Association of polymorphisms in endothelin-1 and endothelin receptor a genes with vasovagal syncope.

The endothelin system may play a role in the pathogenesis of vasovagal syncope (VVS) because it is implicated in blood pressure regulation. We hypothesized that endothelin-related genetic polymorphisms might modulate susceptibility to VVS. This study aimed to evaluate the possible influence of endothelin-1 (EDN1) and endothelin receptor A (EDNRA) gene variants on the occurrence of tilt-induced VVS and autonomic nervous system activity during the head-up tilt test (HUT). Results were expressed as mean +/- SEM. In 254 patients with recurrent syncope (age 45.33+/-1.22 years, 94 males, 160 females), heart rate variability (HRV) was measured during HUT. EDN1 rs5370 G>T and EDNRA rs5333 T>C gene polymorphisms were assessed using high-resolution melting analysis. There was no statistically significant association between polymorphisms EDN1 rs5370 and EDNRA rs5333 and positivity of HUT or hemodynamic types of VVS. Patients with GT or TT genotypes at the rs5370 locus of the EDN1 had significantly higher values of high-frequency (HF) and the standard deviation of the average NN intervals at the time of the syncope, and they tended to have lower low-frequency (LF) and LF/HF ratio when compared to homozygotes (GG). No statistically significant differences were found in HRV parameters concerning the EDNRA rs5333 genotypes. Our findings suggest the potential role of EDN1 rs5370 variants in regulating autonomic nervous activity and pathogenesis of VVS.

An association between rs7635818 polymorphism located on chromosome 3p12.3 and the presence of abdominal aortic aneurysm.

The association between gene variant rs7635818 located on chromosome 3p12.3 and abdominal aortic aneurysm (AAA) was not unambiguously determined by the results of genome-wide association studies. The aim of our study was to examine this possible association in the Slovak population, with respect to the presence and severity of AAA.A cross-sectional study was conducted between August 2016 and March 2020. The study included 329 participans, 166 AAA patients and a control group of 163 subjects without confirmed AAA with comparable distribution of genders. The anteroposterior diameter of the abdominal aorta was determined by duplex ultrasonography. AAA was defined as subrenal aortic diameter ≥ 30 mm. DNA samples were genotyped using real-time polymerase chain reaction and subsequent high-resolution melting analysis in presence of unlabelled probe. Genetic models studying the possible association were adjusted to age, sex, smoking, arterial hypertension, diabetes mellitus, creatinine and body mass index (BMI) in multivariate analysis. In the additive model, presence of each C-allele of rs7635818 polymorphism was associated with an almost 50 % increase in probability of developing AAA (OR 1.49; 95 % CI 1.06-2.08; p=0.020). Compared to GG homozygotes, CC homozygotes had more than two times higher risk of developing AAA (OR 2.23; 95 % CI 1.14-4.39; p=0.020). The risk of AAA was also in the recessive model higher for CC homozygotes compared to G-allele carriers (GC/GG) (OR 1.79; 95 % CI 1.01-3.19; p=0.047).The abdominal aortic diameter in CC homozygotes of the rs7635818 polymorphism was 7.66 mm greater compared to GG homozygotes (42.5±22.0 mm vs 34.8±21.3 mm; p=0.022) and 5.88 mm greater compared to G-allele carriers (GC/GG) (42.5±22.0 mm vs 36.6±21.0 mm; p=0.04) in univariate analysis. C-allele variant in rs7635818 G>C polymorphism is associated with a higher probability of developing AAA in the Slovak population.

Type II deiodinase polymorphism: A potential risk factor of type 2 diabetes mellitus.

ype 2 diabetes mellitus (T2DM) remains one of the most challenging global epidemics of the twenty-first century. It is estimated that more than 350 million people worldwide are affected by this metabolic disorder. It has many risk factors. Several studies presume that type II iodothyronine deiodinase polymorphism Thr92Ala (DII-Thr92-Ala, rs225014) is yet another risk factor. The aim of the study was to assess the impact of this polymorphism on parameters of glycid metabolism. Our group consisted of 200 subjects (74 males and 126 females) at average age of 63.85 ± 18.98 without prediabetes, diabetes mellitus or any thyropathy. Blood tests were performed to evaluate glucose metabolism parameters as well as DII-Thr92Ala polymorphism. Our study confirmed the relationship between Ala homozygotes and glycosylated haemoglobin (HbA1c) serum levels (Tab. 2, Ref. 14). Keywords: diabetes mellitus 2, deiodinase II, polymorphism Thr92Ala.

Beta 3 subunit of G-protein and its influence on autonomic nervous system in patients with vasovagal syncope.

OBJECTIVES: The aim of this prospective study was to investigate the impact of genetic polymorphisms of ß3 subunit of G-protein on the occurrence of vasovagal syncope, hemodynamic parameters and heart rate variability during head-up tilt test (HUT). BACKGROUND: G-proteins play an important role in the intracellular transmission of impulses in cardiovascular autonomic reflexes. METHODS: In 157 patients with suspected vasovagal syncope HUT was performed. Ninety-one patients (38 men, 53 women, mean age 48 ± 17 years) had positive HUT. Control group consisted of 109 subjects (69 men, 40 women, mean age 37 ± 16 years) with no history of syncope. Results of HUT, hemodynamic parameters and LF, HF, LF/HF, SDNN, RMSSD parameters of heart rate variability were compared in patients with different genotypes. C825T polymorphism of ß3 subunit of G-protein was determined in the study subjects. RESULTS: There was no significant difference in the distribution of genotypes between patients and control group. Also, there was no significant difference in hemodynamic parameters. A statistically significant difference was found between genotypes in LF/HF in the early HUT (mean rank CC: 48.68 vs CT: 35.51 vs TT: 34.14; p = 0.039) and at RMSSD at the time of syncope (mean rank CC: 32.38 vs CT: 42.74 vs TT: 18.50; p = 0.026). CONCLUSIONS: In this study, the relation of C825T polymorphism of ß3 subunit of G-protein to vasovagal syncope was not documented (Tab. 2, Fig. 4, Ref. 37).

T45G and G276T adiponectin gene polymorphisms in primary aldosteronism and healthy controls in an East Slovak population.

Metabolic complications are frequent in primary aldosteronism (PA) and adiponectin gene polymorphisms seem to confer a genetic risk for metabolic alterations. Aim of the study was to evaluate the prevalence of metabolic symptoms in patients with PA compared to controls and the prevalence of two single nucleotide polymorphisms (SNPs), T45G and G276T, in the adiponectin gene and their relationship to metabolic syndrome (MS). The study involved 47 patients with PA and 90 controls selected from general population. Body mass index (BMI), and selected biochemical parametres were examined, and the mentioned SNPs were genotyped in all subjects. PA patients had a significantly higher BMI (p<0.0001), blood glucose level (p<0.01), and triglycerides (p<0.0005) compared to controls. There were no significant differences in the prevalence of the studied genotypes of adiponectin gene polymorphisms. The 276GT genotype was linked with lower levels of triglycerides (p

[Relationship of the CDKAL1 and KCNQ1 gene polymorphisms to the age at diagnosis of type 2 diabetes in the Slovakian population]. / Vzt'ah polymorfizmov génov CDKAL1 a KCNQ1 k veku diagnózy diabetu 2. typu v populácii slovenska.

BACKGROUND/AIMS: The association of CDKAL1 and KCNQ1 genes with type 2 diabetes mellitus (DM2T) was confirmed by several genome-wide association studies in both Caucasian and Asian populations. For both genes, it is supposed that the risk of DM2T development is related to impaired insulin secretion. Based on assumption that the presence of risk allele might predispose to an earlier onset of DM2T, the aim of the present study was to assess the frequency of risk alleles of CDKAL1 rs7756992 and KCNQ1 rs163184 polymorphisms and to analyze their association with the age at DM2T diagnosis in the Slovakian population. METHODS: CDKAL1 rs7756992 A/G and KCNQ1 rs163184 G/T polymorphisms were genotyped using asymmetric PCR with subsequent melting curve analysis in a group of 538 patients with DM2T. Anthropometric and laboratory parameters were determined by using standard methods. Since two genes were analysed, the required level for statistical significance was defined as p < 0.025. RESULTS: Risk homozygotes (CG) for KCNQ1 polymorphism had higher mean age of DM2T diagnosis by 2 years when compared to T-allele carriers (GT + TT) in a recessive model, but the difference did not reach the predefined level of statistical significance. No relationship of CDKAL1 polymorphism to the age at onset of DM2T diagnosis was observed. CONCLUSIONS: In the present study, no relationship of CDKAL1 and KCNQ1 polymorphisms to the earlier onset of type 2 diabetes was observed.

Effect of sulphonylurea treatment on glycaemic control is related to TCF7L2 genotype in patients with type 2 diabetes.

The aim of the present study was to analyse effects of sulphonylurea treatment on parameters of glycaemic control in relation to transcription factor 7-like 2 (TCF7L2) genotypes. In 87 patients with type 2 diabetes who failed to achieve glycaemic control on metformin monotherapy, effects of 6-month sulphonylurea in addition to metformin on reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels were evaluated. Reduction in HbA1c and FPG in response to 6-month sulphonylurea treatment was significantly higher in patients with CC genotype compared to those with the CT+TT genotype (1.16 ± 0.07 vs. 0.86 ± 0.07%, p = 0.003; 1.57 ± 0.12 vs. 1.14 ± 0.14 mmol/l, p = 0.031, respectively). In the multivariate analysis, baseline HbA1c and the TCF7L2 genotype were the only significant predictors of HbA1c reduction. In conclusion, the magnitude of HbA1c and FPG reductions after 6-month sulphonylurea treatment in addition to metformin is related to the TCF7L2 gene polymorphism.

Relationship of five type 2 diabetes candidate gene polymorphisms to the age at diagnosis of diabetes in the Slovakian population.

OBJECTIVES: To examine the relationship between polymorphisms of five candidate genes for type 2 diabetes mellitus (T2DM) and the age at diagnosis of T2DM. METHODS: 538 Slovakian patients with T2DM were included and their age at diagnosis of T2DM retrieved from their medical records. Polymorphisms of genes encoding peroxisome proliferator activated receptor gamma (PPARG), PPARG-coactivator-1 (PGC1), insulin-receptor substrate 1 (IRS1), the subunit Kir 6.2 of the ATP-dependent potassium-channel (KCNJ11) and transcription factor 7-like 2 (TCF7L2) were detected by PCR-RFLP methods. RESULTS: No significant relationship between the risk alleles of the examined gene polymorphisms to the lower mean age at diagnosis of T2DM was observed. The carriers of the TT-genotype of TCF7L2 rs7903146 polymorphism had significantly increased odds ratio for diagnosis of diabetes before the age of 40 years [OR 3.02 (1.34, 6.81), p = 0.008], in comparison with the CC/CT genotype carriers. CONCLUSION: No significant association of PPARG, PGC1, IRS1, KCNJ11 and TCF7L2 gene polymorphisms and the age at diagnosis of T2DM was observed in the present study. Homozygotes for the risk allele of TCF7L2 had more frequently early onset of T2DM, before age of 40 years (Tab. 4, Ref. 15).

MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome.

P-glycoprotein (PGP), the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of carcinogens and cytostatics. It has been suggested that MDR1 polymorphisms contribute to the variability in cancer risk and therapeutic outcome. We examined the relevance of C3435T polymorphism in relation to breast cancer susceptibility, clinical and pathological characteristics of breast carcinoma, the therapeutic response and hematologic toxicities after anthracycline-based chemotherapy. A significant association between allele frequencies and histological type, stage and histological grade was observed (P=0.024, 0.014, 0.006, respectively, chi(2)-test or Fisher's exact test). We also found significantly higher (P=0.019, chi(2)-test) T allele frequency in breast cancer patients (n=221) than in controls (n=113). A significantly enhanced therapeutic outcome after neoadjuvant therapy (n=38; P=0.021, Fisher's exact test) and longer time to progression after anthracycline-based chemotherapy (n=102; P=0.049, log-rank test) were observed in CC homozygotes. However, no significant association between hematologic toxicities and C3435T polymorphism was detectable.

Gene polymorphisms of renin angiotensin system and serotonin transporter gene in patients with vasovagal syncope.

UNLABELLED: Objective of this study was to compare the distribution frequencies of gene polymorphisms of renin-angiotensin and serotonin system in patients with positive and negative head- up tilt test (HUT). METHODS: DNA from 191 patients (mean age 44+ 18 years, 61 men) was collected. HUT was positive in 117 and negative in 74 patients. Following gene polymorphisms were determined by the PCR method: ACE insertion/deletion (I/D ACE), angiotensinogen (AGT) (M 235), angiotensin II receptor (ATR1) (A 1166C) and serotonin transporter (SERT) polymorphism (5HTTLPR). RESULTS: No significant differences in the distribution of gene polymorphisms between syncopal patients with positive and negative HUT were dectected. Distribution of polymorphisms included: I/D ACE: II 19 vs 20%, ID 55 vs 52%, DD 26 vs 28%. Angiotensinogen gene polymorphism MM 27% vs 30%, MT 48% vs 46%, TT 25% vs 24%. ATR1 polymorphism AA 44 vs 32%, AC50 vs 60%, CC 6 vs 8%, 5HTTLPR serotonin transporter gene polymorphism LL 42 vs 43%, SL 41 vs 39%, SS 17 vs 18%. CONCLUSIONS: An association between polymorphisms of ACE, AGT, ATR1 and SERT gene, and predisposition to VVS was not proven by the present study (Tab. 2, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

The prevalence of 21-hydroxylase deficiency in adrenal incidentalomas - hormonal and mutation screening.

UNLABELLED: The aim of the present study was to evaluate and compare the response of 17 OHP to ACTH stimulation in patients with various types of adrenal incidentalomas and to examine the occurence of germline CYP21 mutation in these patients. SUBJECTS AND METHODS: 40 patients (27 females, 13 males) with unilateral and bilateral masses were screened for fi ve most common mutations of the CYP21 in peripheral blood DNA samples. A hormonal evaluation, i.e. baseline plasma values of 17OHP, DHEAS as well as plasma 17OHP and DHEA after ACTH stimulation, was performed in all patients. 21 of them had unilateral adrenal adenoma, 13 patients had adrenal hyperplasia (six of them unilateral) and 6 patients had CT characteristics of other tumors (myelolipomas, cysts, adrenocortical carcinoma). RESULTS: There were no significant differences in plasma 17OHP, DHEAS and plasma cortisol between all three groups. Stimulated plasma values of DHEA and 17OHP after ACTH administration were significantly higher in patients with adenomas (p < 0.05 and p < 0.01) and with hyperplasia (p < 0.05 and p < 0.05) compared with those with other tumors. An exaggerated response of 17 OHP was found in 5 (12 % ) patients. However, mutation screening in peripheral blood samples revealed no CYP21 mutation in all examined groups. SUMMARY: Although 12 % of patients with adrenal incidentalomas had an exaggerated response of 17 OHP after ACTH administration indicating a possible 21-hydroxylase deficiency, these findings are not associated with CYP21 mutation estimated in peripheral blood samples. There was found no germline CYP21 mutation in all patients with various adrenal incidentalomas.

A pilot study testing the genetic polymorphism of N-acetyltransferase 2 as a risk factor in lung cancer.

NAT2 as phase II enzyme is involved in the detoxification/activation of various drugs, environmental substances and carcinogenic compounds. A genotyping approach has been used to investigate NAT2 genotype with putative relevance in lung cancer in population of 110 Slovak-Caucasians patients and 167 non-malignant individuals from the same region. Slow acetylation was not observed to be a significant risk factor of lung cancer development (OR=1.19; 95% CI: 0.71-1.99). However, one genotype responsible for slow acetylation (NAT2*5B/*6) was observed significantly more frequently in lung cancer patients with squamous cell carcinoma compared with control subjects (OR=2.24; 95% CI: 1.14-4.34). Stratified analysis showed an increasing impact of the specific allelic combination NAT2*5B/*6 in non-smokers (OR=6.5; 95% CI: 1.25-15.08). In the case of squamous lung carcinoma an analysis revealed a tendency to adversely affect cancer risk in the individuals with the mentioned genotype in younger than 60 years (OR=3.14; 95% CI: 0.98-9.72) non-smokers (OR=10.40; 95% CI: 1.35-118.89) and in females (OR=4.25; 1.08-16.25). Additional studies are needed to confirm the results we observed and to assess the impact of other effects (specific allelic combinations, sex differences and histological subtype of lung cancer) on NAT2 susceptibility in lung carcinogenesis.

Combined analysis of polymorphisms in glutathione S-transferase M1 and microsomal epoxide hydrolase in lung cancer patients.

Many genes involved in the metabolism of carcinogens have been found to be polymorphic in the human population, and specific alleles are associated with increased risk of cancer at various sites. The etiology of most commonly occurring cancers cannot be explained by allelic variability at a single locus. A combined analysis of two polymorphic enzymes, glutathione S-transferase M1 (GSTM1), microsomal epoxide hydrolase (EPHX1)) and their implication as lung cancer risk factors was performed in a case- control study of non small cell lung cancer. Polymerase chain reaction (PCR) or PCR-RFLP-based methods were used to detect variant genotypes of GSTM1 and EPHX1 (113Tyr-113His in exon 3 and 139His-139Arg in exon 4) in 150 controls and group of lung cancer patients (n=121). The slow 113His EPHX1 allele tended to be more frequent among the patients (frequency 0.587) than among the controls (0.320) (Fisher s exact test, p=0.33). The combined EPHX1 homozygote genotype His113/His139 (predicted very slow activity) versus all other genotype combination was associated with an increased risk of lung cancer (OR=2.29; 95% C.I.=0.94- 5.82), particularly in non-smokers (OR=11.23; 95% C.I.=1.48- 88.41). Polymorphism in GSTM1 had no statistically significant impact on lung cancer risk alone (OR=1.09; 95% C.I.: 0.65-1.82). However, obtained the results revealed that combinations GSTM1 null with homozygote His113/His139 genotype (predicted very slow activity EPHX1) significantly increased lung cancer risk (OR=3.65; 95% C.I.: 1.04-16.07). No overall relationship between genotype combinations predicted high EPHX1 activity and lung cancer risk was confirmed in all followed respects. However, the number of investigated individuals in our study was relatively small, therefore these findings should be judged with circumspectness.

p53 single nucleotide polymorphisms and bladder cancer.

Two p53 germline polymorphisms, a BstUI in exon 4 and a MspI in intron 6 were studied using polymerase chain reaction (PCR) based methods in 50 patients with bladder cancer and 145 healthy controls. Increased frequencies of the BstUI and MspI A2 alleles were found to be associated with statistically non-significant (p = 0.2308 and p = 0.5959) but increased odd ratios for bladder cancer (OR 1.44, 95% CI 0.82-2.27 and OR 1.20, 95% CI 0.61-2.33). Statistically significant difference between patients with bladder cancer and controls was found in the distribution of MspI genotypes. There was a significantly lower proportion of the heterozygous A1A2 genotype in all patients but not in controls (p = 0.0354). The results of this study suggest that BstUI and Msp1 germ line polymorphisms of the tumor suppressor gene p53 marginally modify the risk of bladder cancer.

Reciprocal adaptive response of human peripheral lymphocytes induced by bleomycine or gamma rays.

The adaptive response and reciprocal adaptive response induced in vitro by exposure to low doses of gamma rays (0.05 Gy) or bleomycin (0.05 microg/ml) in human peripheral blood lymphocytes were assessed by the frequency of chromosome aberrations. Gamma rays (1.5 Gy) or bleomycin (1.5 microg/ml) were used as the challenge doses. In the experiments, blood samples from 5 healthy donors were investigated. It has been found that low doses of bleomycin and gamma rays induced a reciprocal adaptive response to high doses of gamma rays or bleomycin. Moreover, the results confirmed that the adaptive response did not correlate with the radiosensitivity of the peripheral blood lymphocytes.

The role of human glutathione S-transferases M1 and T1 in individual susceptibility to bladder cancer.

Several genes involved in the metabolism of carcinogens have been found to be polymorphic in the human population, and specific alleles are associated with increased risk of cancer at various sites. This study is focused on the polymorphic enzymes glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) that are involved in the detoxification of many xenobiotics involved in the etiology of bladder cancer. To investigate the role of GSTM1 and GSTT1 in bladder carcinogenesis, the polymerase chain reaction was used to determine GSTM1 and GSTT1 genotypes of cancer patients (n = 76) and controls (n = 248). The proportion of putative risk GSTM1 null genotype in the case group was 52.6%, compared to 49.6% in the control group, but the GSTT1 0/0 frequency in the bladder cancer group was significantly higher (P = 0.04) in comparison with the control group (27.6 vs 16.9%). Individuals lacking the GSTT1 gene are at an approximately 1.9-fold higher risk (OR = 1.87, C.I. 95% = 1.03-3.42) of developing bladder cancer in comparison with individuals with at least one active allele in the GSTT1 locus. A significantly higher incidence of GSTM1 deletion genotype (P = 0.02) was found in smokers with bladder cancer compared to the controls (70.6 vs 49.6%). Smokers lacking the GSTM1 gene are at an approximately 2.4-fold higher risk of bladder cancer (OR = 2.44, C.I. 95% = 1.10-5.30). The effect of smoking associated with the GSTT1 0/0 genotype was not found to affect the risk of bladder cancer.

Cytogenetic monitoring in coke oven workers.

Cytogenetic markers (chromosomal aberrations, sister chromatid exchanges (SCE), cells with high frequency of SCE (HFC), the heterogeneity index SCE (SCE-H) and genetic polymorphism of genotypes GSTM1 and NAT2 were evaluated in the peripheral lymphocytes of 64 coke oven workers and 34 control subjects from the same plant. Personal monitors were used to evaluate exposure to eight carcinogenic (polycyclic aromatic hydrocarbons) PAHs, including B[a]P, during an 8-h working shift. Smoking habits were checked by urinary cotinine measurement. The exposure among coke oven workers ranged widely from 0.6 to 547 microgram/m3 and 2 to 50 137 ng/m3, for carcinogenic PAHs and B[a]P, respectively. The respective values in controls were 0.07 to 1.51 microgram/m3 and from 2 to 63 ng/m3. The results of biomonitoring in exposed vs. control subjects were as follows: frequency of chromosomal aberrations (% AB.C.), 2. 30% AB.C. vs. 1.09% AB.C. (P<0.05); sister chromatid exchanges, 7.47 SCE/cell vs. 5.49 SCE/cell (P<0.05); HFC, 5.94% vs. 2.06% (P<0.05) and SCE-H index, 1.49 vs. 1.01 (P<0.05). All the cytogenetic markers were significantly increased in the exposed vs. control groups. The effect of smoking was observed only in SCE when evaluated as HFC. Using individual exposure data for carcinogenic PAHs, a significant correlation between exposure and %AB.C. (r=0.372, P=0.0002), SCE/cell (r=0.331, P=0.001), HFC (r=0.467, P=0.007) and SCE/H (r=0. 286, P=0.004) was found. No effects of GSTM1 and NAT2 genotypes, individually or in combination, on the cytogenetic markers was observed. It is concluded that occupational exposure of coke oven workers involved in this study resulted in an increased level of chromosomal aberrations and SCE. The frequency of AB.C. and SCE/cell was found to be related to exposure to carcinogenic PAHs.

Genetic polymorphism of glutathione S-transferases M1 and T1 as a risk factor in lung and bladder cancers.

A combined analysis of two polymorphic enzymes, glutathione S-transferase mu (GST M1) and q (GST T1) and their implication as cancer risk factors was performed in a case-control study of lung and bladder cancers. Using a multiplex polymerase chain reaction (PCR) based method, the frequency of the homozygous deleted GSTM1 and GSTT1 genotypes was examined in 117 lung cancer patients, 67 urinary bladder cancer patients, and in a community-based sample of 248 healthy, unrelated individuals. In both cancer groups the frequency of the GSTM1 null genotype was higher in comparison with that of the control group (59% and 59.7% vs. 49.6%), but this increase did not reach statistical significance (p > 0.05). After grouping by the smoking status, among smokers in both cancer groups (62.1% in lung cancer and 71.4% in the bladder cancer group, respectively) there were statistically significantly (p < 0.05) increased frequencies of the GSTM1 deletion genotype as compared to the control group (49.6%). Smokers with absence of the GSTM1 gene were at an approximately 1.7-fold higher risk for lung cancer (odds ratio--OR = 1.67, 95% confidence interval--CI 95% = 1.0-2.7, p = 0.04) and an approximately 2.5-fold higher risk for bladder cancer (OR = 2.54, CI 95% = 1.2-5.5, p = 0.02). As related to GSTT1, our study demonstrated an overall GSTT1 effect on bladder cancer risk. Individuals with absence of the GSTT1 gene were at an approximately 2.5-fold higher risk of developing bladder cancer. In the lung cancer cases, the frequency of the putatively high risk GSTT1 null genotype was not increased as compared with controls. No effect of smoking was found on risk of lung and bladder cancer associated with the GSTT1 0/0 genotype. In combined analysis, the obtained results suggested that individuals who were both GSTM1 null and GSTT1 null may be at increased risk because they lack both enzymes. The findings suggest that the GSTM1 null genotype may be associated with susceptibility to lung and urinary bladder cancer in dependence on the exposure to carcinogens in cigarette smoke and that the GSTT1 null genotype is not a critical factor in mediating the risk of lung cancer, but may be associated with an increased susceptibility to bladder cancer.