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PubMed1999

[Use of RAPD-PCR-analysis of cellular DNA for the evaluation of genetic polymorphism and subspecies diagnostics of the Far Eastern leopard Panthera pardus orientalis].

Genetic polymorphism in the Far-Eastern leopard subspecies Panthera pardus orientalis was examined by RAPD-PCR analysis of total cellular DNA. Primers diagnostic for the leopard subspecies were detected. These primers can be used for differentiating wild-living animals from those kept in captivity and distinguishing different breeding lines. Genetic diversity was shown to be lower in animals from the zoo (D = 0.058) and higher in a natural population (D = 0.137). Two lines of the Persian subspecies were genetically closest (D = 0.042), and the Persian and Far-Eastern subspecies represented by wild animals, genetically most remote (D = 0.274). The level of genetic divergence of the Persian subspecies and Far-Eastern subspecies (zoo animals) was lower (D = 0.108) than between representatives of the Persian subspecies from the captive and natural population (D = 0.220). On the basis of analysis of relatedness, performed using NTSYS and PHYLIP software packages, the possibility cannot be excluded that some P. p. orientalis animals from the zoo have a hybrid origin and may be assigned to another Far-Eastern subspecies.

Animals↗
PubMed1998

Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS: We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS: The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS: The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.

Adult↗
PubMed2000

Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer.

Cytochrome P450 1B1 (CYP1B1) participates in the metabolic activation of a number of procarcinogens including benzo[a]pyrene and the hydroxylation of 17beta-estradiol at the C-4 position. In this study, we investigated the association between CYP1B1 genetic polymorphism and breast or lung cancer incidence. The Ala-Ser polymorphism at codon 119 in presumed substrate recognition site 1 was significantly associated with the incidence of breast or squamous cell carcinoma of the lung. On the other hand, Leu-Val polymorphism at codon 432 did not show any association to the cancers. An allele containing both Ala and Leu simultaneously, comprised 75% of alleles among 315 Japanese healthy controls, was significantly inversely associated with breast cancer incidence. When expressed in a recombinant system, this CYP1B1 cDNA showed the lowest 17beta-estradiol 4-hydroxylase activity among four different variant forms of CYP1B1. Thus, inter-individual differences in activation of procarcinogens or metabolism of oestrogen originating from genetic polymorphisms of the human CYP1B1 gene may contribute to the susceptibility of human cancers.

Adenocarcinoma↗
PubMed2001

Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver.

The human cytochrome P450, CYP2B6, is involved in the metabolism of several therapeutically important drugs and environmental or abused toxicants. In this study, we present the first systematic investigation of genetic polymorphism in the CYP2B6 gene on chromosome 19. A specific direct sequencing strategy was developed based on CYP2B6 and CYP2B7 genomic sequence information and DNA from 35 subjects was completely analysed for mutations throughout all nine exons and their exon-intron boundaries. A total of nine novel point mutations were identified, of which five result in amino acid substitutions in exon 1 (C64T, Arg22Cys), exon 4 (G516T, Gln172His), exon 5 (C777A, Ser259Arg and A785G, Lys262Arg) and exon 9 (C1459T, Arg487Cys) and four are silent mutations (C78T, G216C, G714A and C732T). Polymerase chain reaction-restriction fragment length polymorphism tests were developed to detect each of the five nonsynonymous mutations in genomic DNA. By screening a population of 215 subjects the C64T, G516T, C777A, A785G and C1459T mutations were found at frequencies of 5.3%, 28.6%, 0.5%, 32.6% and 14.0%, respectively. Haplotype analysis revealed six different mutant alleles termed CYP2B6*2 (C64T), *3 (C777A), *4 (A785G), *5 (C1459T), *6 (G516T and A785G) and *7 (G516T, A785G and C1459T). By analysing a large number of human liver samples, significantly reduced CYP2B6 protein expression and S-mephenytoin N-demethylase activity were found in carriers of the C1459T (R487C) mutation (alleles *5 and *7). These data demonstrate that the extensive interindividual variability of CYP2B6 expression and function is not only due to regulatory phenomena, but also caused by a common genetic polymorphism.

Aryl Hydrocarbon Hydroxylases↗
PubMed1988

Genetic polymorphisms of orosomucoid and alpha-2-HS-glycoprotein in a Philippine population.

A Philippine population was investigated for genetic polymorphism of orosomucoid 1 (ORM1), orosomucoid 2 (ORM2), and alpha-2-HS-glycoprotein (A2HS) by isoelectric focusing. The allele frequencies were: ORM1*1 = 0.7904, ORM1*2 = 0.1687, ORM1*2.1 = 0.0409, ORM2*1 = 1.0000; A2HS*1 = 0.6870, A2HS*2 = 0.3130. Compared with the Japanese population, the Philippine population has higher frequencies of ORM1*1 and A2HS*2, and lower frequencies of ORM1*2.1 and A2HS*1.

Alleles↗
PubMed2000

Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension.

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Adult↗
PubMed2006

[Genetic polymorphisms of Penta D and E loci in Korean racial Chinese of Yanbian area in China].

OBJECTIVE: To analyze genetic polymorphisms of Penta D and E loci in Korean racial Chinese of Yanbian area. METHODS: One hundred unrelated individuals of Korean racial Chinese were analyzed by methods of PCR and restriction fragment length polymorphism. RESULTS: Eight alleles and 22 genotypes were observed from Penata D locus, and 16 alleles and 35 genotypes were observed from Penta E locus. CONCLUSION: The distribution of two locus genotypes in Korean racial Chinese of Yanbian area met Hardy-Weinberg equilibrium. And the obtained data can be used to individual identity, paternity testing and the study of Korean ethnic group of Chinese population.

Asian People↗
PubMed2005

Lack of association of cathepsin D genetic polymorphism with Alzheimer's disease in Koreans.

Cathepsin D (CatD) is a good candidate susceptibility marker for Alzheimer's disease (AD), since it was found to be involved in the processing of the amyloid precursor protein and the formation of the hyperphosphorylated tau. And recently, a CatD genetic polymorphism was found to be associated with the risk of Alzheimer's disease (AD) in a German population. However, the CatD T-AD association has not been replicated in a series of the successive independent studies in other races. Therefore, we determined CatD genotypes to examine the possible association of the CatD polymorphism with AD in Koreans. We failed to find significant association between the CatD T allele and AD. In addition, the CatD T--AD association was not significant regardless of the age at onset or the occurrence of the apolipoprotein epsilon4 allele. However, we cannot exclude the possible contribution of the CatD in the development of AD, since the power of the present study was not high enough because of low allelic frequency of the CatD T in Koreans and small sample size. In conclusion, the association between the CatD genetic polymorphism and AD was not found in Koreans, although it waits for further replication in an extended sample.

Aged↗
PubMed2000

Parental smoking, CYP1A1 genetic polymorphisms and childhood leukemia (Québec, Canada).

OBJECTIVE: To evaluate the effect of parental smoking on childhood acute lymphoblastic leukemia and to determine if it is modified by child genetic polymorphisms. METHODS: We carried out a case-control study in Quebec, Canada, including 491 incident cases aged 0-9 years and as many healthy controls matched on age and sex. Each parent was interviewed separately with respect to smoking habits during and after pregnancy. In addition, we carried out a case-only substudy with 158 cases classified according to presence or absence of the alleles *2A, *2B, and *4 in the CYP1A1 gene. RESULTS: There were small risk increases with maternal smoking during the later trimesters. Interaction odds ratios were increased (although often not significantly) for the CYP1A1*4 allele at high levels of maternal smoking in the last trimesters and at low level of paternal postnatal smoking, and decreased for the CYP1A1*2B allele. The latter appeared to confer a protective advantage at low levels for maternal prenatal smoking and at high levels for paternal postnatal smoking. CONCLUSIONS: Reported smoking habits showed no association with leukemia; risks for genetic polymorphisms lacked precision but indicated that the effect of parental smoking could be modified by variant alleles in the CYP1A1 gene.

Alleles↗
PubMed2000

Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer.

Cytochrome P450-1B1 (CYP1B1) is a major enzyme catalyzing the formation of genotoxic 4-hydroxyestradiol. This enzyme is also involved in the activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, mammary carcinogens in experimental animals. CYP1B1 is genetically polymorphic, and the variations in the CYP1B1 gene may be related to the risk of breast cancer. We evaluated this hypothesis among 186 breast cancer cases and 200 age-matched controls as part of a large population-based case-control study conducted in urban Shanghai during 1996 to 1998. Genomic DNA from cases and controls was analyzed for genetic polymorphism in codon 432 (Val-->Leu) of the CYP1B1 gene using a PCR-RFLP-based assay. The frequency of the Leu allele was 53% in cases and 46% in controls (P = 0.06). Compared with those with the Val/Val genotype, women with the Leu/Leu genotype had a 2.3-fold [95% confidence interval (CI), 1.2-4.5] elevated risk of breast cancer after adjusting for potential confounding variables. This positive association was more pronounced among postmenopausal women (Odds ratio, 3.1; 95% CI, 1.0-9.1) than premenopausal women (OR, 1.9; 95% CI, 0.8-4.3). Elevated risks of breast cancer associated with homozygosity for the Leu allele were observed in virtually all subgroups of women defined by major risk factors for breast cancer. The results from this study were consistent with recent findings from in vitro and animal experiments implicating a potentially important role of CYP1B1 in the etiology of human breast cancer.

Adult↗
PubMed2002

Genetic polymorphisms of matrix metalloproteinases: functional importance in the development of chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a major cause of global morbidity and mortality. COPD usually arises from an interaction between both host and environmental risk factors. Cigarette smoking is the major known environmental risk factor for the development of COPD, however, only a minority of smokers (approximately 15 to 20%) develop symptoms. COPD is known to cluster in families, which suggests that there is a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often unclear. Here we review evidence that genetic polymorphisms in matrix metalloproteinase genes MMP1, MMP9 and MMP12 may be important in the development of COPD. In a Caucasian population, polymorphisms in the MMP1 and MMP12 genes, but not MMP9, have been suggested to be either causative factors in smoking-related lung injury or are in linkage disequilibrium with other causative polymorphisms. Another study found an association between an MMP9 polymorphism and the development of smoking-induced pulmonary emphysema in Japanese smokers. Understanding the role of genetic polymorphisms in MMP1, MMP9 and MMP12 may help in the discovery of new and more effective therapies.

Humans↗
PubMed2004

Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of gamma-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance because of their increased mutagenic/carcinogenic risk.

Base Sequence↗
PubMed2005

Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease.

BACKGROUND: Minimal-change nephrotic syndrome (MCNS) has been associated with atopy. As interleukin-13 (IL-13) has been implicated in the pathogenesis of MCNS, we postulated that IL-13 genetic polymorphisms could influence either susceptibility or clinical course of the disease. METHODS: Seventy-two Singapore Chinese children with MCNS and 78 normal controls were screened for single nucleotide polymorphisms (SNPs) in the IL-13 gene by direct sequencing. Allele and genotype frequencies of these SNPs were determined and their relationship with different clinical courses was analysed. RESULTS: Six SNPs were identified in the 5' promoter, exon 4 and 3' untranslated region (3'UTR). The three SNPs in the 3'UTR--4738 (G/A), 4793 (C/A) and 4926 (C/T)--were in tight linkage disequilibrium (Delta > or = 0.99). There was no difference in allele or genotype frequencies between MCNS children and normal controls. However, there was a significantly lower frequency of allele 4738G in those MCNS children who were still relapsing after 5 years of follow-up (G = 0.52), compared with those in complete remission (G = 0.72; P<0.05) and normal controls (G = 0.69; P<0.05). Haplotype analysis showed a significantly higher frequency of the GCC haplotype in controls and MCNS patients in complete remission (chi2 = 6.35; P<0.02), while the frequency of AAT haplotype was higher in those MCNS children still relapsing after 5 years of follow-up (chi2 = 5.38; P<0.02). Moreover, peripheral blood mononuclear cell IL-13 mRNA expression in patients with haplotype AAT was significantly higher than in those with haplotype GCC. CONCLUSIONS: These results suggest that genetic polymorphisms in the 3'UTR of the IL-13 gene correlate with long-term outcome of MCNS, rather than disease susceptibility, in Singapore Chinese children.

Child↗
PubMed2006

Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors.

PURPOSE: The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined. SUMMARY: The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial. CONCLUSION: For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25-45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

No evidence of a genetic polymorphism in the oxidative metabolism of midazolam.

The benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t1/2) is about 2.4 hours. A recent study showed a prolonged t1/2 from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam's metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (alpha-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and alpha-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 +/- 961 x 10(5) h/ml; mean +/- SD) and for the metabolic plasma ratio (AUC of alpha-OH-midazolam/AUC-midazolam: 0.52 +/- 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 +/- 2.4%), urinary excretion of alpha-OH-midazolam (55.9 +/- 22.7% of dose) and the values for t1/2 (2.9 +/- 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p less than 0.05) metabolic ratio. Only in 3 patients could a prolonged t1/2 of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of alpha-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.

Age Factors↗
PubMed2001

Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes.

Urinary cotinine, one of the main metabolites of nicotine, has been widely used as a biomarker for assessment of direct or passive exposure to cigarette smoke. However, there is wide variation of the cotinine level among smokers who smoke the same number of cigarettes. To use urinary cotinine as a proper exposure-biomarker for cigarette smoke, interindividual variations of cotinine formation must be considered. Therefore, we studied the effects of genetic polymorphisms in drug metabolic enzymes on urinary cotinine levels among 190 male Japanese smokers (ages 19-66 years; mean, 40.6 years). Genetic polymorphisms in cytochrome P-450s (CYP1A1, CYP2A6, CYP2E1), and aldehyde dehydrogenase 2 (ALDH2) were determined by analyzing DNA isolated from peripheral blood. Cotinine in morning spot urine was analyzed by high-performance liquid chromatography. Lifestyle, i.e., smoking, alcohol consumption, and intake of coffee or tea, was examined using a questionnaire. The number of cigarettes smoked and CYP2A6 polymorphism were significantly associated with the urinary cotinine level. Especially, the urinary cotinine levels was drastically lower in CYP2A6-deleted homozygous (CYP2A6*4/*4) subjects than in CYP2A6*1 allele-positive subjects. The polymorphism in the CYP2E1 5'-flanking region was related to the urinary cotinine level in intermediate smokers (who smoke 11-20 cigarettes/day; P < 0.01). Polymorphisms in CYP1A1 or ALDH2, and consumption of alcohol, coffee, or tea were not associated with the urinary cotinine level.

Adult↗
PubMed2006

CYP19A1 genetic polymorphisms may be associated with obesity-related phenotypes in Chinese women.

OBJECTIVE: To examine the relationship between genetic polymorphisms of the CYP19A1 gene and obesity-related phenotypes, body mass index (BMI) and waist-to-hip ratio (WHR). SUBJECTS: In total, 1241 Chinese women, who were recruited as community controls for a population-based case-control study of breast cancer. METHODS: Nineteen haplotype tagging single nucleotide polymorphisms (htSNPs) in four haplotype blocks were genotyped. RESULTS: Significant associations were observed for WHR at three SNPs that are located in haplotype block 1, including rs2445765, rs1004984 and rs1902584 (P=0.05, 0.04 and 0.01, respectively). Women, particularly premenopausal women, who carried the minor allele at any of these SNPs, had higher WHR than those without it. Of these three SNPs, the strongest association was observed at rs1902584, which is the closest to Promoter I.4, the major promoter for adipose tissue. Haplotype analyses indicated an association between the haplotype TCCAT in block 1 and WHR with a P-value of 0.02. CONCLUSION: These results suggested that CYP19A1 genetic polymorphisms may be associated with the risk of obesity among Chinese women, especially among premenopausal women. The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus affects body fat distribution and regulation.

Adult↗
PubMed2004

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: effects on levels of sister chromatid exchanges and chromosomal aberrations.

Elevated levels of chromosomal aberrations (CAs) in peripheral blood lymphocytes, widely used as a cytogenetic biomarker of genotoxic effects, have been linked to cancer predisposition. However, tobacco smoking, occupational carcinogen exposure, or time since CA analysis do not appear to explain the cancer predictivity of CAs. Alternatively, the observed CA-cancer association could reflect unidentified exposures or individual susceptibility. We assessed the effects of genetic polymorphisms of DNA repair proteins and xenobiotic-metabolizing enzymes (XMEs) on the levels of CAs and sister chromatid exchanges (SCEs) in peripheral lymphocytes of 145 (CAs) and 60 (SCEs) healthy Caucasians. Genotypes of DNA repair genes X-ray repair cross-complementation group 1 (XRCC1 codons 194, 280, 399) and 3 (XRCC3 codon 241 [corrected]), and XME genes glutathione-S-transferase (GST) M1 and T1 and N-acetyl transferase 2 (NAT2) were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP)-based methods. After Poisson regression adjustment for age, sex, smoking, country, and genotypes, a higher frequency of chromosome-type breaks was observed for NAT2 slow acetylators (in nonsmokers) and GSTT1 null subjects (in smokers). Individuals carrying variant alleles for XRCC1 codons 280 and 194 showed a decreased level of chromosome-type breaks. The effect of GSTM1 null and XRCC1 codon 399 genotypes on the frequency of CAs was modified by smoking. In linear regression models adjusting for age, sex, smoking, and genotypes, none of the polymorphisms significantly affected SCE frequency, although GSTT1 null subjects had a slightly elevated SCE level. Our results are in line with earlier findings on the influence of NAT2, GSTT1, and GSTM1 polymorphisms on the level of lymphocyte chromosome damage and suggest that also XRCC1 polymorphism affects CA frequencies, thus apparently influencing DNA repair phenotype. It remains to be examined whether these or other genetic polymorphisms could explain the observed cancer risk predictivity of high CA frequency.

Adult↗