Sinem Atik

Recurrent Pregnancy Loss and Its Relation to Combined Parental Thrombophilic Gene Mutations

BACKGROUND AND AIM Recurrent pregnancy loss (RPL) is a heterogeneous disorder that has been associated with antiphospholipid syndrome and other prothrombotic parameters. We aimed to investigate the prevalence of 12 thrombophilic gene mutations in RPL couples in the current results. METHOD In a total of 543 Turkish women with RPL and 327 of their male partners (870 individuals with RPL), and a control group of 106 fertile couples (control) were analyzed for factor V leiden (FVL), factor V H1299R, factor II prothrombin G20210A, FXIII V34L, β-fibrinogen -455G>A, plasminogen activator inhibitor-1 (PAI-1), GPIIIa L33P (HPA-1 a/b L33P), methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q, and Apo E genes. RESULTS The overall, heterozygous and/or homozygous point mutations in FVL-FVR2, ApoE2, PAI-1, MTHFR C677T-A1298C, and ACE genes were associated with RPL. There was no meaningful association between RPL and other studied genes. CONCLUSION The homozygosity of 4G in PAI-1 and MTHFR C677T genes in women with RPL, and heterozygosity of FVL, FVR2, ACE, and ApoE2 genes in both parents play crucial role in RPL and should be considered as a risk factor in RPL. Current results showed that RPL is related to combined parental (not only maternal) thrombophilic gene mutations.

Increased T-Allele Frequency of 677 C>T Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Differentiated Thyroid Carcinoma

BACKGROUND Epigenetic alterations in the global DNA methylation status may be associated with an increased risk of some cancer types in humans. The methylenetetrahydrofolate reductase (MTHFR) gene is involved in folic acid metabolism and plays an essential role in inherited DNA methylation profiles. The common 677 C>T and 1298 A>C polymorphisms in the MTHFR gene cause the production of a thermolabile enzyme with reduced function and, eventually, genomic DNA hypomethylation. The current preliminary study was designed to determine the association between germ-line polymorphism in the MTHFR gene and differentiated thyroid carcinoma (DTC). METHODS In the current case-control study of 60 thyroid carcinomas (TC); 45 papillary TC, 9 follicular TC, and 6 DTC of an uncertain malignant potential were examined. Genomic DNA was extracted from peripheral blood with EDTA, genotyped by a multiplex real-time polymerase chain reaction. RESULTS An elevated 2.33-fold risk was observed for DTC in individuals with the 677TT genotype when compared with the control group (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.03-3.58). Current DTC patients showed similar results as a control group for the 1298 A>C allele. No significant risk was detected for the homozygous 1298CC genotype (CC vs. AA or AC) (OR: 1.30, 95% CI: 0.73-2.29). CONCLUSION The current results are supportive of the hypothesis that the homozygous MTHFR 677TT genotype increases the risk factor of developing thyroid cancer, and further large-scale studies are needed to validate this association.

Association between ABCB1 (MDR1) Gene 3435 C>T Polymorphism and Colchicine Unresponsiveness of FMF Patients

The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.

Possible Roles of the Xenobiotic Transporter P-glycoproteins Encoded by the MDR1 3435 C>T Gene Polymorphism in Differentiated Thyroid Cancers

BACKGROUND P-glycoprotein (Pgp), encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter which plays an important role in pharmacokinetics. The current preliminary study was designed to determine associations between a germ-line polymorphism in the MDR1 gene with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS In the current case-control study, 60 differentiated thyroid cancers (DTC)- 45 papillary TC (PTC), 9 follicular TC(FTC) and 6 well-differentiated tumors of uncertain malignant potential (WDT-UMP) were examined. Results were compared to a healthy control group (n=58) from the same population. Genomic DNA was extracted from peripheral blood with EDTA and the target gene was genotyped by real-time PCR. RESULTS Carriers of the variant allele of MDR1 exon 26 polymorphism were at 2.8-fold higher risk of DTC than the control group (odds ratio [OR]: 0.3805, 95% confidence interval [Cl]: 0.1597-0.9065 (p> 0.046). CONCLUSIONS Presented results suggest that the MDR1 3435TT genotype might influence risk of development of DTC and that the CC genotype might be linked to a poor prognosis. Large-scale studies are now needed to validate this association.

Combined point mutations in codon 12 and 13 of KRAS oncogene in prostate carcinomas

Prostate cancer is a common malignancy that develops by structural mutation(s) and/or other genetic alterations in specific genes.The G to T transversions in codon 12 and C to T transitions in codon 13 of KRAS proto-oncogene are predominant point mutations that occur in about 20% of different cancers in human. In the current study it was aimed to investigate the prevalence and predictive significance of KRAS mutations in patients with prostate carcinomas. In a total of 30 fresh tumoural tissue specimens were investigated in patients with prostate carcinoma. All tumoural specimens were histo-pathologically diagnosed and genotyped for codon 12, 13 KRAS point mutations by reverse hybridisation and direct sequencing methods. KRAS mutations were found in 12 (40%) samples with 29 samples deriving from adenocarcinomas and 1 sample was small cell prostate carcinoma. In 1 (3.44%) sample codon 12 was found to be mutated and in 2 (6.8%) samples codon 13 and in 9 (31%) samples combined codon 12 and 13 were found to be mutated particularly in higher grade of tumoural tissues. Our study, based on representative collection of human prostate tumours, indicates that combined mutations in codons 12 and 13 KRAS are relatively infrequent and most commonly occur in prostate carcinomas.

Combined Effect of Factor V Leiden, MTHFR, and Angiotensin-Converting Enzyme (Insertion/Deletion) Gene Mutations in Hypertensive Adult Individuals: A Population-Based Study from Sivas and Canakkale, Turkey

BACKGROUND Hypertension is one of the leading causes of mortality and morbidity in the world, which is influenced by environmental and genetic factors. The methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzymes (ACE) are possible candidate genes that may influence both body fatness and blood pressure (BP). The purpose of this study was to examine the carriage of gene combinations of the ACE (insertion/deletion [I/D]), MTHFR 677T and 1298C, and lipid profiles in patients with essential hypertension (EH) in Turkey. METHODS A total of 150 adult individuals (50 hypertensive, 50 first-degree relatives, and 50 healthy controls) from Sivas/Turkey with the same age and gender were assessed for body composition, lipid profiles, resting BP, and gene profiles. Additionally, 149 individuals (99 hypertensive, 50 controls) from Canakkale/Turkey had been investigated for ACE I/D polymorphism. Peripheral blood samples were genotyped using strip assay reverse-hybridization multiplex polymerase chain reaction tests for target genes. RESULTS Heterozygous mutation in FV Leiden was found to be higher in the hypertensive and first-degree relatives when compared with the control group (p<0.05). Homozygous DD alleles of the ACE gene were also higher than the ACE I/D and control groups (p<0.05). The high rates of cholesterol and low-density lipoprotein and low rates of high-density lipoprotein were found in patients with EH when compared with the control. CONCLUSION Results show that ACE with DD alleles and mutated alleles of FV Leiden and MTHFR genes were significantly different between genotypes and have a combined effect on EH in Turkish population. Further studies are needed to investigate the genetics of obesity, EH, and BP phenotypes in the current adult population.