Adult↗
PubMed2000

Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer.

Epidemiologic studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. For a number of years, the mechanism for estrogens in carcinogenesis was thought to be that of mitotic stimulation, with the growth promotion of ductal epithelial cells harboring precursor mutations in the breast. However, evidence is now available that estrogens may act as initiators of cellular alterations and tumorigenesis. Investigation and measurement of serum levels of estrogens in epidemiologic studies may, therefore, be misleading, because they may reflect levels quite different from those of hormone metabolites to which the target tissue is exposed. Proportions of hormone metabolites may be estimated by evaluation of associations between breast cancer risk and genetic polymorphisms in enzymes involved in hormone metabolism. A number of molecular epidemiologic studies have been conducted to evaluate associations between polymorphic genes involved in steroid hormone metabolism (i.e., CYP17, COMT, CYP1A1, CYP19, GST, and MnSOD) that may account for a proportion of enzymatic variability, and results are discussed in this review. There are strengths and limitations to such an approach, foremost of which may be the lack of insight into the extent to which individual variability in estrogen exposure may be explained by allelic variation. Variability in other endogenous and exogenous factors that impact parent hormones and their metabolites along activation and conjugation pathways may also affect associations in case-control comparisons. This and other possible reasons for inconsistencies in results of molecular epidemiologic studies are discussed. Contributions from population-based studies and those from the laboratory may together move this field ahead and more clearly elucidate the basis of hormonally related cancers, identifying etiologic factors and susceptible populations for preventive strategies.

Breast Neoplasms↗
PubMed2003

[Genetic polymorphisms of short tandem repeats loci F13A01, FESFPS, vWA from Han population in Guizhou].

OBJECTIVE: To understand the allele structure and genetic polymorphism at F13A01, FESFPS and vWA short tandem repeats (STRs) loci for Han population in Guizhou province of China, and to construct a preliminary database. METHODS: One hundred sixty unrelated individuals in Han population from Guizhou were analyzed by multiplex polymerase chain reaction. The resultant allele frequencies were compared with those of other population or race database. RESULTS: The genotype distributions of F13A01, FESFPS and vWA were in accordance with Hardy-Weinberg equilibrium. The combined discrimination power and polymorphism information content were 0.9984 and 0.9700 respectively. CONCLUSION: All of the three loci in this study provide useful markers for forensic paternity test and for genetic purposes.

Alleles↗
PubMed2000

Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity.

Arsenic is a recognized human carcinogen, but experimental cancer studies are negative. There is a variation in susceptibility among individuals, which probably is related to variation in metabolism. Inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are less toxic and more readily excreted in urine than the inorganic arsenic. The rate of methylation of arsenic varies considerably between species. Most population groups studied so far have on average 10-30% inorganic, 10-20% MMA, and 60-70% DMA in urine, but there is a considerable inter-individual variation. Also, recent studies have identified groups with unusually low or high urinary excretion of MMA. Thus, there seems to be a genetic polymorphism in the biomethylation of arsenic. However, the methyltransferases involved in arsenic methylation have not been characterized.

Animals↗
PubMed2007

Genetic polymorphisms and treatment response in advanced non-small cell lung cancer.

BACKGROUND: Genetic polymorphisms involved in DNA repair and apoptosis are suspected to influence patient response to cancer treatment. To evaluate the effect of genetic variations on chemotherapy and/or radiotherapy, we genotyped four single nucleotide polymorphisms (SNPs) in ATM (A60G), ERCC1 (Asn118Asn), APE1 (Asn148Glu), and iASPP (A67T), and examined their associations with treatment response among patients with advanced non-small cell lung cancer (NSCLC). METHODS: Included in the study were 230 patients diagnosed with inoperable advanced NSCLC. Of these patients, 76 received platinum-based chemotherapy, 125 received chemotherapy plus radiation, and 29 received radiotherapy only. The SNPs were genotyped using the TaqMan methods. RESULTS: Among the patients who received chemotherapy only, ERCC1 (Asn118Asn) genotype was significantly associated with treatment response. Patients with either one or two T alleles (T/T+C/T) at Asn118Asn were more likely not to respond to platinum-based chemotherapy compared to those without the T allele (OR=4.10, 95% CI: 1.31-12.85). For patients who were treated with both chemotherapy and radiotherapy, treatment response seemed to differ substantially between patients with different genotypes of iASPP (A67T). Patients carrying an A allele (A/T+A/A) at A67T were more likely to respond to combined chemotherapy and radiotherapy compared to those not carrying the A allele (OR=0.25, 95% CI: 0.08-0.74). An association with treatment response was also suggested for the selected polymorphism in APE1, but no association was found for the ATM polymorphism. CONCLUSION: We found that SNPs in ERCC1 and iASPP were associated with response to chemotherapy or combined chemotherapy and radiotherapy in NSCLC patients. These findings support the notion that genetic variations related to DNA repair or apoptosis may affect the effect of chemotherapy or radiation on NSCLC.

Adult↗
PubMedDate not supplied

Genetic polymorphism of drug metabolizing enzymes (CYP2E1, GSTP1) and susceptibility to bladder cancer in North India.

Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens and genetic polymorphisms of CYP2E1 and GSTP1 genes have been studied extensively to evaluate the relative risk of various cancers. In the present study, we examined associations with CYP2E1 and GSTP1 gene polymorphisms in sporadic bladder cancers from North Indian patients. The subjects were 106 bladder cancer (Ca-B) cases and 162 age-matched controls. The GSTP1 313 A/G polymorphism was determined by the PCR/RFLP method using peripheral blood DNA. Binary Logistic Regression Model was used for assessing differences in genotype prevalence and their associations between patient and the control group. We observed a non-significant association in Pst1 polymorphism of the CYP2E1 gene; though the A/G genotype (OR = 2.69, 95% CI=1.57- 4.59, P= 0.000) and G/G genotype (OR = 7.68, 95% CI=2.77- 21.26, P= 0.000) of the GSTP1 gene polymorphism alone or in combination with tobacco users were highly significant (OR=24.06; 95% CI: 4.80- 120.42; P =0.000) when compared to the controls. The results of our study demonstrated that the GSTP1 313 G/G polymorphism is a strong predisposing risk factor for bladder cancer in the North Indian population.

Case-Control Studies↗
PubMed1999

Glutathione S-transferase (GST) M1, T1, P1, N-acetyltransferase (NAT) 1 and 2 genetic polymorphisms and susceptibility to colorectal cancer.

A case-control study was carried out to examine the relation between genetic polymorphisms of five genes, cigarette smoking and colorectal cancer risk. We collected blood samples from 106 colorectal cancer patients and 100 healthy persons, then analyzed them to identify genotypes for glutathione S-transferase (GST) M1, T1, P1, N-acetyltransferase (NAT) 1 and 2 by the PCR method. We also collected smoking history data from all participants by questionnaire. From statistical evaluation on various combinations of genotypes, we observed that the cancer risk of those who have both GSTM1 present genotype and GSTP1 Adenine/Adenine homozygous genotype was significantly less than those who have other combinations of genotypes for two genes. For other combinations of genes, there was no significant association between genotype and cancer risk. There was also no significant association between amount of cigarette smoking and the cancer risk. These findings suggest that it is valuable to study cancer risk when examining genotypes of more than two genes at the same time. For further study, we need to collect more samples to increase statistical reliability, and besides cigarette smoking, include the nutrition data as an environmental factor.

Arylamine N-Acetyltransferase↗
PubMed1982

Genetic polymorphism of phenformin 4-hydroxylation.

The ability to oxidize a single 50-mg dose of phenformin to its 4-hydroxy metabolite was determined in 195 individuals. Variations in the urinary ratio of phenformin/4-hydroxyphenformin ranged from 1 to 184. Family studies were consistent with the hypothesis that this variability resulted from a single gene mode of inheritance in which impaired hydroxylation of phenformin appears as an autosomal recessive trait. Both genotype frequencies and the degree of dominance of the extensive metabolizer phenotype over the recessive showed a remarkable resemblance to those described for debrisoquine 4-hydroxylation, which was confirmed by the high degree of correlation (rs=0.785, P less than 0.0001) between the phenformin ratio and the debrisoquine metabolic ratio. Such close agreement between the metabolism of these drugs may indicate that the same genetic control is in operation. Such genetic polymorphism of phenformin hydroxylation may have important implications for therapeutic response and for the possibility of toxic effects in a few individuals.

Adolescent↗
PubMed1986

The significance of over- and underdominance for the maintenance of genetic polymorphisms. II. Overdominance and instability with random mating.

Part I of the present series demonstrates that globally stable polymorphic equilibria may show underdominance in Darwinian fitness. Hence, overdominance in fitness can no longer be conceived of as a necessary condition for the stability of a polymorphism. In the present paper, the question is posed as to whether overdominance is at least sufficient for this stability. A population of randomly mating individuals is considered, where selection operates uniquely through differential fecundities of particular mating types and may generate either a heterozygote excess or deficit relative to Hardy-Weinberg proportions. It turns out that both unstable central overdominance and stable central underdominance are possible and that their occurrence is strongly related to an excess or a deficiency of heterozygotes in the vicinity of the regions of instability or stability. As one consequence, the above suggested sufficiency of heterozygote superiority is not valid, even in random mating populations. Based on the results of both papers of this series, which demonstrate the inadequacy of over- and underdominance as indicators of stability or instability, a modified overdominance principle is discussed. This principle states that a biallelic polymorphism is maintained if the heterozygote is superior in its degree of "heterogamous self-replication" to the degrees of "autogamous self-replication" of the corresponding homozygotes. It is derived with the help of fractional fitnesses, and it is pointed out that certain ratios of these may be more useful for finding evolutionary constants which govern the maintenance of genetic polymorphisms than are ratios of total fitnesses.

Animals↗
PubMed2002

The human glutathione transferase alpha locus: genomic organization of the gene cluster and functional characterization of the genetic polymorphism in the hGSTA1 promoter.

By searching the human genome sequence database with human hGSTA1 and hGSTA4 cDNA sequences, we identified three PAC and one BAC clones covering more than 400 kilobases and containing the entire GST alpha gene cluster. The cluster consists of five genes: hGSTA1, hGSTA2, hGSTA3, hGSTA4 and hGSTA5, and seven pseudogenes that are distinguished as such by single-base and/or complete exon deletions. Using gene-specific probes we demonstrated that hGSTA1, hGSTA2 and hGSTA4 mRNAs are widely expressed in human tissues, whereas hGSTA3 mRNA appears to be a rare message subject to splicing defects. Although examination of the hGSTA5 gene sequence suggests that it is a functional gene, hGSTA5 mRNA could not be detected in human tissues we studied. hGSTA1 expression has been shown to be influenced by a genetic polymorphism, that consists of two alleles hGSTA1*A and hGSTA1*B, containing three linked base substitutions in the proximal promoter, at positions -567, -69 and -52. Constructs consisting of the luciferase gene controlled by variant hGSTA1 promoters showed differential expression when transfected into HepG2, GLC4 and Caco-2 cells: hGSTA1*A > hGSTA1*B. Directed mutagenesis for each base substitution indicated that the base change -52G>A was responsible for the differential promoter activity of hGSTA1*A and hGSTA1*B. The base at position -52 also altered binding of the ubiquitous transcription factor Sp1, as determined by gel shift analysis. Thus it may be postulated that hGSTA1 genotyping will be of importance to determine individual susceptibility to certain cancers or the efficacy of chemotherapeutics via its effect on hGSTA1 expression.

Amino Acid Sequence↗
PubMed2002

Enantioselective analytical methods in pharmacokinetics with specific reference to genetic polymorphic metabolism.

The new trend towards developing enantiospecific drugs has increased the interest in enantiospecific pharmacokinetics of chiral drugs, mainly in the case where only one of the two enantiomers is responsible for the pharmacological activity. Enantiospecific bioassays are also useful in investigating the pharmacokinetic behaviour of the two enantiomers when a given drug is marketed as racemate. The stability of the stereogenic centre in vitro and in vivo, as far as unidirectional and bidirectional inversions are concerned, is another reason for requiring stereospecific assay and bioassay. These assays are often complicated in order to achieve quantification, mainly for in vivo measurements, which are often in the low pg/ml range. This paper considers the enantiospecific bioassays, the methods and approaches used, the need for chemical derivatization, and the difficulties involved. It includes a specific discussion for the genetic polymorphic metabolism involving stereogenic centres.

Chromatography↗
PubMed2001

[Genetic polymorphism and risk of thromboses].

We have attempted to establish a systematic pathogenetic analysis of thrombophilia by including assays of antithrombin III(AT III), protein C(PC), protein S(PS), fibrinogen, plasminogen and heparin cofactor II by both functional and immunological methods as well as detecting lupus anticoagulants. Such a comprehensive scheme was instrumental in systematically identifying and confirming the pathogenesis of 164 cases which otherwise would have escaped detection since 1994 in our laboratory (Kyushu University Hospital). The analysis was conducted on 485 consecutive patients with venous thrombosis, arterial thrombosis and disorders in which small vessel thrombosis were implicated. Hundred and sixty four patients, (40% of the examined patients), were found to have low activities of PS, PC, ATIII etc. Among them, seventy five patients(46%) had low PS activity, and twenty nine(18%) had low PC activity. Genetic analyses performed on specimens with low PS/PC activities resulted in the confirmation of 24 genetic abnormalities. Such genetic abnormalities, however, does not solely lead to the pathogenesis of thromboses. We have found that some genetic polymorphisms, such as PS Tokushima, factor XII 46C allele, were also additional risk factors for thromboses.

Antithrombin III↗
PubMed2000

Genetic polymorphisms in the cell growth regulated gene, SC1 telomeric of the HLA-C gene and lack of association of psoriasis vulgaris.

Psoriasis vulgaris is associated with the HLA-Cw6 and Cw7 antigens. We have previously narrowed down the critical region most likely to contain the psoriasis vulgaris gene to 111 kb spanning 89 kb to 200 kb telomeric of the HLA-C locus by microsatellite mapping. This segment includes three known genes (POU5F1, SC1 and S) and four new expressed genes. Among them, SC1 (TCF19) is the cell growth regulated gene possibly with trans-activator activity. Since psoriasis vulgaris is a common skin disorder characterized by hyperproliferation of epidermal cells, it is tempting to speculate that the SCI gene is one of the strong candidate genes responsible for the development of psoriasis vulgaris. Here, we investigated genetic polymorphisms in the SC1 gene by direct DNA sequencing and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) techniques. Three single nucleotide polymorphisms in exon 2, two of which are accompanied by amino-acid substitutions, were identified. Further, one 4-bp deletion polymorphism was detected around the acceptor site of the lariat-shaped structure necessary for RNA splicing in intron 2. No significant difference in the dimorphic or haplotypic distribution at these four polymorphic sites was observed between the patients with psoriasis vulgaris and healthy controls. This suggests that the susceptible gene for psoriasis vulgaris is not the SC1 gene itself, although a unique homozygous haplotype was identified in the patients.

Base Sequence↗
PubMed2002

Relationship between serum hormone concentrations, reproductive history, alcohol consumption and genetic polymorphisms in pre-menopausal women.

Reproductive characteristics, alcohol intake and polymorphisms in genes encoding sex-steroid metabolizing enzymes might influence the risk of hormone-related cancers by changing circulating concentrations of sex hormones. The relationship between these factors and serum concentrations of estradiol, progesterone, androstenedione, testosterone and DHEA was evaluated in a cross-sectional study of 218 pre-menopausal women from Kaiser Permanente Health Plan in Portland, Oregon. Risk factor information was obtained from questionnaires and hormone serum concentrations were determined by radioimmunoassays. Genotypes for CYP11A 5'UTR(tttta)n, CYP17 5'-UTR -34 T>C, CYP19 IVS4(ttta)n, CYP1B1 (L432V and S453N) and COMT (V158M) were determined from genomic DNA samples. Increasing number of full-term pregnancies was associated with a significant decrease in late-follicular progesterone levels (p-trend = 0.03). Increasing alcohol consumption was associated with higher estradiol levels averaged through the menstrual cycle (p-trend = 0.009) and higher progesterone levels during luteal phase (p-trend = 0.04). Androstenedione and testosterone levels were higher among light to moderate drinkers compared to non-drinkers, although we only observe a significant trend with increasing levels of alcohol consumption for androstenedione. Women heterozygous or homozygous for the CYP1B1 L432V or the S453N polymorphisms had increased luteal estradiol levels (p-value = 0.04 for L432V and 0.04 for S453N). None of the other factors evaluated was significantly associated with serum concentration of hormones. In conclusion, results from this cross-sectional study of pre-menopausal women provide support for an association between light to moderate alcohol intake and elevated levels of estrogen and androgen levels. Our data suggest that circulating levels of progesterone might be related to parity and alcohol consumption, however the biological plausibility of the observed associations is unclear. We found little support for an influence of the evaluated genetic polymorphisms in the steroid synthesis and metabolism pathway on serum hormone levels, except for a possible effect of the CYP1B1 L432V and S453N polymorphisms on serum estradiol levels.

Adolescent↗
PubMed2006

Glutathione S transferase M1 and T1 genetic polymorphisms are related to the risk of primary open-angle glaucoma: a study in a Turkish population.

BACKGROUND: Genetic factors and oxidative damage have been shown to have a role in the development of primary open angle glaucoma (POAG). AIM: To determine the effects of genetic polymorphisms of glutathione S transferase (GST)M1 and GSTT1 on the risk of POAG in a Turkish population. METHODS: Using a multiplex polymerase chain reaction (PCR), GSTM1 and GSTT1 gene polymorphisms were analysed in 144 patients with POAG and in 121 otherwise healthy controls of similar age. RESULTS: The GSTM1 positive genotype and the GSTT1 null genotype had an increased risk of developing POAG (p<0.001, OR 2.93, 95% CI 1.66 to 5.20 and OR 4.25, 95% CI 2.30 to 7.80, respectively). The risk of glaucoma also increased significantly in subjects with a combination of GSTM1 positive and GSTT1 null genotypes (p<0.001, OR 3.46, 95% CI 1.64 to 7.38). CONCLUSION: The GSTM1 positive genotype and GSTT1 null genotype or the combination of both may be associated with the increased risk of development of POAG in the Turkish population.

Aged↗
PubMedDate not supplied

Genetic polymorphism of chemokine receptors CCR2 and CCR5 in Swedish cervical cancer patients.

Chemokines are chemotactic cytokines that orchestrate leukocyte trafficking in tissues, thus, playing an important role in regulation of immunological processes. The aim of this study was to investigate the association of human papillomavirus (HPV) infection and cervical cancer with two DNA polymorphisms of the chemokine receptors CCR5-delta32 and CCR2-64I. The study material consisted of 50 cervical intraepithelial neoplasia (CIN) cases and 50 of age and sampling-date matched controls, 100 invasive cervix cancer cases and 100 of their corresponding matched disease-free controls. Pyrosequencing was employed to genotype the CCR2-64I polymorphism. CCR5-delta32 was genotyped using standard PCR fragment length analysis. The frequencies of CCR2 and CCR5 genotypes from 150 patients and 150 healthy controls were representative of the general population according to the Hardy-Weinberg equilibrium analysis. Risk association was computed with conditional logistic regression analysis. HPV-positive individuals with the rare CCR5deelta32/delta32 genotype have a risk of 4.58 (CI = 0.40-52.64, p-value = 0.045) compare to HPV negative group. The delta-32 mutation on the CCR locus is imperceptibly associated with increased risk of HPV infection. In total, cervical neoplasia was not associated with genetic polymorphism of CCR2 and CCR5.

Base Sequence↗