CYP2C19 polymorphisms in patients with gastric and colorectal carcinoma

Background It has been reported that up to 80% of human cancer arise as a consequence of environmental exposure and host susceptibility factors. Environmental carcinogens are predominantly metabolized by the cytochrome P450 (CYP) superfamily of drug-or xenobiotic-metabolizing enzymes. Genetic variations in these enzymes affect individuals' susceptibility to carcinogens. Aim of the study The aim of this study was to evaluate the relationship between CYP2C19 polymorphism and susceptibility to these cancers by means of CYP2C19 genotyping among Turkish subjects. Methods DNA of subjects were isolated from leukocytes by high pure template preparation kit (Roche Diagnostics, GmbH, Mannheim, Germany) and genotypes were detected by LightCycler CYP2C19 Mutation Detection Kit by real-time PCR with LightCycler instrument (Roche Diagnostics, cat. no. 3113914). Results Being male was associated with a 3.5-fold (OR: 4.27, CI: 2.27–8.05) and 4.27-fold (OR: 3.50, CI: 1.948–6.301) risk for colorectal and gastric carcinoma, respectively. The CYP2C19 ^* 3 heterozygote genotype was not found in either gastric or colorectal carcinoma patients. Although the frequency of CYP2C19^*2 heterozygote genotype is high in patients with gastric and colorectal carcinoma, it is not significantly associated with cancer (OR: 1.79, CI: 0.829–3.865 and OR: 1.998, CI: 0.961–4.154, respectively). Conclusion Although the frequency of CYP2C19 ^* 2 heterozygote genotype is high in our patients with gastric and colorectal carcinoma, there is no the relationship between CYP2C19 polymorphism and susceptibility to these cancer.     

Low presence of <Emphasis Type="Italic">p53</Emphasis> abnormalities in <Emphasis Type="Italic">H. pylori</Emphasis>-infected gastric mucosa and in gastric adenocarcinoma

Background: Alterations of the p53 gene and/or its abnormal protein accumulation have been observed in gastric cancer and preneoplastic lesions. Our aim was to assess possible associations between different H. pylori strains and p53 abnormalities in patients with dyspepsia and with gastric cancer. Methods: Seventy-five dyspeptic patients and 40 patients with gastric adenocarcinoma entered the study. H. pylori status was determined by the rapid urease test, histology, and polymerase chain reaction (PCR) analysis. Overexpression of the p53 protein was evaluated by immunohistochemistry. Detection of p53 mutations was done by direct DNA sequencing. Results: Fifty-four of the 75 (72.0%) dyspeptic patients and 27 of the 40 (67.5%) gastric cancer patients showed H. pylori infection. Cytotoxin-associated gene (cagA)-positive strains were found in 31 of the 54 (58%) dyspeptic patients and in 25 of the 27 (92.6%) neoplastic patients. As regards vacA, s2 strains showed the highest prevalence among dyspeptic patients (24 of 54 patients; 44.4%), whereas s1 strains were more expressed among cancer patients (23 of 27; 85.2%). Among the dyspeptic patients, 1 patient with duodenal ulcer showed p53 overexpression. Three mutations were identified by DNA sequencing: one in a patient with normal endoscopic findings and two in patients suffering from gastritis. Among the neoplastic patients, 16 subjects (40%) showed p53 overexpression (9 had diffuse-type and 7 intestinal-type cancer). Four mutations (10%) occurred in patients with intestinal-type gastric cancer. No association between p53 abnormalities (overexpression/mutation) and H. pylori infection was found in either group of patients. Conclusions: These results lead us to hypothesize that H. pylori infection does not affect the p53 pattern in gastric mucosa. Moreover, mutations of the p53 gene do not seem to be a predominant event in gastric carcinogenesis, at least in our populations. Received: December 14, 2001 / Accepted: May 17, 2002 RID="*" ID="*"  These authors contributed equally to the work RID="*" ID="*"  These authors contributed equally to the work Acknowledgments. The authors would like to thank Mrs B. D'Attoma and Mrs P. Fiorente for their valuable technical assistance, and Mrs M.V.C. Pragnell, B.A., for her help in revising the English. Reprint requests to: A. Di Leo     

Distribution of CYP1A1*2A polymorphism in adult patients with acute lymphoblastic leukemia in a Mexican population

The effects of the CYP1A12A genotype on susceptibility to leukemia have received particular attention in recent years because this enzyme plays a central role in the activation of carcinogens. Several polymorphisms at the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We evaluated the role of the CYP1A12A genotype in adults with acute lymphoblastic leukemia (ALL) by genotyping 210 patients and 228 healthy controls from the Mexican population. The frequency of the CC genotype was 8% (18/228) in the control group and 42% (88/210) in ALL patients; the frequency of the CT genotype was 39% (89/228) and 29.5% (62/210), respectively; and that of the TT genotype was 53% (121/228) and 28.5% (60/210), respectively. The odds ratio was 8.4 (95% CI, 4.7–15.5; P < 0.001). These data indicate that the CYP1A12A genotype contributes significantly to susceptibility to adult ALL in a sample of the Mexican population.     

The COX-2-1195AA Genotype Is Associated with Diffuse-Type Gastric Cancer in Korea

Background/Aims

The potential role of the cyclooxygenase (COX)-2 polymorphism has been reported in relation to the risk of gastrointestinal tract malignancies. Therefore, we investigated whether COX-2 polymorphisms are associated with the risk of gastric cancer (GC) in Korea, one of the areas with a high prevalence of this condition.

Methods

We evaluated the genotypic frequencies of COX-2-765 and -1195 in 100 peptic ulcer patients, 100 GC patients, and 100 healthy controls. The polymorphisms of the COX-2-765 and -1195 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphisms.

Results

The frequencies of the COX-2-1195 GG, GA, and AA genotype were 20%, 60%, and 20% in intestinal-type GC and 8%, 48%, and 44% in diffuse-type GC, respectively (p=0.021). There were no significant differences in the frequency of COX-2-765 genotypes between intestinal-type GC and diffuse-type GC (p=0.603). Age- and sex-adjusted logistic regression analysis showed that the COX-2-1195 AA genotype was the independent risk factor of diffuse-type GC compared with the COX-2-1195 GG genotype (p=0.041; odds ratio, 6.22; 95% confidence interval, 1.077 to 35.870).

Conclusions

The COX-2-1195 AA genotype may render subjects more susceptible to diffuse-type GC.     

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

In this study, we investigated the contribution of vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes, age, and body surface area (BSA) on warfarin dose requirements and in an adult Turkish population. Blood samples were collected from 100 Turkish patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the therapeutic range. Genetic analyses for CYP2C9 genotypes (*2 and *3 alleles) and VKORC1 −1639 G>A polymorphism were performed and venous INR determined. The mean warfarin daily dose requirement was higher in CYP2C9 homozygous wild-type patients, compared to those with the variant *3 allele (P < 0.05), similar to those with the variant *2 allele (P > 0.05) and highest in patients with the VKORC1 −1639 GG genotype compared to those with the GA genotype and the AA genotype (P < 0.01). The time to therapeutic INR was longer in CYP2C9 homozygous wild-type patients compared with those with the variant *2 and *3 alleles (P < 0.01), and longer in patients with the VKORC1 (position −1639) GG genotype compared with those with the GA genotype and the AA genotype (P < 0.01). The multivariate regression model including the variables of age (R ² = 4.4%), BSA (R ² = 27.4%), CYP2C9 (R ² = 8.1%), and VKORC1 genotype (R ² = 34.1%) produced the best model for estimating warfarin dose (R ² = 60.4%). VKORC1 genotype and CYP2C9 polymorphism affect daily dose requirements and time to therapeutic INR in Turkish patients receiving warfarin for anticoagulation.     

Cytochrome p450 2E1 polymorphisms and the risk of gastric cardia cancer

AIM: Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. Cytochrome P450 2E1 (CYP2E1) enzyme catalyzes the metabolism of many procarcinogens, such as N-nitrosamines and related compounds. The gene coding for this enzyme is polymorphic and thus may play a role in gastric cardia cancer (GCC) etiology. In this hospital-based case-control study, we evaluate the relationship between genetic polymorphisms of CYP2E1 and the risk of GCC. METHODS: The study subjects comprised 159 histologically confirmed GCC cases identified via hospital cancer registry and surgical records at five hospitals in Fuzhou, Fujian Province, China, between April and November 2001. Controls were 192 patients admitted to the same hospitals for nonmalignant conditions. The genotypes of CYP2E1 were detected by a PCR-based RFLP assay. The odds ratios were estimated by logistic regression analyses and were adjusted for potential confounding factors. RESULTS: The distribution of three genotypes of CYP2E1 in GCC cases and controls was significantly different (X2 = 16.04, P<0.01). The frequency of the CYP2E1 (c1/c1) genotype in GCC cases and controls was 60.4% and 40.1%, respectively. The CYP2E1 (c1/c1) genotype was associated with an increased risk for GCC (the adjusted (OR) was 2.37, 95% confidence interval (CI): 1.52-3.70). Subjects who carried the CYP2E1 (c1/c1) genotype and were habitual smokers were at a significantly higher risk of developing GCC (OR = 4.68,95%CT. 2.19-10.04) compared with those who had the CYP2E1 (c1/c2 or c2/c2) genotype and did not smoke. CONCLUSION: These results suggest that the CYP2E1 genotype may influence individual susceptibility to development of GCC, and that the risk increases significantly in smokers.     

Thep53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers

We previously reported that introduction of the wild-typep53 gene into human cancer cells with deletedp53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 542287]. This suggests thatp53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer forp53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery.p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutantp53, however, significantly showed fewer apoptotic cells compared with those expressing wild-typep53. Thep53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, where-as mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude thatp53 mutations are associated with the poor response of chemotherapy and radiotherapy.Abbreviations TUNEL terminal deoxynucleotidyltransferase-mediated biotin-dUTP nick-end labeling     

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

MIM: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/PsА 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 observde,due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group.The GSTT1 null genotype occurred more frequently in Negroid subjicts,and the GSTM1 null genotype was observed mainly in individuals with chronic gastritis infected with H pylori.CONCLUSION:Our findings indecate that there is no obvious relationship between the GSTT1,GSTM1 and CYP2E1 polymorphisms and gastric cancer.     

p53 Mutation Pattern and Expression of c-erbB2 and c-met in Gastric Cancer: Relation to Histological Subtypes, Helicobacter pylori Infection, and Prognosis

The molecular mechanisms of Helicobacter pylori associated tumor development are poorly understood. The spectra of genetic alterations in neoplasms may provide clues to the molecular carcinogenesis of a tumor and may be relevant for the prognosis of the patients. We investigated the p53 mutation pattern and the protein expression of p53, c-erbB2, and c-met in 42 gastric cancers and correlated these alterations with H. pylori infection, histological subtypes and survival of the patients after curative resection. There were no differences in the incidences of the expression of p53, c-erbB2, and c-met in the tumor tissues according to H. pylori infection. Fifteen p53 mutations in 12 (29%) tumors were identified. More p53 mutations were found in patients with positive serology for H. pylori (43% vs 14%). This difference was not significant, but the small sample size may be insufficient to detect a potential statistical difference. There was neither a H. pylori-associated p53 hot-spot codon mutation nor a H. pylori characteristic mutational pattern of p53. Positive lymph nodes (P = 0.0061) and p53 mutations (P = 0.0035) were the only significant bad prognostic markers for survival after curative resection of the gastric cancers in our study. Our study does not indicate a unique molecular mechanism of p53 mutagenesis through H. pylori infection. The fact that p53 mutations were significantly correlated with poor survival of patients after potentially curative resection of gastric cancer may have clinical implications for multimodal therapies.     

Rugal hyperplastic gastritis increases the risk of gastric carcinoma, especially diffuse and p53-independent subtypes

OBJECTIVES: Infection with Helicobacter pylori has been linked to chronic gastritis with atrophy or hyperrugosity. The development of noncardia gastric carcinoma, especially the intestinal type in Lauren's classification, has been associated with severe atrophic gastritis and p53 mutations. The objective of this study was to determine the association between hyperrugosity and gastric carcinogenesis, including p53 mutations. PARTICIPANTS AND METHODS: Barium meal roentgenograms were performed in 395 control participants and 132 gastric carcinoma patients. The fold width was measured at the greater curvature of the middle portion of the gastric body. Serum pepsinogens I and II were determined along with gastrin levels. Complete coding sequences and splice junctions for exons 5-8 of p53 gene were screened for mutations by polymerase chain reaction-based single-strand conformational polymorphism analysis. RESULTS: Rugal hyperplastic gastritis (gastric body fold width>or=5 mm) increased the risk of gastric carcinoma [odds ratio, 2.60; 95% confidence interval, 1.69-4.01] as compared with the control group, especially diffuse-type gastric carcinoma (odds ratio, 4.13; 95% confidence interval, 2.36-7.24). The p53 mutational rate was significantly lower in gastric carcinoma patients with rugal hyperplastic gastritis. In intestinal-type gastric carcinoma with hyperrugosity, the incidence of p53 gene mutations decreased, but no association was found in diffuse-type gastric carcinoma between p53 mutations and rugal hyperplastic gastritis. CONCLUSIONS: Rugal hyperplastic gastritis was associated with an elevated risk of gastric carcinoma, especially diffuse-type, and a lower frequency of p53 mutations.     

Polymorphisms in GSTM1, CYP1A1, CYP2E1, and CYP2D6 are Associated with Susceptibility and Chemotherapy Response in Non-small-cell Lung Cancer Patients

Background  

Studies of polymorphisms in CYP1A1, CYP2E1, CYP2D6, and GSTM1 and their relationship to lung cancer susceptibility and chemotherapy response have been reported, but the results are not consistent. In this study we selected four polymorphisms in these genes, several of which have previously been researched, and investigated their association with lung cancer susceptibility and chemotherapy response.     

Gastric adenocarcinoma: pathomorphology and molecular pathology

Two types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type. Molecular pathology supports this theory by showing differences in the genetic pathways of both tumor types. In addition to known pathomorphological factors of prognosis, e.g., depth of tumor infiltration, number of lymph node metastases and resection margins, a few genes have been suggested to have prognostic impact in gastric carcinoma. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. Gene amplification and protein overexpression of the growth factor receptors c-erbB-2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. In addition, genetic instability is commonly seen. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of diffuse-type gastric cancer and could be used to identify individuals that are at high risk. Received: 13 July 2000 / Accepted: 3 August 2000     

Warfarin Dose Adjustments Based on CYP2C9 Genetic Polymorphisms

Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0–3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.     

Analysis of CYP2E1 polymorphism for the determination of genetic susceptibility to gastric cancer in Koreans

BACKGROUND: Interindividual genetic differences in susceptibility to chemical carcinogens are among the most important host factors in human cancer. The present study was undertaken to reveal the association between the polymorphism of CYP2E1 (CYP2E1/PstI and CYP2E1/DraI) with genetic susceptibility to gastric cancer development in Koreans. METHODS: In the present study, 120 gastric cancer patients and 145 controls with no history of tumors were analyzed. CYP2E1 was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP), or PCR and direct gel electrophoresis. RESULTS: The overall genotype distribution of CYP2E1 was not significantly different from that of controls. However, the genotype distribution of the patient subgroups with a history of heavy cigarette smoking (>30 pack/year) in the CYP2E1/PstI and CYP2E1/DraI polymorphisms were significantly different from those of non-smoking patients (P = 0.0122 and P = 0.0029, respectively). The difference was also noticeable in the younger patient subgroup (aged 相似文献   

A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives

High penetrance genes such as BRCA1 or BRCA2 account for only a small proportion of familial breast cancer in Chinese population. Estrogen has been proposed to participate in the proliferation and carcinogenesis of breast cancer. To investigate the association between genetic polymorphisms in genes encoding estrogen metabolizing, estrogen biosynthesizing enzyme and estrogen receptor and the breast cancer risk in BRCA1/BRCA2 negative Shanghai women, we conducted a case-control study including 114 cases with early-onset breast cancer or affected relatives and 121 healthy controls. The genotypes of estrogen receptor alpha (ERα), aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed by direct DNA-sequencing. Compared with H/H genotype of COMT Val158Met, COMT Val158Met L/L genotype was associated with a nonsignificantly elevated risk of breast cancer (OR: 3.72; 95% CI: 0.99–13.96, P = 0.051). There was no statistically significant difference in genotype frequency of the ERα PvuII, ERα XbaI and CYP19 Arg264Cys polymorphism between controls and cases. When stratified by menopausal status, COMT Val158Met L/L (OR: 11.94; 95% CI: 1.48–96.03, P = 0.02) and ERα PvuII P/p genotypes (OR: 2.67; 95% CI: 1.01–7.05, P = 0.048) were associated with a significantly elevated risk of breast cancer in premenopausal women, and there was a association between ERα XbaI x/x genotype and the nonsignificantly increased risk of breast cancer in premenopausal women (OR: 6.88; 95% CI: 0.80–59.15, P = 0.079). The multigenic analysis showed maybe these high risk genotypes had combined effect on breast cancer risk. Our findings suggest that polymorphism of genes involving estrogen-metabolizing pathway, estrogen- biosynthesizing pathway and estrogen receptor pathway may play an important role in the etiology of BRCA1/2 negative breast cancer with hereditary predisposing factors. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhen Hu and Chuan-Gui Song contributed equally to the work.     

CYP1B1 Polymorphisms and K-ras Mutations in Patients with Pancreatic Ductal Adenocarcinoma

The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy–Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways. PANKRAS II study group—Members of the multicenter prospective study on the role of K-ras and other genetic alterations in the diagnosis, prognosis and etiology of pancreatic and biliary diseases (PANKRAS II) study group are mentioned in previous publications.     

A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans

Background: Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population. Methods: The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status). Results: No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C‐c2‐C‐A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C‐c2‐C‐A1) and H10 (1C‐c2‐D‐A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C‐c2‐D‐A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C‐c1‐D‐A2) in alcoholic‐smokers was much higher than in alcoholic‐nonsmokers (p = 0.0028). In contrast, alcoholic‐smokers carried less H2 (1C‐c1‐D‐A1) in comparison with alcoholic‐nonsmokers (p = 0.0417). The H3 (1D‐c2‐C‐A2) frequency in alcoholic‐smokers was much lower than in alcoholic‐nonsmokers (p = 0.0042) and control‐smokers (p = 0.0363). Conclusions: Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans.     

The effect of CYP2C9, VKORC1 and CYP4F2 polymorphism and of clinical factors on warfarin dosage during initiation and long-term treatment after heart valve surgery

The dosage of warfarin is restricted due to its narrow therapeutic index, so, the required dose must be adapted individually to each patient. Variations in warfarin dosage are influenced by genetic factors, the changes in patient diet, anthropometric and clinical parameters. To determine whether VKORC1 G3730A and CYP4F2 G1347A genotypes contribute to warfarin dosage in patients during initiation and long-term anticoagulation treatment after heart valve surgery. From totally 307 patients, who underwent heart valve surgery, 189 patients (62 %) who had been treated with warfarin more than 3 months, were included into the study. A hierarchical stepwise multivariate linear regression model showed, that during initiation clinical factors can explain 17 % of the warfarin dose variation. The addition of CYP2C9 and VKORC1 G-1639A genotype raises the accuracy about twice—to 32 %. The CYP4F2 G1347A genotype can add again about 2–34 %. During long-term treatment clinical factors explain about 26 % of warfarin dose variation. If the CYP2C9 *2, *3, VKORC1*2 alleles are detected, model can explain about 49 % in dose variation. The *3 allele of VKORC1 raises the accuracy by 1–50 %. The carriers of CYP4F2 A1347A genotype required higher daily warfarin doses during initiation of warfarin therapy after heart valve surgery than comparing to G/G and G/A carriers, but during the longer periods of warfarin use, the dosage of warfarin depended significantly on VKORC1 *3 allele (G3730A polymorphism) and on the thyroid stimulating hormone level in the blood plasma.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

CYP2E1 PstI/RsaI polymorphism and colorectal cancer risk: A meta-analysis

AIM: To clarify the association between CYP2E1 PstI/RsaI polymorphism and susceptibility to colorectal cancer.METHODS: A meta-analysis based on 10 eligible case-control studies involving 4979 cases and 6012 controls was carried out to summarize the data on the association between CYP2E1 RsaI/PstI polymorphism and colorectal cancer risk.RESULTS: In comparison of the homozygote c2c2 and c2 carriers (c1c2 + c2c2) and the homozygous wild-type genotype (c1c1), no association was found between CYP2E1 RsaI/PstI polymorphism and colorectal cancer risk [odds ratio (OR) = 1.24 (95% CI: 0.93-1.66) for c2c2; OR = 1.02 (95% CI: 0.88-1.19) for c2 carriers]. In stratified analysis, Caucasians with c2c2 homozygote appeared to have an increased risk of colorectal cancer (OR = 2.67, 95% CI: 1.03-6.89, P = 0.043), no significant associations were found in other groups.CONCLUSION: c2c2 homozygote of CYP2E1 PstI/RsaI polymorphism may be associated with the increased risk of colorectal cancer in Caucasians, which needs further investigations.