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.     

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.     

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.     

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.     

Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan

The relationship between diet and colorectal cancer has been previously demonstrated and supported with strong epidemiological evidence. The role of genetic polymorphisms has, however, been less well elaborated upon. We conducted a hospital-based case–control study including 727 cases and 736 healthy controls to evaluate the associations of the polymorphic phase-I and -II biotransformations (CYP1A1, CYP1A2, GSTM1, GSTT1, GSTP1, NAT1 and NAT2) and DNA-repair enzymes (XRCC1, XRCC3 and XPD) with the risk of contracting colorectal cancer. We found that men featuring the CYP1A1*2C G/G genotype, the GSTT1 null genotype and XPD 751 with the Gln allele were associated with an elevated risk of colorectal cancer than were men who did not exhibit such genetic features. Multivariate logistic regression analysis revealed that individuals featuring more than two high-risk genotypes increased the colorectal-cancer risk 3.1-fold (OR = 3.1, 95% CI = 1.8–5.2). For women, subjects featuring the CYP1A1*2C G/G genotype and the XRCC3 Thr/Thr genotype faced a 3.1-fold greater risk (95% CI = 1.3–7.0) of colorectal cancer when compared to those featuring the CYP1A1*2C A allele and the XRCC3 Met allele. Taken together, this study suggests that polymorphisms of genes involved in biotransformation and DNA repair could modulate colorectal-cancer risk in Taiwan.     

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.     

Polymorphisms of CYP1a1, CYP2e1, GSTM1, GSTT1, and TP53 genes in Amerindians

Polymorphisms at the TP53, cytochrome P‐450 (CYP), and glutathione S‐transferase (GST) genes are related to cancer susceptibility and present high diversity in allele frequencies among ethnic groups. This study concerns the CYP2E1, GSTM1, and GSTT1 polymorphisms in seven Amerindian populations (Xavante, Guarani, Aché, Wai Wai, Zoró, Surui, and Gavião). Polymorphic sites at CYP1A1 and TP53 were also studied in the Aché and Guarani tribes and compared with previous results about these systems already obtained in the other populations. The CYP2E1*5B haplotype showed, respectively, the highest and the lowest frequencies already observed in human groups. High frequencies of CYP1A1*2A and CYP1A1*2C alleles and mostly low values of GSTM1*0/*0 and GSTT1*0/*0 genotypes were observed. These data may be interpreted as being due to genetic drift or selection for these high‐frequency CYP1A1 alleles and against GST null genotypes during America's colonization. Intrapopulation diversity varied from 0.19 (Guarani) to 0.38 (Surui), and 90% of the total diversity was due to the variability within populations. The relationships between these Amerindians and with other ethnic groups were evaluated based on D_A distances and the neighbor‐joining method. Low correlation was observed between genetic relationships and geographic distances or linguistic groups. In the TP53 comparison with other ethnic groups, Amerindians clustered together and then joined Chinese populations. The cluster analysis seems to indicate that the Aché tribe might descend from a Gê group that could have first colonized that Paraguayan region, but had also assimilated some amount of the Guarani gene pool, maybe through intertribal admixture. Am J Phys Anthropol 119:249–256, 2002. © 2002 Wiley‐Liss, Inc.     

Analysis of Polymorphic Alleles of the Genes Encoding the Phase 1 and 2 Detoxication Enzymes in Patients with Endometriosis

Polymorphysms of the three genes encoding phase 1 (CYP1A1, mEPHX1, and CYP2E1) and the three genes encoding phase 2 (NAT2, GSTM1, and GSTT1) xenobiotic detoxication enzymes were typed by use of PCR in 74 patients with extragenital endometriosis. Distribution of the CYP1A1, mEPHX1, CYP2E1, NAT2,and GSTM1polymorphic alleles in the patient group corresponded to that in the control group. At the same time, functionally defective genotypes GSTM1 0/0, NAT2 S/S; GSTM1 0/0, GSTT1 0/0; and GSTT1 0/0, NAT2 S/S were three, four, and eight times more frequent among the patients than in healthy individuals. This observation suggests the existence of a distinct association between the functionally defective alleles of the phase 2 xenobiotic detoxication and endometriosis. Possible mechanisms underlying this association are discussed. It is suggested that typing of the NAT2, GSTM1, and GSTT1 genes can be useful for the assessment of the predisposition to endometriosis.     

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.     

Polymorphisms of arylamine N-acetyltransferase2 and risk of lung and colorectal cancer

The arylamine N-acetyltransferase 2 (NAT2) enzymes detoxify a wide range of naturally occurring xenobiotics including carcinogens and drugs. Point mutations in the NAT2 gene result in the variant alleles M1 (NAT2 *5A), M2 (NAT2*6A), M3 (NAT2*7) and M4 (NAT2 *14A) from the wild-type WT (NAT2 *4) allele. The current study was aimed at screening genetic polymorphisms of NAT2 gene in 49 lung cancer patients, 54 colorectal cancer patients and 99 cancer-free controls, using PCR-RFLP. There were significant differences in allele frequencies between lung cancer patients and controls in the WT, M2 and M3 alleles (p < 0.05). However, only M2 and M3 allele frequencies were different between colorectal cancer patients and controls (p < 0.05). There was a marginal significant difference in the distribution of rapid and slow acetylator genotypes between lung cancer patients and controls (p = 0.06 and p = 0.05, respectively), but not between colorectal cancer patients and controls (p = 1.0 and p = 0.95, respectively). Risk of lung cancer development was found to be lower in slow acetylators [odds ratio (OR): 0.51, 95% confidence interval (95% CI): 0.25, 1.02, p-value = 0.07]. No effect was observed in case of colorectal cancer. Our results showed that NAT2 genotypes and phenotypes might be involved in lung cancer but not colorectal cancer susceptibility in Jordan.     

Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients

The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene–environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.     

Polymorphisms in the CYP2E1 and GSTM1 Genes as Possible Protection Factors for Leprosy Patients

Background

The CYP2E1 and GSTM1 genes encode metabolic enzymes that have key functions in drug modification and elimination.

Methodology/Principal Findings

We investigated the possible effects of CYP2E1 and GSTM1 polymorphisms in 71 leprosy patients and in 110 individuals from the general population. The GSTM1*0 null allele and INDEL CYP2E1*1D mutant genotypes were analyzed by conventional PCR, while CYP2E1 SNPs (1053C>T, 1293G>C and 7632T>A) were determined by RT-PCR. In leprosy patients, the GSTM1*0 and CYP2E1*5 alleles and the combined alleles GSTM1*0/CYP2E1*6 and GSTM1*0/CYP2E1*5 were significantly related to a baciloscopic index (BI) (BI<3), while the CYP2E1*6 allele was related to a better clinical evolution in the leprosy spectrum.

Conclusions/Significance

Therefore, GSTM1*0, CYP2E1*5 and CYP2E1*6 may be possible protection factors for leprosy patients.     

Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population

Polymorphisms of CYP450 metabolizer enzymes and transport proteins play crucial roles in the inter‐individual variability of drug efficiency. The aim of our study was to predict the frequency of functional variants of CYP2D6, CYP2C19 and ABCB1 genes in the Hungarian population. One hundred twelve unrelated healthy subjects donated DNA sample in the study. ABCB1 C3435T and G2677T/A single‐nucleotide polymorphisms (SNPs) were determined by LightCycler polymerase chain reaction. Because only limited amount of data is available on the rare allelic variants of CYP2D6 in the European populations, our study applied an expanded set of CYP2D6 and CYP2C19 alleles by using AmpliChip test. Our results show that the CYP2D6 phenotypes were 1.9% ultra‐rapid metabolizer, 6.5% intermediate metabolizer (IM), 8.3% poor metabolizer (PM) and 83.3% extensive metabolizer (EM), and the CYP2C19 phenotypes were 1.8% PM, 31.2% IM and 67% EM. The prevalence of the commonly observed CYP2D6 and CYP2C19 alleles in our study corresponds with that of other European populations. Nevertheless, our study confirms that extending the CYP2D6 allele set with loss‐of‐function variants such as CYP2D6*7, *9, *41 is worth considering. Frequency of the wild type ABCB1 3435C was 42.8% whereas the prevelance of 2677 G was 50.4%. Although frequency data of G2677T/A SNP in the European area are limited, some discrepancies with other studies were found. Copyright © 2011 John Wiley & Sons, Ltd.     

Benzo(a)pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes

We investigated whether the presence of (+)-anti-benzo(a)pyrene diolepoxide adducts to serum albumin (BPDE-SA) among workers exposed to benzo(a)pyrene (BaP) and unexposed reference controls was influenced by genetic polymorphisms of cytochrome P4501A1 (CYP1A1), microsomal epoxide hydrolase (EHPX), glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), all involved in BaP metabolism. Exposed workers had significantly higher levels of adducts (0.124 ± 0.02 fmol BPTmg^?1 SA, mean ± SE) and a higher proportion of detectable adducts (40.3%) than controls (0.051 ± 0.01 fmol BPT mg^?1 SA; 16.1%) (p = 0:014 and p = 0:012). Smoking increased adduct levels only in occupationally exposed workers with the GSTM1 deletion (GSTM1 null) (p = 0:034). Smokers from the exposed group had higher adduct levels when they were CYP1A1 *1/*1 wild-type rather than heterozygous and homozygous for the variant alleles (CYP1A1 *1/*2 plus *2/*2) (p = 0:01). The dependence of BPDE-SA adduct levels and frequency on the CYP1A1 *1/*1 genotype was most pronounced in GSTM1-deficient smokers. Exposed workers with GSTM1 null/GSTP1 variant alleles had fewer detectable adducts than those with the GSTM1 null/GSTP1*A wild-type allele, supporting for the first time the recent in vitro finding that GSTP1 variants may be more effective in the detoxification of BPDE than the wild-type allele. Logistic regression analysis indicated that occupational exposure, wild-type CYP1A1*1/*1 allele and the combination of GSTM1 null genotype+EHPX genotypes associated with predicted low enzyme activity were significant predictors of BPDE-SA adducts. Though our findings should be viewed with caution because of the relatively limited size of the population analysed, the interaction between these polymorphic enzymes and BPDE-SA adducts seems to be specific for high exposure and might have an impact on the quantitative risk estimates for exposure to polycyclic aromatic hydrocarbons.     

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.     

Influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to organophosphate pesticides

Previous studies have revealed that organophosphate pesticides (OPs) are primarily metabolized by xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticides-exposed workers. Present study was designed to determine the influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to OPs. We examined 268 subjects including 134 workers occupationally exposed to OPs and an equal number of normal healthy controls. The DNA damage was evaluated using alkaline comet assay and genotyping was done using individual polymerase chain reaction (PCR) or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Acetylcholinesterase and paraoxonase activity were found to be significantly lowered in workers as compared to control subjects which were analyzed as biomarkers of toxicity due to OPs exposure (p<0.001). Workers showed significantly higher DNA tail moment (TM) compared to control subjects (14.32±2.17 vs. 6.24±1.37 tail % DNA, p<0.001). GSTM1 null genotype was found to influence DNA TM in workers (p<0.05). DNA TM was also found to be increased with concomitant presence of NAT2 slow acetylation and CYP2C9*3/*3 or GSTM1 null genotypes (p<0.05). DNA TM was found increased in NAT2 slow acetylators with mild and heavy smoking habits in control subjects and workers, respectively (p<0.05). The results of this study suggest that GSTM1 null genotypes, and an association of NAT2 slow acetylation genotypes with CYP2C9*3/*3 or GSTM1 null genotypes may modulate DNA damage in workers occupationally exposed to OPs.     

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.     

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.     

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.     

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.