Analysis of genetic predisposition to pulmonary tuberculosis in native Russians

Tuberculosis (TB) is one of the most important concerns of public health. There is evidence suggesting that genetic status is responsible for predisposition to infectious diseases including TB. To determine genetic risk factors of TB development, the frequencies of polymorphisms of genes CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, NAT2, MDR1, and NRAMP1 in 73 TB patients and 352 healthy individuals were determined by allele-specific hybridizatio n using microarray technology. The TB patients have shown a significant increase in the frequency of the null GSTT1 genotype (OR = 3.26, 95% CI = 1.91–5.55, p = 0.000028) as well as the double null GSTT1/GSTM1 genotype (OR = 4.05, 95% CI = 2.14-7.65,p = 0.000034) compared to the group of healthy donors. It was shown that the NAT2* 5/* 5 genotype in combination with the “null” GSTT1 and the double “null” GSTT1/GSTM1 genotypes was observed significantly more often in the TB patients than in the control sample. Thus the examined GSTT1, GSTM1 and NAT2 gene polymorphisms may potentially alter the risk of TB development in ethnic Russians and are of interest for further research using larger cohorts of patients.     

N-acetyltransferase 1 and 2 gene sequence variants and risk of head and neck cancer

Polymorphisms that alter the function of genes involved in the activation or detoxification of carcinogenic compounds can influence an individuals risk of developing cancer. Polymorphic changes modulating the acetylation capacity of the N-acetyltransferase (NAT) genes have been implicated in the risk of developing cancer. In this study the role of genetically determined individual NAT1 and NAT2 genotypes, haplotypes and haplotype combinations in the predisposition to head and neck cancer was investigated. Polymorphic regions of the NAT1 and NAT2 genes were analyzed in patients with head and neck cancer and healthy individuals by polymerase chain reaction-restriction fragment length polymorphism. Distribution of the genotypes, allele frequencies, diplotypes and haplotypes and correlation with clinical characteristics were evaluated. No association was observed between the NAT1*3, NAT1*10, NAT1*11, NAT2*5 and NAT2*6 genotypes and risk of head and neck cancer. The NAT2*7 slow genotype was associated with reduced risk of disease. A significant association was observed between the fast acetylator NAT2*4/NAT1*10 diplotype and risk of head and neck cancer. Combined haplotypes harboring the T1088A and C1095A variants characterizing the NAT1*10 allele were associated with increased risk. Our results suggest that NAT1 and NAT2 gene combinations may influence the risk of developing head and neck cancer.     

Association of polymorphisms of xenobiotic metabolism genes with childhood atopic diseases in Russian patients from Bashkortostan

Biotransformation enzymes involved in the metabolism of exogenous and endogenous compounds efficiently protect the organism from harmful environmental factors. Decreased activity or insufficient synthesis of biotransformation enzymes due to genetic polymorphism is a risk factor for various complex diseases, including atopy. Allele-specific hybridization on a biochip was used to evaluate the frequencies of xenobiotic metabolism gene polymorphisms in children with bronchial asthma and/or allergic rhinitis and in healthy donors, all residents of the Republic of Bashkortostan of Russian descent. Polymorphisms of CYP1A1, GSTT1, GSTM1, NAT2, MTHFR, CYP2C9, and CYP2C19 were not associated with atopic diseases in children. The genotype CYP2D6*1934G/G and the allele CYP2D6*1934G were associated with an increased risk of allergic rhinitis in boys.     

An investigation on the polymorphisms of two DNA repair genes and susceptibility to ESCC and GCA of high-incidence region in northern China

Aim To investigate the possible association of three SNPs, XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a population of northern China. Methods XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G SNP were genotyped by polymerase-chain reaction (PCR)–restriction fragment length polymorphism (RFLP) analysis in 583 cancer patients (329 ESCC and 254 GCA) and 614 healthy controls. Results The genotype distribution of the XRCC2 C41657T in ESCC and GCA patients were significantly different from that in healthy controls (P values = 0.04 and 0.04 respectively). And a significant difference was found in the allele distribution of GCA patients from that in controls (P = 0.01). The XRCC2 C41657T polymorphism was associated with a modest enhancement in ESCC risk and GCA risk: OR for C/T genotype was 1.38 (1.01–1.89) in GCA risk and for T/T genotype was 2.24 (1.10–4.57) in ESCC risk. When stratified for age, smoking status and family history of UGIC, the C/T genotype showed a modest significant trend on the risk of GCA patients in the groups of age ≤50 years and non-smokers, the adjusted OR were 2.84 (1.21–6.66) and 1.62 (1.06–2.49). The T/T genotype significantly increased the susceptibility of GCA patients in negative family history of UGIC (3.04, 1.02–8.32) and to ESCC patients in the group of age >50 years (3.03, 1.31–6.98), Negative family of UGIC (3.03, 1.12–7.07) and smokers (2.64, 1.02–6.83). The genotype and allele distribution of XRCC2 G4234C and XRCC3 A17893G in ESCC and GCA patients were not significantly different from that in healthy controls (all P values were above 0.05). Conclusion In this study, we found that the C41657T polymorphism of XRCC2 genes might modify the risk of ESCC and GCA development.     

CYP1A1, GSTM1 and GSTT1 polymorphisms and lung cancer: a pooled analysis of gene–gene interactions

Gene–environment interactions have been extensively studied in lung cancer. It is likely that several genetic polymorphisms cooperate in increasing the individual risk. Therefore, the study of gene–gene interactions might be important to identify high-susceptibility subgroups. GSEC is an initiative aimed at collecting available data sets on metabolic polymorphisms and the risks of cancer at several sites and performing pooled analyses of the original data. Authors of published papers have provided original data sets. The present paper refers to gene–gene interactions in lung cancer and considers three polymorphisms in three metabolic genes: CYP1A1, GSTM1 and GSTT1. The present analyses compare the gene–gene interactions of the CYP1A1*2A, GSTM1 and GSTT1 polymorphisms from studies on lung cancer conducted in Europe and the USA between 1991 and 2000. Only Caucasians have been included. The data set includes 1466 cases and 1488 controls. The only clear-cut association was found with CYP1A1*2A. This association remained unchanged after stratification by polymorphisms in other genes (with an odds ratio [OR] of approximately 2.5), except when interaction with GSTM1 was considered. When the OR for CYP1A1*2A was stratified according to the GSTM1 genotype, the OR was increased only among the subjects who had the null (homozygous deletion) GSTM1 genotype (OR=2.8, 95% CI=0.9–8.4). The odds ratio for the interactive term (CYP1A1*2A by GSTM1) in logistic regression was 2.7 (95% CI=0.5–15.3). An association between lung cancer and the homozygous CYP1A1*2A genotype is confirmed. An apparent and biologically plausible interaction is suggested between this genotype and GSTM1.     

Allele and genotype frequencies of metabolic genes in Native Americans from Argentina and Paraguay

Interethnic differences in the allele frequencies of CYP2D6, NAT2, GSTM1 and GSTT1 deletions have been documented for Caucasians, Asians, and Africans population. On the other hand, data on Amerindians are scanty and limited to a few populations from southern areas of South America. In this report we analyze the frequencies of 11 allele variants of CYP2D6 and 4 allele variants of NAT2 genes, and the frequency of GSTM1 and GSTT1 homozygous deleted genotypes in a sample of 90 donors representing 8 Native American populations from Argentina and Paraguay, identified as Amerindians on the basis of their geographic location, genealogical data, mitochondrial- and Y-chromosome DNA markers. For CYP2D6, 88.6% of the total allele frequency corresponded to *1, *2, *4 and *10 variants. Average frequencies for NAT2 *4, *5, *6 and *7 alleles were 51.2%, 25%, 6.1%, and 20.1%, respectively. GSTM1 deletion ranged from 20% to 66%, while GSTT1 deletion was present in four populations in less than 50%. We assume that CYP2D6 *2, *4, *10, *14; NAT2 *5, *7 alleles and GSTM1 and GSTT1 *0/*0 genotypes are founder variants brought to America by the first Asian settlers.     

Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer

Objective The glutathione S-transferases (GSTs) are a superfamily of proteins that participates in detoxification. The GSTs were dividing into several classes including omega (GSTO), mu (GSTM) and theta (GSTT) classes. In human GSTO2, GSTM1, and GSTT1 are polymorphic. In order to study whether GSTO2, GSTM1, and GSTT1 polymorphisms are associated with increased gastric cancer risk in Iranian patients, the present case–control study was done. Methods Genomic DNA was extracted from peripheral blood of 67 gastric cancer patients and 134 control subjects. The genotyping was performed using PCR-based method. The possible association of gastric cancer with the GSTO2 N142D polymorphism was estimated with assuming additive, dominant, and recessive effect of the variant 142D allele. To investigate whether profiles of GST genotypes are associated with the risk of gastric cancer, we used unconditional logistic regression analysis. Results The GSTO2 142D allele in additive, dominant and recessive models was not associated with the risk. Because GSTM1, GSTT1, and GSTO2 genes belong to low-penetrance genes which might be involved in the carcinogenesis, patients and controls without family of cancer in first-degree relatives were also analyzes separately. To investigate whether profiles of GST genotypes are associated with the risk of gastric cancer, we used unconditional logistic regression analysis with GSTM1, GSTT1, and GSTO2 genotypes as predictor factors. The GSTO2 DD genotype was associated with decreased risk as compared to GSTO2 NN genotype (OR = 0.21, 95% CI: 0.05–0.92, P = 0.038). Conclusions Present findings show that GSTO2 DD genotype decreases the risk of gastric cancer in individuals without history of cancer in their first-degree relatives.     

Polymorphisms in <Emphasis Type="Italic">RAD51, XRCC2</Emphasis> and <Emphasis Type="Italic">XRCC3</Emphasis> genes of the homologous recombination repair in colorectal cancer—a case control study

XRCC2 and XRCC3 proteins are structurally and functionally related to RAD51 which play an important role in the homologous recombination, the process frequently involved in cancer transformation. In our previous work we show that the 135G>C polymorphism (rs1801320) of the RAD51 gene can modify the effect of the Thr241Met polymorphism (rs861539) of the XRCC3 gene. We tested the association between the 135G>C polymorphism of the RAD51 gene, the Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism (rs3218536) of the XRCC2 gene and colorectal cancer risk and clinicopathological parameters. Polymorphisms were evaluated by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) in 100 patients with invasive adenocarcinoma of the colon and in 100 sex, age and ethnicity matched cancer–free controls. We stratified the patients by genotypes, tumour Duke’s and TNM stage and calculated the linkage of each genotype with each stratum. Carriers of Arg188Arg/Me241tMet, His188His/Thr241Thr and His188His/G135G genotypes had an increased risk of colorectal cancer occurrence (OR 5.70, 95% CI 1.10–29.5; OR 12.4, 95% CI 1.63–94.9; OR 5.88, 95% CI 1.21–28.5, respectively). The C135C genotype decreased the risk of colorectal cancer singly (OR 0.06, 95% CI 0.02–0.22) as well as in combination with other two polymorphisms. TNM and Duke’s staging were not related to any of these polymorphisms. Our results suggest that the 135G>C polymorphism of the RAD51 gene can be an independent marker of colorectal cancer risk. The Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism of the XRCC2 gene can modify the risk of colorectal cancer.     

Polymorphic Genes of Xenobiotic-Metabolizing Enzymes Associated with Predisposition to Bronchial Asthma in Hereditarily Burdened and Nonburdened Children

The frequencies of theCYP1A1valine allele, homozygous deletions of GSTM1 and GSTT1, and two point mutations of the NAT2 gene, NAT2: S1(C⁴⁸¹ T) and S2 (G⁵⁹⁰ A), were compared in healthy children and children having bronchial asthma. The S1 mutation was associated with resistance, and all of the other traits, with predisposition to the disease. In families of patients with diseased progenitors and in those with healthy progenitors, the estimates of the asthma risk were similar. In both groups, parameters of the trait association with the disease depended on passive smoking. At passive smoking, a trend to an overrepresentation (high odds ratio, OR) of the GSTM1 null genotype and S2 mutation of theNAT2 gene was observed, whereas the odds ratio of the GSTT1 null genotype decreased, and those of the CYP1A1 and S1 mutation of the NAT2 gene remained unchanged. The highest OR = 36.25 (P < 0.01) was characteristic of theGSTT1 null genotype in nonsmoking hereditary burdened patients. The results obtained suggest an important role of xenobiotic-metabolizing enzymes in development of bronchial asthma.     

Lack of association between human longevity and genetic polymorphisms in drug-metabolizing enzymes at the NAT2, GSTM1 and CYP2D6 loci

In the present study, the possible role of genetic polymorphism of three drug-metabolizing enzymes, debrisoquine/sparteine hydroxylase (CYP2D6), glutathione S-transferase μ (GSTM1), and N-acetyltransferase (NAT2), as a putative genetic component of human longevity, was explored. A total of 817 DNA samples from a centenarian and a control (20–70 years) population was subjected to PCR-coupled RFLP methods. Subjects were genotyped for the CYP2D6*3 (A₂₆₃₇ deletion) and CYP2D6*4 (G₁₉₃₄A transition) alleles, for four mutations of NAT2 [namely, NAT2*5A (C₄₈₁T), NAT2*6A (G₅₉₀A), NAT2*7A (G₈₅₇A), and NAT2*14A (G₁₉₁A)], and for the presence or absence of GSTM1 gene deletion. No significant difference was found at these three loci between centenarian and control subjects with respect to allelic variant frequencies, genotype distributions or predicted phenotypes deduced from genotype combinations. By comparing the distribution of combined genotypes for the polymorphisms tested at the CYP2D6, NAT2, and GSTM1 loci, none of the predicted phenotypes concerning debrisoquine hydroxylase extensive-metabolizer or poor-metabolizer phenotypes, slow or fast N-acetylation capacities, and active or defective glutathione S-transferase, could be correlated with human longevity, alone or in combination. Received: 4 September 1997/Accepted: 13 December 1997     

Effect of NAT2 gene polymorphism on bladder cancer risk in Slovak population

N-acetyltransferase 2 (NAT2) is phase II enzyme with major roles in catalyzing the detoxification of aromatic amines, which are known risk factors for bladder cancer, and are ubiquitously present in the environment. We assessed the association between common polymorphisms in NAT2 gene and the risk of bladder cancer in 90 Slovak patients and 274 ethnicity-matched healthy controls. Effect modifications by smoking, age and gender were also evaluated. Overall, NAT2 slow acetylation was associated with significantly increased risk of bladder cancer (OR = 1.90; 95% CI, 1.15–3.16). In stratified analyses by age and gender, the elevated risk conferred by slow acetylator genotype was evident in older individuals (OR = 3.55; 95% CI, 1.77–7.35) and males (OR = 4.65; 95% CI, 1.68–16.10), with further increasing in NAT2*5B/*6A genotype carriers. Smoking was confirmed to be important risk factor, moreover, the risk was markedly increased in smokers with NAT2 slow acetylator genotype, and NAT2*5B/*6A carriers especially. In summary, these findings are consistent with previous literature suggesting that individual susceptibility to bladder cancer may be modulated by NAT2 polymorphisms, particularly in interaction with relevant environmental exposures such as smoking.     

Pharmacogenetic Study of Drug-Metabolising Enzyme Polymorphisms on the Risk of Anti-Tuberculosis Drug-Induced Liver Injury: A Meta-Analysis

Background

Three first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury (ATLI) ranges from a mild to severe form, and the associated mortality cases are not rare. In the past decade, many investigations have focused the association between drug-metabolising enzyme (DME) gene polymorphisms and risk for ATLI; however, these studies have yielded contradictory results.

Methods

PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between polymorphisms from 4 DME genes (NAT2, CYP2E1, GSTM1 and GSTT1) and susceptibility to ATLI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and their publication bias were also tested.

Results

38 studies involving 2,225 patients and 4,906 controls were included. Overall, significantly increased ATLI risk was associated with slow NAT2 genotype and GSTM1 null genotype when all studies were pooled into the meta-analysis. Significantly increased risk was also found for CYP2E1*1A in East Asians when stratified by ethnicity. However, no significant results were observed for GSTT1.

Conclusions

Our results demonstrated that slow NAT2 genotype, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI.     

CYP1A1 and CYP2D6 polymorphism and risk of lung cancer in a North Indian population

This case–control study was conducted to examine the association between the CYP1A1 and CYP2D6 genotypes and lung cancer risk among North Indians. The estimated relative risk for lung cancer associated with the CYP1A1 Val/Val allele was 2.68, and was four-fold when cases with small cell lung cancer (SCLC) were considered alone. With regard to the metabolism of debrisoquine, no poor metabolizers were found amongst the subjects. The odds ratio of risk with the heterozygous extensive metabolizer (HEM) genotype was 1.5. However, in the presence of at least a single copy of the variant CYP1A1 MspI allele and the CYP2D6 HEM genotype, the risk was two-fold for squamous cell carcinoma (SQCC). When the CYP1A1 Val/Val and CYP2D6 HEM genotypes were taken together, the risk for SCLC was four-fold. Stratified analysis indicated an interaction between bidi smoking and variant CYP1A1 genotypes on the risk for SQCC and SCLC. Heavy smokers (Brinkman index>400) with Val/Val genotypes were at a very high risk of developing lung cancer (odds ratio 29.30, 95% confidence interval 2.42–355, p=0.008). Heavy smokers with CYP1A1 MspI (CYP1A1*1/2A or CYP1A1*2A/*2A) genotype had a seven-fold risk for SCLC compared with non-smokers. This study is the first to be carried out on a North Indian population, and, although small, suggests that CYP1A1 and CYP2D6 polymorphisms might have a role in determining the risk for lung cancer and should be investigated further.     

The Incidence of Liver Injury in Uyghur Patients Treated for TB in Xinjiang Uyghur Autonomous Region,China, and Its Association with Hepatic Enzyme Polymorphisms NAT2, CYP2E1, GSTM1 and GSTT1

Background and Objective

Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury.

Methods and Design

In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays.

Results

2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes.

Conclusions

In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.     

CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma

Polymorphisms in the selected genes controlling carcinogen metabolism (CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1, GSTT1) considered separately or in different combinations, were investigated for an association with tobacco smoke-associated squamous cell carcinoma (SCC) of the larynx. The case-control study was performed in 289 patients with laryngeal SCC and in 316 cancer-free controls; all were Caucasian males from the same region of Poland and current tobacco smokers. The DNA samples were genotyped using PCR-RFLP and multiplex PCR. The variants' frequencies in both groups were compared; odds ratios and their 95% confidence intervals were calculated by logistic regression analyses. The CYP1A1*1/*4, CYP2D6*4/*4, NAT2*4/*6A genotypes, as well as the CYP1A1*4, CYP2D6*4 and NAT2*4 alleles, were found at significantly higher frequencies in cases than in controls indicating their role as "risk-elevating" factors in laryngeal SCC. Combined genotypes, characterized by the presence of the "risk-elevating" variants at more than one locus, often occurred together with the null variant of the GSTM1 gene and homozygous XPD A/A (Lys751Gln, A35931C) genotype. Furthermore, we identified some "protective" variants, found more frequently in controls than in cases, i.e. the NAT2*6A/*6A and NAT2*5B/*6A genotypes. A distribution of "risk" or "protection" genotypes/alleles seems to be connected with age as an occurrence or risk genes was more frequent in the group of "young" cases (< or = 49 years). Accumulation of certain alleles or genotypes of the CYP1A1, NAT2, GSTM1 and XPD seems to be associated with either increased or decreased risk to develop laryngeal SCC. Therefore, polymorphisms in these genes may play a role in the laryngeal cancer etiology.     

Study the polymorphism of CYP3A5 and CYP3A4 loci in Iranian population with laryngeal squamous cell carcinoma

Cancer reflects a complicated network of interactions between genes and environmental factors. Cytochrome P450 (CYP) is a multi-gene superfamily participating in the metabolism of xenobiotics. The aim of our study was to examine whether polymorphisms in the CYP enzyme genes affect the risk of developing larynx squamous cell carcinoma (SCC). Polymorphism of CYP3A5 and CYP3A4 genes were investigated in 50 patients with laryngeal SCC and 100 control subjects by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). In patients the CYP3A5 3*/3* and 1*/3*genotypes were detected in 92% and 8% respectively. There was no relation between genotype, allele frequency and grade/stage of tumor. In control group, the frequency of CYP3A5 3*/3* and CYP3A5 1*/3* genotype were 98% and 2% respectively. There was no significant difference in genotype and allele frequency of this gene between patient and control group. In respect of CYP3A41A*/B*, people in both patient and control groups had the same genotype of CYP3A41A*/1A*. In this study, the CYP gene variants were not associated with increased risk of laryngeal SCC. Study on the other genetic factors which are involved in activation/detoxication of procarcinogenes, such as CYP1A1, CYP1B1, CYP2E1 and gluthation S transferase is recommended.     

Polymorphic genes of xenobiotic-metabolizing enzymes associated with bronchial asthma in genetically predisposed children

The frequencies of the CYP1A1 valine allele, homozygous deletions of GSTM1 and GSTT1, and two point mutations of the NAT2 gene, (C481-->T) and S2 (G590-->A), were compared in healthy children and children having bronchial asthma. The S1 mutation was associated with resistance, and all of the other traits, with predisposition to the disease. In families of patients with diseased progenitors and in those with healthy progenitors, the estimates of the asthma risk were similar. In both groups, parameters of the trait association with the disease depended on passive smoking. At passive smoking, a trend to an overrepresentation (high odds ratio, OR) of the GSTM1 null genotype and S2 mutation of the NAT2 gene was observed, whereas the odds ratio of the GSTT1 null genotype decreased, and those of the CYP1A1 and S1 mutation of the NAT2 gene remained unchanged. The highest OR = 36.25 (P < 0.01) was characteristic of the GSTT1 null genotype in nonsmoking hereditary burdened patients. The results obtained suggest an important role of xenobiotic-metabolizing enzymes in development of bronchial asthma.     

GST,CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83–2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88–2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74–3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85–2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92–3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72–10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.     

An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer

DNA repair genetic polymorphisms have been studied extensively in relation to lung cancer susceptibility, but much less is known about their role in clinical outcome modulation. In this report, we examined effect of the XPA −4G>A, XPD Asp312Asn, Leu751Gln, hHR23B Ala249Val, XPG Asp1104His, XRCC1 Arg399Gln, XRCC2 −4234G>C and XRCC3 Thr241Met polymorphisms on overall survival in 162 patients with resected non-small cell lung cancer (NSCLC). The XRCC3 Met/Met genotype was significantly associated with increased risk of death among all patients and men in uni- and multivariate analyses. The risk was higher for adenocarcinoma patients possessing the XRCC3 Met/Met or XRCC1 Gln/Gln genotypes, although their frequency was small. The XRCC1 399Gln allele was also associated with poor prognosis in stage II–IIIA and among older individuals. Men homozygous for the XPD 312 Asn/Asn had significantly better survival with the risk of death being at borderline significance in uni- and multivariate models. Younger cases and ever smokers smoking less than median pack-years showed significantly increased risk of death associated with the XPA −4A allele. A presence of one or two XRCC2 −4234C alleles had a protective effect in males and ever smokers with lower cumulative smoking dose, although the CC genotype was rarely observed. When number of combined risk alleles was considered, we found that carriers of >4 adverse alleles were at significantly increased risk of death in uni- and multivariate models. Therefore, our results indicate that selected genetic polymorphisms in DNA repair genes may influence overall survival in resected NSCLC.     

Genotype frequencies of polymorphic GSTM1, GSTT1, and cytochrome P450 CYP1A1 in Mexicans

The genotype frequencies of three metabolic polymorphisms were determined in a sample of a typical community in central Mexico. CYP1A1*3, GSTM1, and GSTT1 polymorphisms were studied in 150 donors born in Mexico and with Mexican ascendants; with respect to ethnicity the subjects can be considered Mestizos. PCR reactions were used to amplify specific fragments of the selected genes from genomic DNA. An unexpected 56.7% frequency of the CYP1A1*3 allele (which depends on the presence of a Val residue in the 462 position of the enzyme, instead of Ile) was found, the highest described for open populations of different ethnic origins (i.e., Caucasian, Asian, African, or African American). The GSTM1 null genotype was found with a frequency of 42.6%, which is not different from other ethnicities, whereas the GSTT1 null genotype had a frequency of 9.3%, one of the lowest described for any ethnic group but comparable to the frequency found in India (9.7%). The frequency of the combined genotype CYP1A1*3/*3 and the GSTM1 null allele is one of the highest observed to date (or perhaps the highest): 13.7% among all the ethnicities studied, including Caucasians and Asians, whereas the combination of CYP1A1*3/*3 with the GSTT1 null allele reached only 2.8%. The GSTM1 null allele combined with the GSTT1 null allele, on the other hand, has one of the lowest frequencies described, 4.24%, comparable to the frequencies found in African Americans and Indians. Finally, the combined CYP1A1*3/*3, GSTM1 null allele, and GSTT1 null allele genotype could not be found in the sample studied; it is assumed that the frequency of carriers of these combined genotypes is less than 1%. CYP1A1*3 and CYP1A1*2 polymorphisms were also evaluated in 50 residents in a community of northern Mexico; the CYP1A1*3 frequency was 54%, similar to that found in the other community studied, and the CYP1A1*2 frequency was 40%, which is high compared to Caucasians and Asians but comparable to the frequency found in Japanese and lower than the frequency found in Mapuche Indians. Haplotype frequencies for these CYP1A1 polymorphisms were estimated, and a linkage disequilibrium value (D) of 0.137 was calculated.