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PubMed1989

Second genetic polymorphism of tear proteins in the rat (Rtp-2).

Electrophoresis of tear proteins on agarose gel showed polymorphism in the fastest migrating protein among 32 inbred strains of rats. In 8 strains, the protein was missing (RTP-2 B), while the other strains expressed the protein (RTP-2 A). The trait was found to be controlled by a single autosomal locus. The designation Rtp-2 locus, with two alleles (Rtp-2a, Rtp-2b), is tentatively proposed. The Rtp-2 locus is loosely linked to c locus, with a recombination frequency of 36.7 +/- 5.4 percent.

Animals↗
PubMed2005

Genetic polymorphism of the serine rich antigen N-terminal region in Plasmodium falciparum field isolates from Brazil.

In this work we investigated the frequency of polymorphism in exon II of the gene encoding most of the amino-terminal region of the serine rich antigen (SERA) in Plasmodium falciparum field samples. The blood samples were collected from P. falciparum infected individuals in three areas of the Brazilian Amazon. Two fragments have been characterized by polymerase chain reaction: one of 175 bp corresponding to the repeat region with 5 octamer units and one other of 199 bp related to the 6 repeat octamer units of SERA protein. The 199 bp fragment was the predominant one in all the studied areas. The higher frequency of this fragment has not been described before and could be explained by an immunological selection of the plasmodial population in the infected individuals under study. Since repeat motifs in the amino-terminal region of SERA contain epitopes recognized by parasite-inhibitor antibodies, data reported here suggest that the analysis of the polymorphism of P. falciparum isolates in different geographical areas is a preliminary stage before the final drawing of an universal vaccine against malaria can be reached.

Amino Acid Sequence↗
PubMed2000

Genetic polymorphisms of the IL-1alpha and IL-1beta genes in African-American LJP patients and an African-American control population.

BACKGROUND: A functional polymorphism of the interleukin-1 beta (IL-1beta) gene has been proposed to be a risk factor for periodontitis. In adult forms of periodontitis, non-smokers of northern European heritage carrying the "2" allele of the IL-1alpha-889 and the IL-1beta +3953 RFLPs in either the heterozygous or the homozygous state at both loci were observed to have a greater risk for developing severe periodontitis. Studies of early-onset periodontitis (EOP) found that allele "1" of both IL-1alpha-889 and IL-1beta +3953 was transmitted more frequently with the EOP phenotype. The purpose of the present study was to determine the prevalence of the IL-1alpha and IL-1beta genotype polymorphisms in an African-American (AA) control population and in 37 African-Americans with localized juvenile periodontitis (LJP). METHODS: The IL-1alpha +4845 and IL-1beta +3953 loci were genotyped by PCR amplification, followed by restriction enzyme digestion and gel electrophoresis. The IL-1alpha +4845 locus, in linkage disequilibrium (>99%) with IL-1alpha-889, was genotyped because it is technically easier. Data were analyzed using r x c contingency tables. RESULTS: The IL-1beta +3953 allele "1" was carried by >99% of the AA control population and by 100% of the AA LJP group, with most individuals being homozygous 1,1. The prevalence of the composite genotype with at least one allele "2" at each of the IL-1beta +3953 and IL-1alpha +4845 loci was 14% (AA control group) and 8% (AA LJP group). CONCLUSIONS: Given the high frequency of the IL-1beta allele "1" in the African-American population, it would appear that knowledge of this +3953 polymorphism would provide little diagnostic or predictive information for LJP.

Adult↗
PubMed2002

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

Animals↗
PubMed2006

Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans.

INTRODUCTION: Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS: GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS: Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION: The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION: This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.

Aged↗
PubMed2006

Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1).

C57BL/6 (B6) mice develop glucose intolerance with age, whereas C3H/He (C3H) mice do not. In this study, we examined whether this differential glucose homeostasis was associated with differences of proteolytic activation of pancreatic prohormones. Radioimmunoassays showed comparable levels of fasting plasma insulin between the two strains but a significantly lower glucagon level in B6 mice. Pulse-chase analysis of glucagon biosynthesis in isolated pancreatic islets revealed that proglucagon was less efficiently processed in B6 mice. Because proprotein convertase (PC)2 and its 7B2 helper protein are required for this processing, we quantified islet mRNA levels by RT-PCR and protein levels by immunoblotting. The levels of proPC2 mRNA were similar between the two strains, but B6 protein extracts contained less of the mature PC2. In contrast, 7B2 mRNA and protein levels were both significantly lower in B6 pancreas. Sequencing of the 7B2 gene promoter and cDNA in the two strains revealed seven single nucleotide polymorphisms and one dinucleotide insertion/deletion in the cDNA as well as a single nucleotide polymorphism and two insertions/deletions in the promoter. Differential expression of 7B2 may contribute to the difference between B6 and C3H mice not only in glucagon production and secretion but also in glucose tolerance.

Aging↗
PubMedDate not supplied

Some aspects of genetic polymorphism in the biotransformation of antidepressants.

Tricyclic antidepressants are all hydroxylated by cytochrome P450 (CYP) 2D6, but the tertiary amines, amitriptyline, clomipramine and imipramine, are also N-demethylated to the active metabolites, nortriptyline, N-desmethylclomipramine and desipramine, by several CYPs, including the polymorphic CYP2C19, CYP1A2 and CYP3A4. The five selective serotonin reuptake inhibitors, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are also oxidised by the CYP enzyme system. Thus, fluoxetine, fluvoxamine and paroxetine are partially metabolised by CYP2D6, citalopram by CYP2C19 and sertraline by at least five different CYPs. Paroxetine and fluoxetine are very potent inhibitors of CYP2D6 while citalopram, fluvoxamine and sertraline are moderate inhibitors of this enzyme. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9. Since the termination of the human genome project, there is no longer a technical hindrance to the identification of all of the genes involved in the clinical response to antidepressants. Research in the future will involve modern technologies and new scientific disciplines, including DNA-micro-array technology and bioinformatics. The research ultimately aims at developing better and safer antidepressants and/or better and safer use of currently available antidepressants.

Animals↗
PubMedDate not supplied

[Genetic polymorphism and treatment of chronic bowel inflammatory diseases: the example of azathioprine].

Azathioprine is an immunosuppressive drug used in the treatment of inflammatory bowel disease. It is a prodrug that is hydrolysed to 6-mercaptopurine, which represents the active form. Azathioprine is also used in the treatment of leukaemia in children and in organ transplantation. Azathioprine treatment is associated with adverse effects such as leukopenia and aplasia. These adverse effects are related to a single nucleotide polymorphism, including the inability of cells to synthesize thiopurine methyltransferase (TPMT). TPMT is a detoxification enzyme that limits 6-thioguanine nucleotide production and thereby interferes with normal DNA and RNA synthesis. This review presents the different approaches used for azathioprine therapeutic monitoring in IBD treatment and discusses the discrepancies in recent clinical trials.

Azathioprine↗
PubMed1995

Genetic polymorphism (Arg353-->Gln) in coagulation factor VII gene and factor VII levels (coagulant activity, antigen and binding ability to tissue factor) in 101 healthy Japanese.

We studied the frequency of the Msp I genotype (Gln353) for factor VII in 101 young healthy Japanese individuals, and the levels of factor VII-related procoagulant activity (FVII:c), antigen (FVII:ag) and binding ability to tissue factor (FVII-TF binding). The frequency of the allele coding for the factor VII Gln353 was 0.05 among this group. Individuals with genotype M1M1 had an FVII:c of 103.52 +/- 17.85% (mean +/- SD), FVII:ag of 102.50 +/- 18.42% (mean +/- SD) and FVII-TF binding of 101.03 +/- 22.22% (mean +/- SD). Triglyceride levels of subjects with the M1M1 genotype were 84.34 +/- 44.97 mg dl-1 (mean +/- SD). FVII:c (50%), FVII:ag (45%) and FVII-TF binding (36%) from an individual with the M2M2 type was the lowest, with a triglyceride value of 39 mg dl-1. On the other hand, individuals with the genotype M1M2 had an FVII:c of 75.57 +/- 9.61% (mean +/- SD), FVII:ag of 72.43 +/- 8.54% (mean +/- SD) and FVII-TF binding of 68.14 +/- 14.91% (mean +/- SD). FVII:c, FVII:ag and FVII-TF binding in individuals with the M1M2 and M2M2 genotypes were significantly lower than those in individuals with the M1M1 genotype.

Adult↗
PubMed1993

Drug metabolism and genetic polymorphism in subjects with previous halothane hepatitis.

To test the hypothesis that halothane hepatitis is caused by a combination of altered drug metabolism and an immunoallergic disposition, the metabolism of antipyrine, metronidazole, sparteine, phenytoin, and racemic R- and S-mephenytoin was investigated in seven subjects with previous halothane hepatitis. The HLA tissue types and the complement C3 phenotypes were also determined. The metabolism of antipyrine and metronidazole was within normal range in all subjects, and they were all fast or extensive metabolizers of sparteine, mephenytoin, and phenytoin. HLA tissue types were unremarkable. Five of the seven subjects had complement C3 phenotypes F or FS. In the general population phenotype S is the most common, but the difference in complement C3 phenotypes is not statistically significant (p = 0.07). We conclude, although in a limited number of patients, that subjects with previous halothane hepatitis do not appear to be different from controls with regard to drug metabolism and HLA tissue type. The possibility of a higher frequency of complement C3 phenotype F and FS needs further investigation.

Adult↗
PubMed1980

Genetic polymorphisms of blood and milk and reproduction in Holstein cattle.

Associations of blood and milk protein polymorphisms with reproductive performance were examined in more than 32,000 services in 15,000 service periods of 6,000 cows and 700 service sires in Holsteins. Seven blood groups, one serum protein, and four milk proteins were analyzed for relation to reproductive traits including conception rate and days open. Associations between polymorphic systems and reproductive traits in 15 of 112 analyses were significant. The S blood system appeared most influential, having statistical significance in five of ten traits. These were conception rates in all services for female phenotypes, male phenotypes, and male by female phenotypes combined, conception rate in first services for female phenotypes, and probability of conception for female phenotypes. The FV system influenced conception rates in all services and in first services for male by female phenotypes combined. Four of the polymorphic systems had no effect on any of the reproductive traits. Maternal-fetal incompatibility was not evident from comparing parental combinations of aborted fetuses and normal calves. Conception rates declined with age of cow. For animals that ultimately conceived, conception rates did not decline consistently from first to later services within a service period.

Animals↗
PubMed1994

Nonlinear effects of chicken endogenous viruses on body weight may be responsible for maintaining these elements in a stable genetic polymorphism.

The effects of presence or absence of individual endogenous virus (ev) genes on production traits was studied in a highly productive commercial layer cross. Age and BW at first egg, egg production, egg weight, and mature BW were recorded for each bird. The birds were examined for presence of ev gene fragments by Southern analysis. A general linear model was used to determine significance of effects of the 21 individual ev fragments on the individual traits and the effects of all ev fragments taken together on each of the traits. Seven significant effects were found for individual ev fragments on individual traits. Four of these involved BW at first egg, and all ev gene fragments taken together had a significant effect on BW at first egg, explaining 17% of total phenotypic variation in this trait. Significant nonlinear correlations were found between total number of ev genes and both BW at first egg and mature BW, with birds having a moderate number of ev genes showing the lowest BW. For age at first egg and egg weight, nonlinear correlations, although not significant, were consistent in sign with those found for BW, implying minimum trait magnitude at moderate number of ev genes. These effects imply that animals with intermediate numbers of ev genes will tend to be favored by commercial selection in layer flocks, whereas birds with either too many or too few ev genes will tend to be culled.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpharetrovirus↗
PubMed2004

GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population.

AIM: To test the hypothesis that, in the Southeastern Brazilian population, the GSTT1, GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer. METHODS: We conducted a study on 100 cases of gastric cancer (GC), 100 cases of chronic gastritis (CG), and 150 controls (C). Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR. CYP2E1/PstI genotyping was performed using a PCR-RFLP assay. RESULTS: No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups. However, a significant difference between CG and C was observed, due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group. The GSTT1 null genotype occurred more frequently in Negroid subjects, and the GSTM1 null genotype in Caucasians, while the GSTM1 positive genotype was observed mainly in individuals with chronic gastritis infected with H pylori. CONCLUSION: Our findings indicate that there is no obvious relationship between the GSTT1, GSTM1 and CYP2E1 polymorphisms and gastric cancer.

Adolescent↗
PubMed2006

A p53 genetic polymorphism of gastric cancer: difference between early gastric cancer and advanced gastric cancer.

AIM: To investigate the role of the polymorphism of p53 codon 72 in early gastric cancer (EGC) and advanced gastric cancer (AGC) in Korean patients. METHODS: DNA was extracted from blood samples of gastric cancer patients (n=291) and controls (n=216). In the p53 codon 72 genotypes were determined by PCR-RFLP. RESULTS: Patients with gastric cancer had a significantly higher frequency of the homozygous proline (Pro) allele than the control (P=0.032). Patients with AGC had a significantly higher frequency of the Arg/Arg (arginine) allele (P=0.038) than EGC and a similar Pro/Pro allele. The signet ring cell type had a higher frequency of the Pro/Pro allele than other types (P=0.031). The Pro/Pro genotype carries a 3.9-fold increased risk of developing gastric cancer (95% CI, 1.3-15.4, P=0.039) when compared to Arg/Arg and Arg/Pro genotypes and to develop EGC is a 5.25 fold increased risk (95% CI, 1.8-19.6, P=0.021). CONCLUSION: The Pro/Pro genotype of the p53 codon 72 polymorphism carries a higher risk for gastric cancer in general and is also associated with a much higher risk for EGC than AGC.

Adult↗
PubMed2005

Genetic polymorphism of GSTM1 in women with breast cancer and interact with reproductive history and several clinical pathologies.

Due to the conflicting results regarding the association between breast cancer and the GSTM1 null mutation, our aim was to research this association in a Brazilian population and correlations with smoking, reproductive history and several clinical pathologies. A case-control study was performed on 105 women with breast cancer and 278 controls. Extraction of DNA was accomplished according to the protocol of the GFX kit and polymorphism analysis by the PCR technique. The control and experimental groups were compared and statistical analysis assessed by X2 or Fisher's exact test. The deletion in the GSTM1 gene in the breast cancer group had a prevalence of 32 (30.4%) individuals with the presence of null mutation. In the control group, the null mutation was present in 104 (37.4%) women. Upon comparison of the two groups, no statistically significant difference of the GSTM1 gene was observed, with an odds ratio (OR) of 0.74, 95%, confidence interval (CI) 0.45 - 1.20, p = 0.277. The results conclusively show that single gene GSTM1 polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, in this study no correlation was found between GSTs and smoking, reproductive history and several clinical pathologies with respect to cancer risk.

Adult↗
PubMed1999

Influence of genetic polymorphisms of biotransformation enzymes on gene mutations, strand breaks of deoxyribonucleic acid, and micronuclei in mononuclear blood cells and urinary 8-hydroxydeoxyguanosine in potroom workers exposed to polyaromatic hydrocarbons.

OBJECTIVES: Airborne exposure to polycyclic aromatic hydrocarbons (PAH) in the potroom of an aluminum reduction plant was studied in relation to genotoxic or mutagenic effects, and the possibility of host genotypes of different metabolizing enzymes modifying associations between PAH exposure and genotoxic or mutagenic response was assessed. SUBJECTS AND METHODS: Ninety-eight male potroom workers and 55 male unexposed blue-collar workers constituted the study population. Micronuclei in CD4+ and CD8+ lymphocytes, DNA (deoxyribonucleic acid) single-strand breaks, hypoxanthine guanine phosphoribosyl transferase (HPRT) mutation frequency, and genotype for cytochrome P-4501A1, glutathione transferases M1, T1 and P1, and microsomal epoxide hydrolase were analyzed using peripheral mononuclear cells. Urine samples were collected for the analysis of 8-hydroxydeoxyguanosine. RESULTS: Micronuclei in peripheral CD4+ and CD8+ lymphocytes, DNA single-strand breaks, HPRT mutation frequency, and 8-hydroxydeoxyguanosine in urine did not differ between the potroom workers and the unexposed referents. With the exception of an observed exposure-response relationship for potroom workers with Tyr/Tyr genotype for microsomal epoxide hydrolase, between airborne PAH and CD8+ micronuclei, no correlations were found between any of the genotoxicity biomarkers and any of the exposure measures (airborne particulate PAH, airborne gas phase PAH, length of employment in the potroom, 1-hydroxypyrene in urine, or PAH-DNA adducts in peripheral lymphocytes), also when genotypes for biotransforamtion enzymes were considered. CONCLUSIONS: The results indicate that the employed biomarkers of mutagenic or genotoxic effects are not appropriate for surveillance studies of potroom workers exposed to current airborne levels of PAH. The significance of the correlation between airborne PAH and CD8+ micronuclei in Tyr/Tyr genotype subjects should be evaluated.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Alcohol metabolism in Asian-American men with genetic polymorphisms of aldehyde dehydrogenase.

BACKGROUND: About half of certain Asians have a deficiency of the low-Km aldehyde dehydrogenase (ALDH2) isoenzyme. This deficiency results from inheritance of a mutant ALDH2*2 allele. OBJECTIVE: To determine whether Asian Americans with ALDH2*2 alleles differ from Asian Americans without this mutation in terms of blood levels of alcohol and acetaldehyde after ingestion of a moderate amount of alcohol. DESIGN: Double-blind, crossover study. SETTING: Private research institute. PARTICIPANTS: 35 healthy Asian-American men. Three men who became ill after alcohol ingestion and one who had outlying data were excluded. INTERVENTION: Alcoholic beverage, containing 0.56 g of alcohol per kg of body weight, or placebo beverage, containing 3 mL of alcohol, given orally on separate occasions. MEASUREMENTS: Blood levels of alcohol and acetaldehyde measured before and several times after ingestion of the alcoholic or placebo beverage. RESULTS: Participants with ALDH2*2 alleles had significantly higher blood acetaldehyde levels after ingesting alcoholic and placebo beverages than did participants with ALDH2*1 alleles, despite similar blood alcohol concentrations. CONCLUSIONS: Blood acetaldehyde levels rather than blood alcohol concentration may mediate enhanced alcohol sensitivity among Asians with ALDH2*2 alleles.

Acetaldehyde↗