Association between the Trp64Arg polymorphism of the ADRB3 gene and overactive bladder.

BACKGROUND: The ß3 -adrenergic receptor (ADRB3) is very important in the regulation of the human detrusor muscle function. The well-known tryptophan64arginine polymorphism of the ADRB3 gene alters the response of the receptor to various stimuli, including adrenalin and noradrenalin, and may increase the susceptibility to develop overactive bladder (OAB). Therefore, this study was performed to determine whether ADRB3 Trp64Arg polymorphism is associated with the pathophysiology of OAB syndrome. METHODS: The study group (n = 150) consists of 72 patients with OAB and 78 controls without OAB. Venous blood samples were taken from all participants to analyze the ADRB3 gene Trp64Arg polymorphism using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay. We compared the distribution of Trp64Arg polymorphism and symptom severity in both OAB and non-OAB subjects using χ2 test and Mann-Whitney's U test, respectively. RESULTS: The frequency of the 64Arg variant (heterozygous plus homozygous) in OAB and non-OAB subjects was 15.3% and 14.1%, respectively. There was no statistically significant difference between the OAB and non-OAB groups in regard to the distribution frequency of ADRB3 Trp64Arg polymorphism. The total frequency (OAB + non-OAB, 76 women and 74 men) of the Arg64 variant allele was 5.9% and 10.8% in women and in men, respectively. Although the frequency of the Arg64 variant was nearly twofold higher in men compared to women, the difference was not statistically significant. CONCLUSIONS: These results demonstrated that the ADRB3 Trp64Arg polymorphism is not significantly associated with OAB syndrome in a sample of Turkish OAB patients.

Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy.

Metformin, a drug widely used in the treatment of type II diabetes mellitus (T2DM), has been the focus of interest as a potential therapeutic agent for certain types of malignancies, including gynaecological cancers [i.e. endometrial cancer (EC)]. Although the exact mechanism behind the potential anticancer activity of metformin is still not completely understood, certain studies have suggested that different effects on cell functions, such as inhibition of cell migration, apoptosis and tumor cell proliferation, are involved in its preventive and therapeutic effects in certain types of malignancies, including EC. In contrast, midkine (MK), a heparin-binding growth factor and cytokine, which induces carcinogenesis and chemoresistance, promotes the development and progression of many malignant tumours by increasing diverse cell functions such as cell proliferation, cell survival and antiapoptotic activities via mainly the activation of phosphatidyl inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The same pathways are also subject to certain therapeutic effects of metformin, although this cytokine and this drug have some different mechanism of action pathways as well. Taken together, MK and metformin appear to have opposite effects in various biological processes such as apoptosis, cell proliferation, cell survival, cell migration, and angiogenesis. On the other hand, MK activates PI3K and MAPK cell signal pathways, whereas metformin inhibits these two pathways. It seems likely that almost all the pathways and cell functions, which play important roles in malignancies, are inhibited by metformin and activated by MK. Given the opposite relationship between the actions of metformin and MK, we hypothesize that metformin may act like a novel MK inhibitor in some malignancies. We also discuss the possible relationship between metformin and MK in the context of EC, the most common gynecological cancer worldwide, which incidence is rising rapidly, in parallel with the increase in obesity, T2DM and insulin resistance. In this respect, the therapeutic use of metformin may improve the survival of EC or other cancers, via inhibiting or overcoming the unwanted effects of MK in carcinogenesis.

Dual inhibition of P-glycoprotein and midkine may increase therapeutic effects of anticancer drugs.

Multidrug resistance (MDR) to chemotherapy may significantly affect the outcome of cancer treatment. ATP-dependent drug efflux pumps, including P-glycoprotein (P-gp), contribute to the resistance of various chemotherapeutic agents. Overexpression of P-gp in tumor cells induces chemoresistance via pumping the anticancer drugs out of the cells. In addition to taking part in many biological processes such as development, reproduction and repair, midkine (MK) also plays important roles in the pathogenesis of malignant diseases as well as in the regulation of MDR. Although, the mechanisms of action of P-gp and MK are different, overexpression of both proteins prevents the accumulation of many chemotherapeutics in tumor cells, leading to decreased therapeutic effects of anticancer drugs. Therefore, identification of the result of dual inhibition of P-gp and MK in overcoming chemoresistance may enhance the likelihood for a more efficient chemotherapy.

Childhood obesity and the role of dopamine D2 receptor and cannabinoid receptor-1 gene polymorphisms.

AIMS: The dopaminergic and endocannabinoid systems are involved in regulation of feeding behavior. The aim of the study is to examine the possible relation between polymorphisms of the dopamine D2 receptor (DRD2) and cannabinoid receptor-1 (CNR1) genes and childhood obesity. METHODS: A hundred obese children and 100 healthy controls were analyzed for DRD2 Taq1A and Taq1B and CNR1 1359G/A polymorphisms. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: There were no statistically significant differences in DRD2 Taq1A and DRD2 Taq1B genotypes or allelic frequencies between obese children and controls (p>0.05). In patients with Taq1B2 allele, morbid obesity was less frequent (p=0.010). The frequency of the A allele of CNR1 1359G/A polymorphism was significantly higher in obese children than in controls (21.0% vs. 13.0%, p=0.0166). The frequency of genotypes AG and GG of the CNR1 1359G/A SNP was different between obese children and control subjects (for AG: 34.0% vs. 22.0%, p=0.0294; for GG: 62.0% vs. 76.0%, p=0.0162, respectively). CONCLUSIONS: No significant difference was found between genotypes and alleles of DRD2 Taq1A and DRD2 Taq1B polymorphism in patients and controls, while the CNR1 receptor 1359G/A polymorphism and the presence of the A allele may be one risk factor for susceptibility to obesity.

Association of angiotensin converting enzyme gene insertion/deletion polymorphism with lung cancer in Turkey.

Angiotensin-converting enzyme (ACE) plays an important role in the physiological control of blood pressure and inflammation. We investigated an insertion/deletion (I/D) polymorphism of the gene for ACE in relation to cardiovascular, cerebrovascular, neurodegenerative, and inflammatory diseases. The purpose of the present study was to investigate a possible association between lung cancer and insertion/deletion polymorphism of the ACE gene. A total of 125 patients with lung cancer and 165 control subjects were enrolled in the present study. ACE I/D genotypes were determined by polymerase chain reaction. Allelic frequencies and genotype distribution of the ACE I/D polymorphism in the patient group were significantly different from control subjects (ACE II genotype 29.6 vs. 17.6%, P = 0.011; ACE I allele 49.6 vs. 39.4%, P =0.009). Our data suggest that the ACE I/D polymorphism could be a risk factor for patients with lung cancer.

Neonatal jaundice and bilirubin UDP-glucuronosyl transferase 1A1 gene polymorphism in Turkish patients.

Bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT) is the rate-limiting enzyme for the conjugation of bilirubin with glucuronic acid in its excretion process into the bile. Variations in B-UGT gene (UGT-1A1) have been related to disorders characterised by hyperbilirubinaemia. The aim of this study was to investigate whether the number of thymine-adenine repeats in the promoter region of UGT-1A1 was related to non-physiologic hyperbilirubinemia of unexplained aetiology in Turkish newborns. These patients (n=106) were genotyped for their thymine-adenine repeat number in the promoter region of UGT-1A1, and were divided into two groups according to their bilirubin level. Forty-nine newborns with bilirubin levels higher than 17 mg/dl within the first ten days of life comprised the hyperbilirubinaemia group and 25 newborns with bilirubin levels higher than 10 mg/dl after fifteen days of life formed the prolonged jaundice group. Thirty-two newborns were included as healthy controls. The observed frequencies for the wild-type six repeat allele thymine-adenine (TA(6)) within each subject group were similar (P>0.05; 75.5%, 78.0% and 73.4%, respectively). Likewise, the distribution of TA(6/6), TA(6/7) and TA(7/7) genotypes among three groups were similar. These results imply that the TA(7) repeat allele of UGT1A1 (UGT1A1*28) is a common variant in the Turkish population. Our results do not suggest an association between thymine-adenine repeat polymorphism of UGT1A1 and hyperbilirubinaemia of unexplained aetiology or prolonged jaundice in Turkish neonates.

Human arylamine N-acetyltransferase 2 polymorphism and susceptibility to allergic contact dermatitis.

BACKGROUND: N-acetyltransferase 2 (NAT2) polymorphism may be involved in the pathogenesis of allergic contact dermatitis. OBJECTIVE: The present study was designed to evaluate whether acetylation polymorphism plays a role in the susceptibility to p-Phenylenediamine (PPD) sensitization. METHODS: The frequencies of seven NAT2 point mutations, namely G191A, C282T, T341C, C481T, G590A, A803G, and G857A, and genotypes were determined by PCR/RFLP in a total of 70 patients with allergic contact dermatitis to PPD and 100 control subjects with no history of allergy, atopy, lung disease, diabetes mellitus and cancer. RESULTS: Genotypes coding rapid acetylation were detected in 52.9% and 37.0% of patients with contact dermatitis and control subjects, respectively (P = 0.04). The frequency of the NAT2*4 allele and NAT2*4/*4 genotype, coding for rapid acetylation, were also significantly higher in the contact dermatitis patients than in the control subjects (P = 0.003). CONCLUSION: Our results suggest an association between rapid acetylation polymorphism and susceptibility to PPD sensitization.

Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.

BACKGROUND: Resistance to antiemetic treatment with 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists is still a major problem resulting in patient discomfort and poor compliance to chemotherapy. We hypothesized that clinical resistance to 5-HT(3) antagonists is associated with the single-nucleotide polymorphism (3435C>T) in the gene that codes for the drug efflux transporter adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1). METHODS: Patients with cancer (N = 216) treated with chemotherapeutic regimens composed of highly or moderately emetogenic agents were examined for their antiemetic responses to tropisetron, ondansetron, or granisetron. The efficacy of antiemetic treatment was documented by self-report charts for 5 days after chemotherapy. ABCB1 3435C>T genotype was determined to analyze its association with the antiemetic efficacy of 5-HT(3) antagonists. RESULTS: Within the first 24 hours of chemotherapy, the complete control rate of nausea and vomiting was higher in subjects with the ABCB1 TT genotype (n = 49) as compared with those with the CC (n = 60) or CT (n = 107) genotype (P = .044). The type of 5-HT(3) antagonists influenced the effect of genotype on antiemetic responses. The complete control rates were 92.9% in TT subjects (n = 14) in comparison to homozygote (47.6%, n = 21, P = .009) or heterozygote (56.1%, n = 41, P = .02) carriers of the 3435 C allele in granisetron-treated patients. However, during the delayed phase of chemotherapy, the complete control rates did not differ across genotypes. CONCLUSION: These results suggest that ABCB1 3435C>T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT(3) antagonists, particularly in granisetron-treated patients, during the short-term phase of chemotherapy.

Protective role of glutathione S-transferase P1 (GSTP1) Val105Val genotype in patients with bronchial asthma.

BACKGROUND: Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. It has been suggested that polymorphisms in the GSTP1 gene are associated with asthma and related phenotypes. As significant interindividual and interethnic differences exist in the distribution of xenobiotic-metabolizing enzymes, we have studied the GSTP1 Ile105Val polymorphism in patients with asthma in a Turkish sample. METHODS: GSTP1 Ile105Val polymorphism in exon 5 was determined in 210 patients with asthma (112 extrinsic and 108 intrinsic) and 265 control individuals without lung diseases and without history of allergy or atopy, using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) techniques. RESULTS: The proportion of GSTP1 Val105 homozygotes was significantly lower in the patients with asthma than in the control individuals (3.8% vs 12.1%). The odds ratio for GSTP1 Val105 homozygotes vs all other genotypes was 0.29 (95%CL 0.13-0.64, p = 0.01) for asthmatics. The distribution of GSTP1 Ile105Val genotypes and the frequency of GSTP1 Val105Val homozygotes (3.7% vs 3.9%) was not significantly different between extrinsic and intrinsic asthmatics. CONCLUSION: These results suggest a significant association between GSTP1 Ile105Val polymorphism and susceptibility to asthma and that the GSTP1 Val105Val genotype may be protective against developing this disease.

Beta 2-adrenergic receptor polymorphism and susceptibility to primary congenital and primary open angle glaucoma.

OBJECTIVE: It has been shown that arginine to glycine (Arg16Gly), glutamine to glutamic acid (Gln27Glu) and threonine to isoleucine (Thr164Ile) exchanges in codons 16, 27 and 164, respectively, of the beta 2-adrenergic receptor (B2AR) gene significantly alter receptor function. As B2ARs are located on the afferent blood vessels supplying the ciliary body and trabecular meshwork cells, which control aqueous humour dynamics, polymorphisms of B2AR may be involved in the pathophysiology of certain eye diseases, such as glaucoma. Therefore, the aim of the present study was to investigate the distribution of B2AR polymorphisms in patients with primary congenital and primary open angle glaucoma. METHODS: A group of 30 patients with primary congenital glaucoma, 105 with primary open angle glaucoma and 92 control patients were analysed for the Arg16Gly, Gln27Glu, and Thr164IIe polymorphisms of the B2AR by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The allelic frequencies of Gly16, Glu27 and IIe164 variant alleles were 66.7, 38.3 and 3.3% in patients with congenital glaucoma, 59.5, 31.0 and 1.0% with glaucoma, and 54.9, 26.6 and 0.5% in controls, respectively. Although statistically non-significant, the frequencies of variant alleles were slightly higher in both groups of the glaucoma patients. CONCLUSIONS: These results suggest no evidence of an association between the Arg16Gly, Glu27Gln and Thr164Ile polymorphisms of the B2AR gene and risk of developing primary open angle glaucoma or primary congenital glaucoma. However, further studies are needed to understand the role of B2AR polymorphisms in patients with eye disease.

Association between the N-acetylation genetic polymorphism and bronchial asthma.

AIMS: Since polymorphic N-acetyltransferase 2 (NAT2) has been suggested as a susceptibility factor for atopic diseases, the study was undertaken to investigate whether an association exists between acetylation polymorphism and asthma patients with atopy. METHODS: The frequencies of NAT2 alleles and genotypes were determined by PCR/RFLP in a total of 210 asthma patients (extrinsic (n = 108) and intrinsic (n = 102) asthmatics) and 240 control subjects. Presence of the NAT2*4 (wild-type) allele defined a NAT2 genotype as rapid and combinations of mutant alleles NAT2*5 A, *5B, *5C, *6 A, and *7B as slow. RESULTS: Genotypes coding for slow acetylation were detected in 70.4, 58.4 and 58.3% of extrinsic asthmatics, but intrinsic asthmatics and control subjects, respectively. The frequency of slow acetylators was higher among extrinsic asthmatics than intrinsic asthmatics, this difference did not reach statistical significance (odds ratio 1.02, 95% confidence interval 0.64, 1.63, P = 0.085). However, we found a relatively moderate, but significantly higher, increased frequency of slow acetylators among extrinsic asthma patients compared with control subjects (odds ratio 1.70, 95% confidence interval 1.04, 2.76, P = 0.042). CONCLUSIONS: This study shows an association between acetylation polymorphism and susceptibility to extrinsic asthma, but not to intrinsic asthma, suggesting a minor role of the NAT2 polymorphism in the development of atopic asthma.

Diagnostic value of CRP and Lp(a) in coronary heart disease.

OBJECTIVES: Increased lipoprotein (a) [Lp(a)] concentration was reported to be an independent risk factor for coronary heart disease (CHD). Recent epidemiological studies affirmed the value of C-reactive protein (CRP) as the strongest, univariate predictor of the cardiovascular events. We decided to establish cut-off levels providing maximum diagnostic efficiency for CHD. METHODS: In this study we measured CRP and Lp(a) concentrations in patients with angiographically demonstrated CHD (group A, n: 120), patients without any angiographically demonstrable lesion (group B, n: 62) and a group of healthy subjects (group C, n: 41). Data were evaluated correcting for lipid and lipoprotein concentrations, diabetes mellitus, hypertension, smoking, age, and body mass index in men and women. ROC curve based cut-off values (comparing group A versus groups B and C) and associated diagnostic performances of the assays were evaluated. RESULTS: Significant increases were noted in serum CRP concentrations in men and women, in groups A vs. B,A vs. C, B vs. C. Lp(a) concentrations were not different among groups in men but were higher in group A vs. B and C in women. Optimal cut-off levels for CRP in women and men were found as 2.1 and 3.0 mg/l with the diagnostic values of 0.792 and 0.770, respectively. For Lp(a) optimal cut-off levels were found as 22.6 and 9.8 mg/dl with the diagnostic values of 0.612 and 0.596 in women and men, respectively. CONCLUSION: The CRP level is quite efficient for separation of patients from controls. Therefore keeping in mind the lack of specificity, the CRP level may be a useful tool in the diagnosis of coronary heart disease. However, the Lp(a) level is not efficient enough to support the use of Lp(a) measurement for management of coronary heart disease.