Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis

Endometriosis, one of the most common gynaecologic disorders, shows significantly elevated prevalence in industrial areas and there is also a possible genetic predisposition. Glutathione-S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The objective of the present study was to investigate whether the polymorphisms of GSTM1, GSTT1 and GSTP1 are related to endometriosis. Blood samples were available from 259 controls and 194 patients with advanced endometriosis diagnosed by both pathology and laparoscopic findings. The proportion of the GSTM1, GSTT1 and GSTP1 genotypes of the control group were comparable to other populations. There was no significant evidence that the distribution of the GSTM1 and GSTT1 genotype differed between the patients and the controls, with an allelic odds ratio (OR)=1.074 [95% confidence interval (CI)=0.737-1.564] and 1.239 (95% CI = 0.853-1.799), respectively. Also, there was no significant difference in the proportion of GSTP1 genotypes between the women with endometriosis and the control group with the OR = 0.823 (95% CI = 0.536-1.264). The higher risk alleles were contended as GSTM1, GSTT1 null mutation and GSTP1 Ile105Ile polymorphism. There was no significant increase in the risk of endometriosis as the number of higher risk alleles of the GST family increased. In conclusion, our findings suggest that the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women.     

Interaction of passive smoking with GST (GSTM1, GSTT1, and GSTP1) genotypes in the risk of cervical cancer in India

Human papilloma virus (HPV) infection is a major cause of cervix cancer, but a number of infected women do not develop invasive lesions, suggesting that HPV infection in itself is not a sufficient factor and that other cofactors, such as smoking, play an important role in development of cervix cancer. Alongside active cigarette smoking, passive smoking is an independent risk factor for cervix cancer. Smoking maintains cervical HPV infection longer and decreases potential of clearing an oncogenic infection. Thus, it is quite possible that polymorphism at detoxifying enzyme coding loci such as GSTM1, GSTT1, and GSTP1 may determine susceptibility to cervix cancer. This study evaluates the combined effects of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 on susceptibility to cervical cancer and interaction of these genes with smoking. On individual analysis of GSTM1, GSTT1, and GSTP1, it was observed that passive smokers having genotypes GSTM1 (null) (OR = 7.0, 95% CI = 2.19-22.36, P = 0.0005), GSTT1 (null) (OR = 10.2, 95% CI = 1.23-84.18, P = 0.02), and GSTP1 (ile/val) (OR = 6.4, 95% CI = 2.25-18.38, P = 0.0005) have an increased risk of developing cervix cancer. It is thus concluded that cervical cancer risk is increased in passive smokers with GSTM1 (null), GSTT1 (null), and GSTP1 (ile/val) genotypes.     

The I,105V polymorphism in glutathione S-transferase P1, parental smoking and the risk for nonsyndromic cleft lip with or without cleft palate

Genetic variations in the detoxification enzyme glutathione S-transferase P1 (GSTP1) may modify the teratogenicity of lifestyles, such as smoking. We investigated the role of the I105V polymorphism in GSTP1, parental periconception smoking, and their interaction with nonsyndromic cleft lip with or without cleft palate (CL/P) risk in the offspring. The GSTP1 I105V polymorphisms were determined in Dutch non-consanguineous Caucasians comprising of 155 CL/P triads (mother, father, child) and 195 control triads. The analyses were also carried out on complete triads only (n=69 CL/P and n=95 controls). Transmission disequilibrium testing and logistic regression analyses were performed. Neither maternal nor paternal smoking increased CL/P risk; odds ratios (OR): 1.2, 95 confidence intervals (CI)=0.7-2.0 and OR: 1.0, 95% CI=0.6-1.6, respectively. Carriership of the polymorphic Val105 allele in mothers may increase CL/P risk, OR: 1.5, 95% CI=0.96-2.5. Children homozygous for the Val105 allele may show an increased risk of CL/P, OR: 2.2, 95% CI=0.8-6.4. Maternal smoking tended to increase CL/P risk in mothers and children carrying Val105 alleles, OR=1.9, 95% CI=0.9-4.0 and OR=2.2, 95% CI=0.98-4.9, respectively. The highest risk for CL/P in children carrying Val105 alleles with a smoking father was 1.7, 95% CI=0.8-3.5. The GSTP1 I105V polymorphism in mothers and/or children either alone or in combination with maternal smoking may contribute to CL/P risk. Although of borderline significance, these results may underline the importance of smoking cessation in the periconception period for the prevention of CL/P in future generations.     

Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma

BACKGROUND: The factors contributing to the oxidant/antioxidant imbalance in asthma are incompletely understood. OBJECTIVE: To determine the factors associated with oxidative stress including asthma severity and the genotype of the antioxidant enzymes. METHODS: A total of 196 children with mild asthma, 116 children with moderate-severe asthma, and 2 healthy control groups (187 and 68 children) were included in the study. Plasma levels of malondialdehyde were measured as the indicator of oxidative stress, and reduced glutathione levels as the indicator of antioxidant defense. Children were genotyped for null variants of glutathione S transferase (GST) T1 and GSTM1, and ile105val variant of GSTP1. Risk factors were analyzed with multivariate logistic regression. RESULTS: Systemic levels of malondialdehyde increased and reduced glutathione levels decreased significantly from healthy controls to patients with mild asthma and then to patients with moderate-severe asthma (P < .001 for each). Multivariate logistic regression identified asthma and asthma severity as independent factors associated with oxidative stress (odds ratio between 17 and 56; P < .001). Children with asthma with GSTP1 val/val genotype had higher malondialdehyde and lower glutathione levels compared with other genotypes (P = .023 and P = .014, respectively). GSTP1 val/val genotype was independently associated with asthma severity (odds ratio, 4.210; 95% CI, 1.581-11.214; P = .004). CONCLUSION: Our study indicates the presence of a strong oxidative stress in children with asthma that increases with the severity of the disease. In this population, val/val genotype at GSTP1 ile105val locus may be an important factor in determining the degree of oxidant injury. CLINICAL IMPLICATIONS: Children with asthma with val/val genotype at GSTP1 ile105val locus may be good candidates for supplemental antioxidant therapy.     

Glutathione S-transferase mu, omega, pi, and theta class variants and smoking in Parkinson's disease

GSTs are a family of inducible phase II enzymes that may play a neuroprotective role in Parkinson's disease (PD). GSTs may also modify PD risk by metabolizing compounds in cigarettes, as cigarette smoking is generally found to be associated with a decrease in PD risk. Using a population-based case-control study design, we examined polymorphisms of the mu, omega, pi, and theta classes of GST to elucidate the main effects and smoking-GST interactions on PD risk. From three rural California counties, we recruited 289 incident idiopathic PD cases, clinically confirmed by our study neurologist, and 270 population controls, marginally matched by age, gender, and race. We assessed main gene polymorphism associations and evaluated interactions between smoking and GST polymorphisms as departures from a multiplicative scale adjusting for age, gender, and race. We also restricted analyses to Caucasian subjects to address the potential for population stratification (n=235 cases, 220 controls). Among Caucasians, we observed a risk reduction in subjects carrying at least one variant allele for GSTO1 (OR=0.68, 95% CI: 0.47-0.98) and also GSTO2 (OR=0.64, 95% CI: 0.44-0.93); both genes were in strong linkage disequilibrium. No main gene effects were observed for the remaining polymorphisms. We noted a multiplicative interaction between ever having smoked regularly and GSTO1 (OR(interaction)=0.55, 95% CI: 0.33-0.92) and GSTO2 (OR(interaction)=0.54, 95% CI: 0.32-0.90). Results were similar when combining all races. These findings and the paucity of similar studies suggest a need for further inquiry into the association between GSTs, smoking, and PD risk.     

Relationship between glutathione S-transferase gene polymorphisms and enzyme activity in Hong Kong Chinese asthmatics

BACKGROUND: Asthma is a disease associated with oxidative stress. The glutathione S-transferases (GST) are a group of enzymes that protect cells from oxidative stress. Functional genetic polymorphisms of GST genes (GSTT1, GSTM1 and GSTP1) have previously been reported. OBJECTIVE: To investigate the association of GST gene polymorphisms and its enzyme activity with the risk of asthma in Hong Kong Chinese adults. METHODS: An age- and smoking status-matched case-control study was carried out on 315 patients with asthma and 315 healthy controls. Genotyping was carried out on genomic DNA using the PCR and/or restriction fragment length polymorphism (PCR-RFLP). Plasma GST activity was measured by fluorometric assay. RESULTS: The distribution of various genotypes or alleles of the GSTT1, GSTM1 and GSTP1 was not significantly different between patients with asthma and healthy controls. The GSTM1 null genotype was found to be protective from the development of asthma in atopic subjects (odds ratios 0.55, 95% confidence interval 0.34-0.90; P=0.017). However, there was no association between GSTT1 and GSTM1 null genotypes and enzyme activity. GSTP1 codon 105 Val variants led to reduced plasma GST activity in healthy controls. Asthma patients had elevated plasma GST activity compared with healthy controls irrespective of their genotypes (P<0.001). CONCLUSION: Our data suggest that among atopic subjects, the GSTM1 null genotype is associated with a decreased risk for asthma despite increased level of plasma GST activity in asthma, but it could not distinguish whether this increase is a potentially protective compensatory effect or a pathogenic factor.     

Association of GSTs gene polymorphisms with treatment outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy

We evaluated the association of GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms with the clinical response to chemotherapy and treatment outcome of NSCLC. Between October 2009 and October 2012, a total of 282 patients with advanced NSCLC were enrolled into our study, and they were followed up until October 2014. The genotypes of GSTM1, GSTT1, and GSTP1 IIe105Val were performed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By logistic regression analysis, our study found that the Val/Val genotype of GSTP1 IIe105Val was associated with more CR+PR response to chemotherapy when compared with the IIe/IIe genotype, and the OR (95% CI) was 2.18 (1.16-4.12). By multivariate Cox proportional hazards regression analysis, we found the Val/Val genotype of GSTP1 was correlated with lower risk of death in advanced NSCLC (HR, 0.48; 95% CI, 0.25-0.93). However, no association was found between GSTT1 and GSTM1 polymorphisms and response to chemotherapy and overall survival of advanced NSCLC. Moreover, the IIe/Val + Val/Val genotypes of GSTP1 were associated with lower risk of death in never smokers, and the adjusted HR (95% CI) was 0.34 (0.12-0.93). In conclusion, we found that the GSTP1 polymorphism was correlated with better response to chemotherapy and lower risk of death in advanced NSCLC patients.     

Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in endometriosis

Endometriosis is a gynaecological disease with a certain genetic background, but the locations of possible genomic aberrations are still poorly clarified. Intercellular adhesion molecule-1 (ICAM-1), which is a surface glycoprotein that promotes adhesion in immunological and inflammatory reactions, seems to play a role in this condition. The aim of this study was to examine the potential associations of ICAM-1 gene polymorphisms with endometriosis and its severity. Specifically, we have studied two polymorphic sites located in codons 241 (G/R241) and 469 (E/K469) of the ICAM-1 gene. Three hundred and sixty-three Italian Caucasian women of reproductive age who underwent laparoscopy for benign pelvic conditions were enrolled in the study. Endometriosis was documented and staged in 188 women while 175 subjects, in whom endometriosis was laparoscopically ruled out, served as the control group. The frequency of the R241 allele was only marginally higher in endometriosis patients than in controls [5.8 versus 2.9%, P = 0.05; odds ratio (OR), 2.1; 95% confidence interval (CI), 1-4.5]. However, a strikingly high frequency of this allele was found in patients with Stage IV endometriosis versus controls (8.6 versus 2.8%, P = 0.008; OR, 3.2; 95% CI, 1.3-7.9). In contrast, the allele and genotype frequencies of the E/K469 polymorphism did not differ significantly between endometriosis and control groups. While the functional correlate of the G/R241 polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM-1 gene domain may contribute to the susceptibility to endometriosis.     

Glutathione S-transferase M1*null genotype but not myeloperoxidase promoter G-463A polymorphism is associated with higher susceptibility to endometriosis

Glutathione S-transferase M1 (GSTM1), one member of the GST family, is responsible for metabolism of xenobiotics and carcinogens. Myeloperoxidase (MPO) plays an important role in the oxidation and activation of carcinogens and nitric oxide. Allelic variants of GSTM1 and MPO gene polymorphisms might impair detoxification function and increase the susceptibility to endometriosis. We aimed to investigate if these polymorphisms are useful markers for predicting endometriosis susceptibility. Women were divided into two groups: (i) endometriosis (n=150); (ii) non-endometriosis (n=159). Polymorphisms for GSTM1 and MPO were amplified by polymerase chain reaction and detected by electrophoresis after restriction digestion. The relative frequencies of the GSTM1*wild (+/+,+/0)/null (0/0) genotypes and MPO-463*G/A gene polymorphisms between both groups were compared. The distribution of GSTM1 polymorphisms was significantly different between the two groups. Proportions of GSTM1*wild/null alleles in both groups were: (i) 36.7/63.3%; (ii) 95/5% (P=0.001). In contrast, MPO-463 genotypes were not significantly different between the two groups. Proportions of MPO*A homozygote/heterozygote/G homozygote in both groups were: (i) 2.7/17.4/79.9% and (ii) 1.9/17/81.1% (P> 0.05). We conclude that the GSTM1*null genotype is associated with a higher risk of endometriosis development. MPO-463*G/A gene polymorphism is not related to the susceptibility of endometriosis.     

Tumor Necrosis Factor and Interleukin‐6 Gene Polymorphisms and Endometriosis Risk in Asians: A Systematic Review and Meta‐Analysis

A relationship between endometriosis and tumor necrosis factor (TNF‐α) and interleukin‐6 (IL‐6) gene polymorphisms has been raised for Asians. However, this topic is controversial. This study was a meta‐analysis to explore whether TNF‐α/IL‐6 gene polymorphisms were associated with a risk of endometriosis in Asians. By searching PubMed, HuGENet, and China National Knowledge Infrastructure (CNKI) databases, 17 studies were identified and included (3372 cases and 4008 controls). The odds ratio (OR) with 95% confidence interval (CI) was used to assess the association between TNF‐α/IL‐6 gene polymorphisms and endometriosis risk. An association of TNF‐α gene ‐1031T/C polymorphism with endometriosis was found (TT + TC vs. CC: OR 0.50, 95% CI 0.30–0.82, I² = 37.1%, P = 0.20; TT vs. CC: OR 0.50, 95% CI 0.30–0.82, I² = 43.0%, P = 0.173; TC vs. CC: OR 0.49, 95% CI 0.29–0.83, I² = 10.6%, P = 0.327). In addition, TNF‐α‐238A/G and IL‐6 ‐174C/G gene polymorphisms were also likely to be associated with endometriosis in Asians. For the TNF‐α‐238A/G gene polymorphism, the OR was 1.577 (95% CI: 1.01–2.48). For the IL‐6 ‐174C/G gene polymorphism, the OR was 1.554 (95% CI: 1.04–2.31). No associations were detected between the TNF‐α‐308A/G and IL‐6 ‐634C/G polymorphisms and susceptibility to endometriosis. Our results indicate that the TNF‐α gene ‐1031T/C polymorphism can reduce the risk of endometriosis, but for Asians, TNF‐α‐238A/G and IL‐6 ‐174C/G gene polymorphisms may be a risk factor for endometriosis. No association was found for the TNF‐α‐308A/G and IL‐6 ‐634C/G gene polymorphisms.     

Genetic polymorphisms of GSTs and their association with primary brain tumor incidence

Glutathione S-transferases GSTM1, GSTT1, and GSTP1 are phase II biotransformation enzymes that function on detoxification of a wide range of exogenous agents including carcinogens. It has been shown that genetic variations in these genes play an important role in determining the response of an individual to environmental carcinogens. Some studies revealed a statistically significant association between the polymorphisms in the genes encoding GST enzymes and some cancers, although contrary reports exist. In this study, the association between polymorphisms in these genes and primary brain tumor incidence was investigated in 228 Turkish individuals (75 patients with primary brain tumor and 153 controls). The prevalence of GSTM1 null genotype in the case group was 43%, compared to 24% in the control group, giving an odds ratio (OR) of 2.33 (95% confidence interval CI=1.24-4.39). No association was observed between the GSTT1 or GSTP1 Ile105Val polymorphism and brain tumor incidence. Polymorphisms in GSTM1, GSTT1, and GSTP1 did not show association with histopathologic type of brain tumor (glioma or meningioma). Analysis of the polymorphisms in the studied genes and smoking status of the brain tumor patients revealed no statistically significant association. The presented data clearly suggest a relation between brain tumor incidence with GSTM1 null genotype but not with GSTT1 or GSTP1 gene variants.     

Combined effects of glutathione S-transferase polymorphisms and thyroid cancer risk

Since exposure to ionizing radiation, a risk factor for thyroid cancer, may produce genotoxins potentially eliminated by glutathione-S-transferases, we conducted a case control study to evaluate the role of the GSTM1- and GSTT1-null genotypes and GSTP1 polymorphisms in thyroid cancer. The frequency of GSTP1 Ile/Ile, GSTM1-, and GSTT1-null genotypes was increased in cancer patients when compared with control population. Considering the genotypes over-represented in thyroid cancer patients as potential risk genotypes, we carried out an odds ratio (OR) analysis considering the presence of none, one, two, or three risk genotypes. The results obtained showed that the presence of three potentially risk alleles (GSTM1 null, GSTT1 null, and GSTP1 Ile/Ile) lead to a significant OR increase for all the cases, irrespective of the type of tumor (OR=2.91), for papillary (OR=3.64) but not for follicular tumors. The presence of GSTP1 Ile/Ile leads to a significant later age of tumor onset when compared with GSTP1 Ile/Val and Val/Val (P<0.05), suggesting a possible association between GSTP1 Ile/Ile and the age of disease manifestation. These results suggest that combined GST polymorphisms lead to a moderate increased risk for thyroid cancer, especially for the papillary type, and GSTP1 polymorphisms might modulate the age of onset of the disease.     

Glutathione S-transferase Mu null genotype affords protection against alcohol induced chronic pancreatitis

Glutathione S-transferases (GSTs) play critical roles in providing protection against electrophiles and products of oxidative stress, by catalysing the formation of glutathione conjugates and by eliminating peroxides. Most extensively studied are four main families of human cytosolic GST: GSTAlpha(A), GSTMu(M), GSTPi(P) and GSTTheta(T). Absence of GSTM1 or GSTT1 can be attributed to absence of the GSTM1 or GSTT1 gene products (null genotype) in approximately 50% and 20% of the Caucasian population, respectively. We investigated whether polymorphisms in the GSTM1, GSTT1 and GSTP1 genes modified the risk for chronic pancreatitis (CP). DNA samples were obtained from 142 adult CP patients with alcoholic (n = 79), hereditary (n = 21) or idiopathic (n = 42) origin. DNA from 204 healthy controls and from 57 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in GSTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects. The rates of GSTT1 and GSTP1 genotypes did not differ between CP patients and healthy controls. However, GSTM1 null genotypes were significantly less common in alcoholic CP patients (OR = 0.56, 95% CI: 0.33-0.95) as compared to healthy controls and to alcoholic controls (OR = 0.52, 95% CI: 0.26-1.04). Age- and sex-adjustment bolstered our finding (adjusted OR = 0.48, 95% CI: 0.26-0.89). The frequency of the GSTM1 null genotype is significantly lower in alcoholic CP patients, especially young female. This suggests that GSTM1 null alcohol users, particularly young female, are less susceptible to CP.     

Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19

BACKGROUND: Endometriosis, an estrogen-dependent disease, is believed to be influenced by multiple genetic and environmental factors. Here, we evaluated whether the risk and severity of endometriosis are associated with polymorphisms in estradiol-synthesizing enzyme genes: the Ser312Gly polymorphism in 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) and the Arg264Cys polymorphism in cytochrome P450, subfamily XIX (CYP19). METHODS: All participants underwent diagnostic laparoscopy, and the stage of endometriosis was determined according to the Revised American Fertility Society classification. Of the 138 women enrolled, 59 had no endometriosis, 21 had stage I, 10 had stage II, 23 had stage III and 25 had stage IV. SNPs were discriminated by allele-specific oligonucleotide hybridization. RESULTS: Individuals having at least one A-allele (A/G or A/A genotype) of HSD17B1 showed a significantly increased risk of endometriosis (A/G genotype: adjusted OR, 3.06; 95%CI 1.21-7.74; A/A genotype: adjusted OR, 3.02; 95%CI 1.08-8.43). There was a significant trend associating A/G + A/A genotypes with severity of endometriosis (P for trend < 0.01). No statistically significant association was found for the CYP19 polymorphism. CONCLUSIONS: Evidence for association between the Ser312Gly polymorphism in HSD17B1 and endometriosis was found in a Japanese population. The A-allele of HSD17B1 appears to confer higher risk for endometriosis.     

A polymorphism in the CYP17 gene relates to the risk of recurrent pregnancy loss

The CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates both 17alpha-hydroxylase and 17,20-lyase activity in the steroid biosynthesis pathway. A T-->C polymorphism in the 5' promoter region of CYP17 has been described. To examine the association between recurrent pregnancy loss (RPL) and a polymorphism in CYP17, a case-control study of 117 cases with RPL and 164 controls was conducted. This polymorphism was investigated by PCR/restriction fragment length polymorphism using DNA from peripheral lymphocytes. The T-->C transition in the variant allele (A2) creates a new recognition site for the restriction enzyme MspA1, which permits designation of the wildtype allele (A1) and A2. Women with the A2 allele of CYP17 had an increased risk of RPL [A1/A1 genotype (reference); A1/A2 genotype: odds ratio (OR), 1.68; 95% confidence interval (CI), 0.94-3.01; A2/A2 genotype: OR, 2.37; 95% CI, 1.16-4.83; P trend, 0.016]. Additionally, there was a similar tendency for the increased risk of primary RPL [A1/A1 genotype (reference); A1/A2 genotype: OR, 2.14; 95% CI, 1.14-4.01; A2/A2 genotype: OR, 2.50; 95% CI, 1.16-5.41; P trend, 0.015]. These results suggest that possession of the A2 variant of CYP17 may predispose to an increased risk of RPL with a gene dosage effect.     

Associations of glutathione S-transferase P1, M1, and environmental tobacco smoke with wheezing illness in school children

BACKGROUND: Polymorphisms at the glutathione S-transferase (GST) were associated with asthma-related phenotypes. We hypothesized that the GSTP1 and GSTM1 genotypes could modify the effects of household environmental tobacco smoke (ETS) on childhood wheezing illness. METHODS: We conducted a case-control study comprised of 216 lifetime wheezing children and 185 nonwheezing controls, all of whom were selected from 2524 fourth- to ninth-grade school children in southern Taiwan. RESULTS: Homozygous GSTP1 Ile-105 was significantly associated with current wheezing (OR = 1.78, 95% CI 1.04-3.12), but insignificantly associated with ever wheezing (OR = 1.26, 95% CI 0.82-1.94). The risks of ever or current wheezing on GSTM1 null genotype were positive but not statistically significant. Although household ETS exposure was not associated with wheezing illness, after excluding subjects having in utero ETS or active smoking habits, the adverse effects of household ETS exposure differed significantly by GSTP1-105 genotypes. In children without any ETS exposure at home, GSTP1 Ile-105 homozygosity was significantly related to increased risks for both ever wheezing (OR = 2.29, 95% CI 1.17-4.49) and current wheezing (OR = 4.86, 95% CI 1.86-12.70). In children with household ETS exposure, the risks of wheezing illness did not increase for those carrying two GSTP1 Ile-105 alleles. Children carrying any GSTP1 Val-105 allele were at a significantly greater risk of both ever and current wheezing when exposed to ETS, with a clear dose-response relationship to the number of smokers at home. CONCLUSION: Household ETS exposure is a modifiable cause of wheezing illness in a genetically susceptible subpopulation.     

Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: A meta-analysis

Abstract

Aims: Several polymorphisms have been identified in TNFSF15, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. Method: Databases were searched until 31 January 2014 for eligible studies on TNFSF15 polymorphisms. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95% CIs) were calculated. Results: Fifteen studies with 8903 CD patients, 4687 UC patients and 12?606 controls were included. Except for rs4263839 polymorphism, significant associations were found between the rest six TNFSF15 polymorphisms and CD risk (rs3810936: OR?=?2.10, 95% CI, 1.47–3.00; rs6478108: OR?=?2.19, 95% CI, 1.53–3.13; rs4979462: OR?=?1.89, 95% CI, 1.42–2.52; rs6478109: OR?=?2.00, 95% CI, 1.39–2.88; rs7848647: OR?=?1.54, 95% CI, 1.15–2.06; rs7869487: OR?=?1.51, 95% CI, 1.06–2.17). And we found rs3810936, rs6478108 and rs6478109 polymorphism were significantly associated with UC risk (rs3810936: OR?=?1.19, 95% CI, 1.06–1.34; rs6478108: OR?=?1.16, 95% CI, 1.06–1.26; rs6478109: OR?=?1.16, 95% CI, 1.03–1.32). According to the subgroup analysis by ethnicity, except for rs4263839 in Caucasian and rs4979462 in Asian, all the rest investigated TNFSF15 polymorphisms were associated with CD risk and rs3810936 and rs7848647 polymorphism in Asian as well as rs6478108 polymorphism in Caucasian were associated with UC risk. Conclusion: This meta-analysis indicated that most of the seven TNFSF15 polymorphisms (except for rs4263839) were risk factors contributed to CD and UC susceptibility. The differences in ethnicity did not influence the risk obviously.     

Association between HSD17B1 rs605059 polymorphisms and the risk of uterine diseases: a systemic review and meta-analysis

The aim of this study was to evaluate the HSD17B1 gene polymorphisms in the risks of endometrial cancer, endometriosis and uterine leiomyoma by meta-analysis. A comprehensive electronic search was conducted in PubMed, Medline (Ovid), Embase, Weipu, Wanfang and CNKI. The pooled ORs were performed using the Revman 5.2 softerware. 8 case-control studies were included: 3 were about endometrial cancer, 4 were about endometriosis and 1 was about uterine leiomyoma. The result showed no significant association between HSD17B1 rs605059 gene polymorphisms and risks of endometrial cancer (AA vs. AG+GG: OR = 1.11, 95% CI = 0.94-1.32; AA+AG vs. GG: OR = 1.79, 95% CI = 0.42-7.52; AG vs. AA+ GG: OR = 0.87, 95% CI = 0.76-1.00; AA vs. GG: OR = 1.43, 95% CI = 0.62-3.30; A vs. G: OR = 1.00, 95% CI = 0.91-1.11) or endometriosis (AA vs. AG+GG: OR = 0.99, 95% CI = 0.75-1.32; AA+AG vs. GG: OR = 1.73, 95% CI = 0.92-3.25; AG vs. AA+ GG: OR = 1.24, 95% CI = 1.00-1.53; AA vs. GG: OR = 1.54, 95% CI = 0.79-2.97; A vs. G: OR = 1.23, 95% CI = 0.90-1.68). No association was found in a subgroup analysis based on Asian ethnicity for endometriosis. This meta-analysis suggested that HSD17B1 rs605059 polymorphisms were not associated with the risks of endometrial cancer and endometriosis. Further studies are needed to validate the conclusion and clarify the relationship between HSD17B1 rs605059 polymorphisms and the risk of uterine leiomyoma.     

Glutathione S-transferases genetic polymorphisms and human diseases: overview of epidemiological studies

Glutathione S-transferases (GST), xenobiotic-metabolising enzymes, are involved in the metabolic detoxification of various environmental carcinogens. Particular genetic polymorphisms of these enzymes have been shown to influence individual susceptibility against various pathologies including cancer, cardiovascular and respiratory diseases. The results from the meta-analysis indicate that GSTM1*0 null allele was associated with enhanced risk for lung (OR (95% IC) = 1,17 (1,07-1,27)), bladder (OR = 1,44 (1,23-1,68) and larynx cancer (OR = 1,42 (1,10-1,84)). GSTT1 null genotype was associated with increased astrocytomas (OR = 2,36 (1,41-3,94)) and meningiomas (OR = 3,57 (1,82-6,92)) cancer risk. GSTP1 allelic polymorphism influence the development of bladder cancer in smokers (OR = 2,40 (1,12-4,95)) and occupational asthma (OR = 3,5 (2,7-4,6)). Finally, GSTM1*0 null allele and GSTT1*1 functional allele were associated with increased risk for coronary heart diseases in smokers (OR = 2,30 (1,40-9,00)) and OR = 2,5 (1,30-4,80), respectively). The GSTT1*1 functional allele was also significantly associated with increased risk of lower extremity arterial disease (OR = 3,60 (1,40-9,00). These epidemiological data suggest that genetic GST polymorphisms influence the individual susceptibility to these diseases. Contrary to cardiovascular disease, no evidence of interaction between GST genotype and smoking status was found in lung cancer but it has not been studied in other cancers. Consequently, other works are necessary to study the potential interaction between GST genotype and environmental carcinogens including tobacco smoke extract.     

Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: relationship with aberrant promoter methylation of the CDKN2A and RARB genes

An association between functional polymorphisms of genes resulting in decreased detoxification of carcinogens or DNA repair and aberrant promoter methylation is an attractive hypothesis in lung carcinogenesis. The genotypes at polymorphic sites of the glutathione S-transferase (GST) M1 (null/wildtype) and P1 (nucleotide 2627 A/G), myeloperoxidase (MPO) (nucleotide -463 G/A), X-ray repair cross-complementing group 1 (XRCC1) (nucleotides 26304 C/T; 28152 G/A), and NADPH quinine oxidoreductase (NQO1) (nucleotide 609 C/T) genes in 75 Chinese patients with non-small cell lung cancer (NSCLC) were characterized with polymerase chain reaction-restriction fragment length polymorphism. Results were correlated with aberrant methylation of the CDKN2A (alias p16(INK4A)), retinoic acid receptor beta (RARB), methylguanine-DNA methyltransferase (MGMT), and death-associated-protein (DAP) kinase genes in the tumors. In comparison with an age-matched control, none of the polymorphisms were associated with increased lung cancer risks. In male patients, however, the MPO -463 GG homozygous state was associated with CDKN2A (alias p16(INK4A)) methylation (odds ratio OR=3.63, 95% confidence interval CI=1.26-10.51), and the XRCC1 26304 T allele in the heterozygous/homozygous state was associated with methylation of CDKN2A (OR=6.13, 95% CI=1.55-24.16) and RARB (OR=7.67, 95% CI=1.62-36.18). In female patients, the GSTP1 G allele in the heterozygous/homozygous state was associated with RARB methylation (OR=18.0, 95% CI=0.76-427.29). These results showed that functional deficiencies in metabolic pathways that protect cells from carcinogen induced DNA damage might be linked to aberrant promoter methylation of the CDKN2A and RARB genes during lung carcinogenesis.