Frequency Of Wild-type Genotype Research Articles

Variations in the frequencies of polymorphisms in the CYP2C9 gene in six major ethnicities of Pakistan

Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Baloch population possesses low activity genotypes. The frequencies found in various ethnic groups in Pakistan were comparable with ethnicities in the South Asian region except for the Baloch population. These results suggest that pharmacogenetics screening for low activity genotypes may be a helpful tool for clinicians while prescribing medications metabolized by CYP2C9.

Association of ABCB1 Gene Polymorphisms and Clopidogrel Responsiveness in Iranian Patients undergoing Percutaneous Coronary Intervention.

Clopidogrel is an antiplatelet agent currently used for preventing stent thrombosis. Despite certain clinical benefits of clopidogrel in patients undergoing percutaneous coronary intervention (PCI), adequate antiplatelet effect has not been obtained in some patients. The present study was designed to investigate the potential association of ABCB1 (ATP-Binding Cassette, Subfamily B, member1) gene polymorphism, and clopidogrel responsiveness in Iranian patients after PCI. Sixty-seven patients were included in the study. Blood samples were taken from patients at baseline, 2 h after administration of 600-mg loading dose of clopidogrel, 24 h and 30 days after PCI. Platelet aggregation was measured by light transmittance aggregometry (LTA) with two levels of adenosine diphosphate (ADP) concentrations (5 and 20 µM). ABCB1 genotyping was performed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). The allelic frequencies of wild type, heterozygote, and homozygote genotypes of ABCB1 were 20.9%, 74.6%, and 4.5%, respectively. There was no significant association between polymorphism of ABCB1 and clopidogrel non-responsiveness (P > 0.05) in various situations. No significant difference was observed for demographic characteristics. Genetic and demographic factors had no significant effect on the platelet activity of clopidogrel in an Iranian population.

Association of vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 polymorphisms with their circulating protein levels in preeclampsia

Introduction: Normal development of placental vascular tree requiring angiogenesis and vasculogenesis is structurally and functionally indispensable for both adequate placental growth and delivery of nutrients from mother to the fetus. Impaired placental angiogenesis has been implicated in the pathophysiology of pregnancy complications which have immediate and long-lasting effects on the mother and her child, such as preeclampsia (PE) and fetal growth restriction. The mechanisms underlying the deregulation of placental angiogenesis in PE include a misbalance between the secretion and activity of pro-angiogenic (vascular endothelial growth factor [VEGF]) and anti-angiogenic (soluble fms-like tyrosine kinase-1 [sFlt-1]) factors. Considering the important roles of VEGF and sflt1 in pregnancy, functional polymorphisms in these genes may be potentially important as genetic markers for susceptibility to PE. Thus, the aim of the study was to screen for the presence of VEGF and sFlt-1 gene polymorphisms and to measure their levels in PE patients and controls of Indian origin. Material and Methods: Fifty each of clinically diagnosed patients and gestational and maternal age-matched normotensive, nonproteinuric controls were recruited after taking informed consent. DNA isolated from blood samples was processed for polymerase chain reaction amplification followed by restriction fragment length polymorphism to screen for the presence of VEGF + 936C/T, sFlt-1 (+4244G/A, −4771G/T, −523C/G) polymorphisms. Serum levels of VEGF-A and sFlt-1 were measured by Sandwich enzyme-linked immunosorbent assay (ELISA). Results: Decreased frequency of wild type genotype with respect to VEGF + 936C/T and sFlt-1 (+4244G/A, −4771G/T, and −523C/G) polymorphisms was seen in patients. ELISA results showed lower VEGF-A (198.43 ± 14.63 pg/ml vs. 235.08 ± 16.72 pg/ml [mean ± standard error of mean]) and higher sFlt-1 levels (2932.81 [1802.33–5760.46] pg/ml vs. 1114.94 [655.03–2694.35] Median [Range]; P

Association of of IL-1 receptor antagonist (IL-1RN) and interleukin-1β genes (IL-1β) polymorphisms with recurrent pregnancy loss in Iranian Azeri women.

Objective One of the most important problems in human reproduction is recurrent pregnancy loss (RPL). RPL is defined as three or more consecutive abortions in the first trimester of pregnancy. The association between the polymorphisms in the immunological factors and RPL was investigated. The aim of our study was to determine the association of interleukin receptor antagonist (IL-IRN) and interleukin-1β (IL-1β) polymorphisms with RPL in Iranian Azeri women. Materials and methods The study participants consisted of 100 women with RPL of Iranian Azeri origin. The control group comprised 100 age- and ethnically-matched healthy women of the same reproductive age. Genomic DNA was extracted from the whole blood and genotype determinations were performed using polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP) analysis. Results Our results showed no significant relationship between IL-1RN polymorphism and RPL. The homozygous state in -857 C/T variant was seen to be higher in RPL patients than in control subjects. Also frequency of wild type genotype was lower in RPL patients than in controls. However, this associations was not significant. Conclusion This study suggested that -511 C/T (rs16944) and -31 C/T (rs1143627) polymorphisms in IL-1β gene may not be involved in RPL in Iranian Azeri women. Also the promoter polymorphism of the IL-1RN gene may not play a role in the susceptibility to RPL.

The effects of tumor necrosis factor-α (TNF-α) and IL-1 receptor antagonist (IL-1Ra) polymorphisms on recurrent abortion in Azari women.

Recurrent pregnancy loss (RPL) is a heterogeneous condition consisting of three or more consecutive abortions before the 20 weeks of gestation. The tumor necrosis factor alpha (TNF-α) gene plays a crucial role in immunology and inflammation responses. Interleukin 1 receptor antagonist (IL-1RN) is an important anti-inflammatory molecule which plays important roles in pregnancy. The aim of this study was to investigate effects of TNF-α and IL-1Ra polymorphisms on RPL in Azari women. The study participants consisted of 100 women with RPL from Iranian Azeri Turkish origin. The control group comprised 100 age and ethnically matched healthy women in the reproductive age. Genomic DNA was extracted from the whole blood and genotype determinations were performed using PCR amplification followed by restriction fragment length polymorphism (RFLP) analysis. No significant association was indicated between IL-1Ra and RPL among Iranian Azeri Turkish women. Unlike the homozygous state, significantly higher frequency of -857 C/T variant was seen in RPL patients than control subjects. Significantly lower frequency of wild type genotype was observed in RPL patients than of controls. Any association was found between the other TNF-α polymorphisms and RPL. TNF-α -857 C/C variant might represent protective effect against RPL and the -857 C/T variant might be a genetic risk factor for the occurrence of RPL. Invariant differences in the prevalence of -511 C/T and -31 C/T polymorphisms and IL-1RN VNTR between RPL patients.

Closed tube method for rapid screening of IL28B polymorphisms involved in response to hepatitis C treatment

Background & aimHepatitis C is a liver disease caused by the hepatitis C virus. Interferon and ribavirin combination therapy has been a standard treatment of chronic hepatitis C. But only about 50% of patients have positive response to treatment and achieve so called sustained virological response. Recent studies indicate association of several single nucleotide polymorphisms near IL28B gene and response of hepatitis C patients to combined interferon/ribavirin treatment. In this study, rapid, specific and cost-effective small amplicon genotyping method for the two clinically important polymorphisms, rs12979860 C > T and rs8099917 T > G, near the IL28B gene is described. MethodsThe distribution of genotypes of 181 HCV-uninfected Slovak Caucasians was analyzed using this novel method, based on a real-time melting analysis of the small amplicon. Results and conclusionsThe frequency of wild-type (TT) homozygotes for rs8099917 was 66.30%, frequency of heterozygotes (TG) was 30.94% and we found only 2.76% subjects homozygous for risk G allele (allelic frequencies: T = 81.77%, G = 18.23%) were found. The frequency of wild-type genotype (CC) for rs12979860 was 49.72%, frequencies of heterozygous (CT) and risk-allele homozygous genotypes (TT) were 39.78% and 10.50%, respectively (allele frequencies: C = 69.61%, T = 30.39%). Statistically significant differences in the distribution of the alleles between the men and the women were not found. The novel method developed in our laboratory proved to be simple and highly customizable.

Valor pronóstico de la concentración del inhibidor de la fibrinolisis activable por trombina y del polimorfismo C1040T en el infarto agudo de miocardio tratado con fibrinolisis

To analyze the prognostic value of thrombin activatable fibrinolysis inhibitor (TAFI) and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis. To analyze C1040T polymorphism influence on its plasma level. An observational, prospective study performed from November 2003 to November 2005 and with a 3 month follow-up. Intensive Medicine Service from a university-affiliated teaching hospital. A total of 53 patients with acute myocardial infarction with persistent ST segment elevation treated with the same fibrinolytic therapy. A control group of 53 biologically similar subjects was included. None. Baseline characteristics; frequency of wild-type genotype (Thr325Thr) and of those corresponding to the mutation (Thr325LLe and LLe325lle), TAFI levels at 6 h, 34 h and 3 months post-fibrinolysis; ejection fraction; Killip-Kimball; reperfusion; ischemic recurrence; death. No relationship was found between biological features and TAFI concentration. The latter was significantly higher in infarct patients (p<0.01) and in the mutation group (p<0.01). The homozygotic mutation (Ile325Ile) was significantly higher in infarct patients (p<0.01). Reperfusion was significantly associated with lower body mass index (p=0.02. OR 0.22. 95% CI), ejection fraction (p=0.004. OR 0.91. 95% CI), triglyceride level (p=0.01. OR 1.02. 95% CI) and cholesterol levels (p=0.001. OR=0.84. 95% CI). Mutation was associated to a significant fall in post-fibrinolysis concentration TAFI antigen and functional TAFI (p=0.01) and (p=0.02), and lower frequency of reperfusion. Reperfusion was associated with a significant post-fibrinolysis reduction in the level of TAFI antigen (p=0.02). Recurrence was associated to a significantly higher post-fibrinolysis level (p=0.05. OR=0.84. 95% CI). This was more frequent in mutation. Post-fibrinolysis TAFI antigen concentration was significantly lower in non-recurrence patients (p=0.028. OR=1.03. 95% CI). A higher concentration of TAFI is associated to a worse prognosis in reperfusion and recurrence in acute myocardial infarction treated with fibrinolysis. Homozygotic mutation was more frequent in myocardial infarction patients. Wild genotype is associated to a better prognosis. Mutation is associated to a higher expression of TAFI.