Insulin receptor substrate-2 gene polymorphism: is it associated with endometrial cancer?

OBJECTIVE: The G1057D polymorphism in the insulin receptor substrate-2 (IRS-2) gene has been reported to be associated with insulin resistance, obesity and type 2 diabetes. However little is known about its possible association with cancer. To investigate this association, we determined the distribution of its genotypes and frequency of alleles in endometrial cancer patients. METHODS: The study population consisted of 184 subjects: 44 patients with endometrial cancer and 140 controls without cancer. All the patients were primarily treated with surgical intervention. DNA was extracted from the leucocytes by high pure polymerase chain reaction (PCR) template preparation kit. Genetic polymorphism of IRS-2 G1057D was detected by using PCR-based restriction fragment-length polymorphism. RESULTS: For IRS-2 G1057D polymorphism, there was a significant difference in genotype distribution and allele frequency between endometrial cancer patients and controls (p < 0.001). The risk for endometrial cancer was 4.87 times higher in the individuals with the IRS-2 DD genotype compared to the GG genotype [95% confidence interval (CI): 1.74-13.63 p = 0.003]. Also individuals with the IRS-2 D allele had a significantly higher risk of endometrium cancer compared with individuals with the IRS-2 G allele, with a relative risk of 2.23 (95% CI: 1.36-3.67, p = 0.001) for cases compared with population controls. CONCLUSION: These results suggest that IRS-2 G1057D polymorphism may be associated with endometrial cancer.

N-acetyltransferase 2 gene polymorphism in patients with cervical cancer.

The aim of the study was to evaluate the role of N-acetyltransferase 2 (NAT2) gene polymorphism in the development of cervical cancer by comparing patients having invasive cervical squamous cell carcinoma (SCC) with healthy control subjects. The study group consisted of 42 women with invasive cervical SCC and 50 control subjects. All of the patients were primarily treated with surgical intervention. Blood samples (5 mL) were obtained from the patients before surgery or during follow-up to 2 years after surgery. DNA was extracted from the leukocytes by a high pure PCR template preparation kit (catalog No. 1 796 828; Roche Diagnostics GmbH, Mannheim, Germany). NAT2*5A, NAT2*6A, and NAT2*7A/B polymorphisms of NAT2 were detected by using a LightCycler-NAT2 mutation detection kit in real-time PCR (catalog No. 3113914, LightCycler instrument; Roche Diagnostics GmbH, Mannheim, Germany). We found that the risk of cervical SCC was 9.045-fold higher in individuals with NAT2*5A mutant allele (95% confidence interval, 1.448-56.524; P = 0.018). The frequency of the NAT2*5A slow genotypes in the patients with cervical cancer (23.8%) was significantly higher compared with that in the control group (6%). Individuals with the NAT2*5A slow genotype had a significantly higher risk of cervical cancer compared with individuals with the NAT2*5A fast genotype (odds ratio, 7.469; 95% confidence interval, 1.673-33.350; P = 0.008). However, there was no significant association between the NAT2*6A and NAT2*7A/B fast or slow acetylator status and the development of cervical cancer. In conclusion, NAT2*5A slow acetylator genotype was found to be significantly higher in patients with cervical cancer. These results suggest that NAT2*5A gene polymorphisms in patients may be associated with genetic susceptibility to cervical cancer.

Relationship between N-acetyl transferase-2 gene polymorphism and risk of bronchial asthma.

There are still uncertainties as to the mechanism of many pathological conditions, among them allergic diseases. It has been suggest that acetylation rate may be a factor that influences the development of allergic diseases. The aim of the present study was to investigate further whether the genetic polymorphism of the NAT2 plays a role in susceptibility to bronchial asthma disease. Ninety-seven patients with bronchial asthma (atopic n= 62; non-atopic n= 35) and 104 healthy individuals were participated in this study. DNA was extracted from the leucocyte by high pure template preparation kit. NAT2*5A, NAT2*6A, NAT2*7A/B and NAT2*14A polymorphisms of NAT2 were detected by using LightCycler-NAT2 mutation detection kit by real time PCR with LightCycler instrument. We found that mutant NAT2*5A (OR= 3.84, 95% CI= 1.08-13.6) and NAT2*6A (OR= 5.27, 95% CI= 1.06-26.05) genotype could be associated with a high risk for the development of bronchial asthma according to the genotype. After grouping phenotype, the risk for bronchial asthma was more than two times higher (OR= 2.7, 95% CI= 1.07-6.97) in individuals with the slow NAT2*5A acetylator phenotype compared to the fast phenotype. Our study suggests that the NAT2 slow acetylators may be a determinant in susceptibility to asthma disease. This finding may have implications for the theories for the pathogenesis of the disease as well as for therapeutic aspects.

Apolipoprotein E polymorphism in diabetic and non-diabetic patients: does it really contribute to atherosclerosis?

OBJECTIVE: The exact mechanism of the increased cardiovascular morbidity and mortality in type-2 diabetes is still undefined. The aim of our study was to assess the impact of apolipoprotein E (apo E) polymorphism and other factors on atherosclerotic vascular disease in type-2 diabetic patients. We also examined the association between apo E polymorphism and lipid profile in diabetic patients. METHODS AND RESULTS: We assessed the apo E polymorphism in 295 atherosclerotic patients (124 of them had diabetes (according to WHO criteria) and 171 of them had coronary artery narrowing > 50). The detection of apo E polymorphism was made by Real-Time PCR using a Light-Cycler (Roche diagnostics, GmbH, Mannheim, Germany). Serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), lipoprotein (a) [Lp(a)], apolipoprotein A (Apo A) and apolipoprotein B (Apo B) levels were determined by biochemical analyser. Genotypic distribution of apo E polymorphism did not differ between diabetic and non-diabetic atherosclerotic patients. The distributions of apo E2/2, E2/3, E2/4, E3/3, E3/4 and E4/4 genotypes in diabetic and non-diabetic atherosclerotic patients were 7.3%: 8.2%, 15.3%: 15.8%, 4.0%: 5.3%, 50.8%: 56.7%, 16.9%: 11.1% and 5.6%: 2.9%, respectively. Participants were grouped as apo E2 (E2/2 or E2/3), apo E3 (E3/3), or apo E4 (E4/4 or E4/3). The distributions of apo E2, E3 and E4 alleles were 23.5%, 52.9%, 23.5%, for diabetic patients, and 25.3%, 59.9%, 14.8% for non-diabetic patients, respectively. The apolipoprotein E genotype was not associated with the lipid levels in diabetic patients. CONCLUSIONS: Our findings imply that apo E polymorphism is not related to the development of atherosclerosis in patients with type-2 diabetes.

Functional association of interleukin-18 gene -607 C/A promoter polymorphisms with endometriosis.

This study evaluated for the first time the relationship between interleukin-18 (IL-18) C607A genotypes and endometriosis in 135 women with endometriosis and 84 controls. In the study population, IL-18 -607∗A homozygote and A allele were positively correlated with the risk of developing endometriosis or the stage of endometriosis.

Association of G1057D variant of insulin receptor substrate-2 with endometriosis.

OBJECTIVE: To investigate whether the insulin receptor substrate (IRS)-2 G1057D polymorphism is associated with the risk of endometriosis, and to evaluate potential correlation of IRS2 gene polymorphism with the stages of endometriosis. DESIGN: Case-control study. SETTING: Gynecology clinics in university hospital. PATIENT(S): Women with (n = 135) or without (n = 135) endometriosis. Afterward, the women with endometriosis were divided into two groups according to the stage: group 1 included 63 women in stages I-II, and group 2 included 72 women in stages III-IV. INTERVENTION(S): Genotyping by polymerase chain reaction-based restriction fragment-length polymorphism method. MAIN OUTCOME MEASURE(S): Genotype distribution of the G1057D polymorphism in the IRS2 gene. RESULT(S): The genotype distribution of the IRS2 G1057D polymorphism in the endometriosis group was significantly different from that of the control group (GG/GD/DD rates were 43.0%/39.3%/17.7% and 55.6%/36.3%/8.1% for the endometriosis and control groups, respectively). Further subgroup analyses according to the stage of endometriosis also revealed a positive association between the IRS2 DD genotype expression and stage III-IV endometriosis patients in the population studied. CONCLUSION(S): These results suggest that the IRS2 G1057D polymorphism may be associated with an increased risk for endometriosis.

The frequency of sister chromatid exchanges in cultured human peripheral blood lymphocyte treated with metronidazole in vitro.

5-Nitroimidazoles are a group of antiprotozoal and antibacterial agents. Thanks to their antimicrobial activity, these chemotherapeutic agents inhibit the growth of both anaerobic bacteria and certain anaerobic protozoa. One of the useful drugs used in the treatment of infections caused by Trichomonas vaginalis, Entamoeba histolytica, and Giardia lamblia is metronidazole (MTZ). The mutagenicity of metronidazole [1-(hydroxyethyl)-2-methyl-5-nitroimidazole] has been previously shown in different prokaryotic systems but not in eukaryotic systems. The objective of this study is to determine the mutagenic and cytotoxic effects of MTZ at plasma concentration and higher in vitro. In this study, we evaluated the mutagenicity and cytotoxicity of MTZ in cultured human peripheral blood lymphocytes. Doses were selected according to plasma concentration of drug. End points analyzed included mitotic index (MI), replication index (RI), and sister chromatid exchange (SCE). An analysis of variance test (ANOVA) was performed to evaluate the results. A significant decrease (p < 0.001) in MI and RI as well as an increase in SCE frequency (p < 0.001) was observed compared with control cultures. Our results indicate the genotoxic and cytotoxic effect of MTZ in cultured human peripheral blood lymphocytes at plasma concentrations slightly higher than encountered therapeutically.