GA Genotype of the Arg280His Polymorphism on The XRCC1 Gene: Genetic Susceptibility Genotype in Differentiated Thyroid Carcinomas?

Differentiated thyroid carcinomas (DTC) are the most common form of endocrine malignancies. The role of genetic variations in the development of papillary thyroid carcinoma (PTC) is approximately 60.0-70.0%. The X-ray repair cross-complementing group 1 (XRCC1) protein has an important role in DNA repair mechanisms and genomic polymorphisms of XRCC1 gene affect the function of the protein. In the present case-control study, we aimed to compare the genotype frequency distributions of XRCC1 single nucleotide polymorphisms (SNPs) in terms of the presence of other risk factors (Hashimoto's thyroiditis, smoking, obesity, radiation exposure) in patients with thyroid nodules who had fine-needle aspiration biopsy (FNAB) and/or thyroid surgery due to thyroid cancer. The genotype frequency distributions of three common XRCC1 SNPs (Arg194Trp, Arg399Gln, Arg280His) were compared to those with DTC (n = 228), benign thyroid nodules (BTN, n = 100) and healthy controls (n = 93) in terms of certain pre defined risk factors such as the presence of Hashimoto's thyroiditis, smoking, obesity, a family history of thyroid cancer and radiation exposure. The frequency of the GA genotype of Arg280His in DTC cases was found to be higher than in those with BTN and the healthy control group (p <0.001). The DTC group had the lowest frequency of AA genotype of Arg280His (35.5%, p <0.001). Among those with a family history of thyroid cancer, 78.9% had a GA genotype and 21.1% had the AA genotype of Arg280His (p = 0.004). The Arg280His GA genotype was more common in DTC than in cancer-free controls. The GA genotype frequency was also high in DTC cases with a family history of thyroid cancer.

Angiotensinogen t235 and angiotensin-converting enzyme insertion/deletion polymorphisms associated with the development of posttransplantation diabetes mellitus in renal allograft recipients.

BACKGROUND: Genetic polymorphisms of the renin-angiotensin system (RAS) have been reported to play an important role in the pathogenesis of diabetes mellitus and hypertension. In addition, a close association has been reported between RAS and the progression of both diabetes and hypertension. But the role of RAS on the development of posttransplantation diabetes mellitus (PTDM) is not known. For this purpose we investigated the association of polymorphisms in the genes for angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) with the development of PTDM. METHODS: Genotyping for ACE insertion/deletion (I/D) and AGT M235T polymorphisms was performed in 50 patients who underwent renal transplantation during a 5-year period. Group 1 consisted of 23 recipients who developed PTDM and group 2 consisted of 27 recipients that did not have PTDM. RESULTS: Of 50 patients, 13 (26%) showed the ACE DD, 21 (42%) the ACE ID, and 16 the ACE II genotype. The frequencies of AGT MM, AGT MT, and AGT TT were 0, 54%, and 46%, respectively. Compared with group 2, there were high frequencies of the AGT TT genotype in group 1 recipients (P<.001). In addition the ACE DD genotype was found significantly higher in group 1 patients compared with group 2 patients (P=.001). CONCLUSION: The high frequencies of the AGT TT genotype and ACE DD genotype in recipients may contribute to the high prevalence of PTDM. Our data suggest a synergistic effect between the ACE and AGT polymorphism in the risk of PTDM, but to support this theory a larger patient group must be studied.

Comparison of IL10 and IL2 genotypes of Turkish population with other populations.

The human genome has been shaped by evolutionary and historical forces. Therefore, genetic polymorphisms are useful tools not only to understand the susceptibility to disease in modern populations, but the history of ancestral populations as well. For this purpose, data on genetic polymorphisms such as human leucocyte antigen, mitochondrial DNA sequence variability and the frequencies of TAP1 and TAP2 gene variants in Turkey have been reported previously. Here we have used interleukin (IL)-10 (-592C/A, -819T/C, -1082G/A) and IL-2 (-330T/G) as genetic markers to study the relationship between Turkish population and other populations.

Prognostic value of the PAI-1 4G/5G polymorphism in invasive ductal carcinoma of the breast.

The study group was derived from the archive materials of 55 invasive ductal breast cancer (IDC) patients who had undergone breast-preserving surgery (partial mastectomy/ axillary dissection). All patients included in the study had clinically T(1)-2, N0-M0 invasive ductal carcinoma. Genomic DNA species were extracted from paraffin-embedded blocks, and plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Patient demographics, axillary metastasis status, metastatic lymph nodi/total dissected lymph nodes from axilla, histopathologic characteristics of tumors, local recurrences, and survival ratio were assessed. PAI-1 4G/5G genotype frequencies were 4G/4G (64%), 4G/5G (31%), and 5G/5G (5%) in the patient group. According to the results based on frequencies, the demographics were not different. Five-year local recurrence rate of 4G/5G patients was the lowest (2/17, 12%) (P = 0.02). Also five-year distant metastases ratio of 4G/5G patients was the highest (18%) (P = 0.01). Five- and 10-year disease-free survival rates for the 4G/4G, 4G/5G, and 5G/5G groups were 97% and 94%, 82% and 77%, and 100% and 94%, respectively (P = 0.004). The results of this study indicate that the 4G allele in the PAI 1 gene had a negative impact on local recurrence and disease-free survival of patients with clinical T(1)-2N0M0 IDC.

Relationship between small-for-gestational age births and maternal thrombophilic mutations.

Small gestational age (SGA) is one of the major causes of fetal mortality and morbidity. Altered maternal homeostasis as a result of point mutations in the coagulation cascade has been reported as an important risk factor for this adverse pregnancy outcome. This study aims to investigate the relationship between mother's thrombophilic mutations and SGA deliveries in our population. The study group was consisted of sixty-six women who gave birth to one or more SGA babies. 104 women who gave birth to appropriate-for-gestational age (AGA) babies were sampled for the control group. Restriction fragment size analysis were performed by visualizing digested PCR products for Factor V Leiden (G1691A), Factor V Cambridge (A1090G), Factor V A1299G, prothrombin G20210A, methylene tetrahydropholate reductase C677T, A1298C and T1317C mutations. The results of this study indicate that maternal C677T (p=0.01) and A1298C (p<0.01) mutations in MTHFR gene may be suggested as risk factors for SGA outcome in our population. Therefore, maternal screening of these two mutations in the first trimester of pregnancy could help in the assessment of patients.

The association between intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms of ecNOS gene and sildenafil responsiveness in patients with erectile dysfunction.

The objective of the study was to determine the association between intron 4 variable number of tandem repeats (VNTR), E298A and IVF 23+10 G/T polymorphisms of ec-NOS gene and sildenafil responsiveness in patients with erectile dysfunction (ED). Ninety-six patients who were evaluated for ED between November 2003 and June 2004 and 167 healthy individuals representing the normal population as controls were included in the present study. The patients were evaluated by medical history, five-item version of International Index of Erectile Function, serum glucose, testosterone levels and lipid profiles. Sixty-seven patients received four consecutive doses of sildenafil from 25 to 100 mg according to the response. The ec-NOS gene intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms were evaluated in the isolated DNA blood samples obtained from the patient group with ED (n=96), from the group received sildenafil (n=67) and from the healthy group (n=167). Genotype distributions of ec-NOS gene intron 4, E298A and IVF 23+10 G/T polymorphisms in the patient group were similar to those in the healthy group. The frequency of the ec-NOS gene intron 4 genotype were found as bb=41.7%, ab=50% and aa=8.3% in the sildenafil responders and bb=93.5% and ba=6.5% in the sildenafil non-responders. This finding was statistically significant. Statistical analysis of ec-NOS gene E298A and IVF 23+10 G/T polymorphisms did not reveal any significant difference between sildenafil responders and non-responders. These findings may indicate that 'a' allele of ec-NOS gene intron 4 VNTR polymorphism associates with a better sildenafil response.

The apoptotic effects of mitomycin C on human endometrial cell cultures and reversal of its effects by beta-carotene and folic acid.

Apoptosis is a complex process involving a variety of mechanisms and it has been shown to be a response of cells to various chemical agents including chemotherapeutic ones. We aimed to induce DNA breaks and apoptosis in cultured endometrial stromal cells by mitomycin C (MMC), a chemotherapeutic agent, and also we aimed to observe the effects of beta-carotene and folic acid on MMC-induced apoptosis. Cultured endometrial stromal cells were exposed to MMC for 48 and 72 hours and in order to reverse MMC effects, we added beta-carotene and folic acid to the cultures. DNA fragmentation was observed in all cells. Apoptotic cell ratios and caspase-3 activity were observed to be dependent on exposure time. Ultrastructural examinations revealed positive effects of beta-carotene and folic acid, however they were not sufficient enough to prevent apoptosis in all cells. Beta-carotene profoundy reduced caspase-3 activity whereas folic acid did not seem to have a similar effect. As apoptosis involves several mechanisms, in a cell in which all these mechanisms are triggered, we think that antioxidants and DNA repair agents alone are not enough to reverse all of them.

Predictors of vascular access thrombosis among patients on the cadaveric renal transplantation waiting list.

Acute thrombotic complications remain a constant, proportionally increasing complication before and after renal transplantation. We sought to investigate predictors for a prothrombotic state that increased the risk of vascular access thrombosis, among chronic renal failure patients during the waiting period prior to cadaveric renal transplantation. Chronic renal failure patients awaiting cadaveric renal transplantation and followed between January 2002 and January 2005 were included in this study. The 109 subjects including, 61 females and 48 males of mean age: 47.4 +/- 12.9 years; There were 36 continuous ambulatory peritoneal dialysis and 73 hemodialysis patients. Serum albumin, prealbumin, CRP, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (immunoglobulins G and M), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total platelet count were measured in each patient. Factor V Leiden, prothrombin 20210, ACE and MTHFR gene mutations were studied in all patients. Vascular Access thrombosis was detected in 62 patients. During follow-up 31 of 109 patients died. Vascular access thrombosis occurred in 78 patients who survived and 31 who died. The patients who died showed a significantly higher rate of thrombosis than those who survived (P = .003, OR: 4.61, CI: 1.70 to 12.50). Among the above biochemical risk factors, multiple regression analysis and backward logistic analysis revealed that d-dimer was the strongest biochemical predictor of thrombosis (P = .013, RR: 17.8). Upon evaluation of genetic risk factors, only factor V Leiden mutation was related to vascular access thrombosis (P = .001). In conclusion, the presence of vascular access thrombosis is a risk factor for mortality during the waiting period for cadaveric renal transplantation. As patients with factor V Leiden mutation or high serum d-dimer levels are at high risk for vascular access thrombosis, we recommend close monitorizing of these patients and use of anticoagulant therapy during the waiting period prior to renal transplantation.

PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations.

The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.

Angiotensin-converting enzyme genotype is a predictive factor in the peak panel-reactive antibody response.

The presence of a high panel-reactive antibody (PRA) level represents an independent risk factor for early graft failure and chronic allograft dysfunction. It has also been reported that patients with the ACE-DD and AGT-AA genotypes display poorer chronic allograft function. We investigated the effects of gene polymorphisms of the renin angiotensin system (RAS) on anti-HLA antibody production among renal transplant candidates. Genotyping was performed on 133 dialysis patients for the ACE (I/D) and AGT (M235T) as well as the type 1 (A1166C) and type 2 (A1223G) angiotensin II receptor genes. Patients with a peak PRA >/= 30% were considered to be positive for anti-HLA antibody (40.6% of 133 patients). Genetic polymorphisms of the RAS were not associated with anti-HLA antibody production at this PRA level. Another analysis comparing the 29 patients with a peak PRA >/=50% with the 104 patients with a peak PRA <50% showed that previous transplants, the presence of ACE-DD genotype, history of blood transfusions, and dialysis duration were all associated with the high levels of antibody production by univariant analysis. A multivariate analysis using a logistic regression model revealed previous transplants, the presence of ACE-DD genotype, and history of blood transfusions to be predictors of anti-HLA antibody production. The ACE-DD genotype is an important risk factor for higher PRA levels. This study suggests that genetic control of RAS activity correlates with production of anti-HLA antibodies, possibly explaining the relationship to chronic allograft outcome.

The renin-angiotensin system and endothelial nitric oxide synthase gene polymorphisms and cyclosporine toxicity in renal transplant patients.

Although cyclosporine has improved graft survival, the toxicity of the drug frequently causes problem for renal transplant patients. Cyclosporine displays deleterious effects due to direct toxicity to the nephrons and vasoconstriction of afferent arterioles, effects that may be due to increased angiotensin II and decreased nitric oxide activity. We sought to examine the relation between cyclosporine toxicity and the RAS (angiotensin-converting enzyme, angiotesinogen, angiotensin 1 and 2 receptors, and ecNOS) gene polymorphisms in 111 renal transplant patients. Retrospectively, we correlated the results of graft biopsies from these 111 patients, with the cumulative drug doses (mg), mean blood levels (mg/mL), mean daily doses (mg), and mean doses (mg/kg/d) of cyclosporine. Overall 125 patients (38 women, 87 men) were enrolled in the study. Their mean age was 34.47 +/- 11.04 years. Twenty patients displayed cyclosporine toxicity on graft biopsy; 91 showed no evidence of the disorder. We could not find any relation between cyclosporine toxicity and gene polymorphisms (P >.05), although the mean mg/kg/d dose was significantly high among cyclosporine toxicity group (P =.028, RR = 1.42). In recent studies angiotensin II and nitric oxide have been suggested to be related to cyclosporine toxicity; however, our results failed to reveal an association between cyclosporine toxicity and angiotensin II or nitric oxide-related gene polymorphisms.

Angiotensin-converting enzyme gene polymorphism significantly affects renal posttransplantation erythrocytosis.

Posttransplantation erythrocytosis (PE) is a frequent problem in renal transplant patients. The pathogenesis and mechanisms of both the problem and therapy strategy are unknown. Since ACE and angiotensin 2 receptor inhibitors have been used to successfully manage PE, we speculated a relation between gene polymorphisms and this complication. Ninety-six ( 30 women, 66 men, age 34.4 +/- 11.0 years) renal transplant patients evaluated retrospectively, for gene polymorphisms of ACE, angiotensinogen, angiotensin 1 and 2 receptors (ATR1 and ATR2), as well as endothelial nitric oxide synthase (ecNOS). They were divided into two groups; patients with versus without PE, which was defined as >15 g/dL hemoglobin levels during the first year after renal transplantation. PE was found to be significantly more prevalent among D/D than I/I gene polymorphism of ACE genes (P <.04). The distribution of D/D, I/D, and I/I polymorphisms were 39.1%, 45.9%, and 7.6%, respectively. There was no difference between D/D and I/D polymorphisms. Comparing the I/D and I/I polymorphisms showed PE to be statistically more prevalent in the I/D polymorphism (P <.01). Logistic regression analysis revealed that D/D and I/D polymorphisms were significant risk factors for PE (P <.05, RR = 7.714 and P <.03, RR = 10.199, respectively). While previous studies revealed a relation between angiotensin II and PE, our study discovered the contribution of ACE gene polymorphism.

Purpura fulminans in a child with combined heterozygous prothrombin G20210A and factor V Leiden mutations.

Although thrombosis is relatively rare in children, reports of young patients with thrombosis are becoming more frequent with time. Activated protein C resistance and prothrombin 20210 A mutation are results of point mutations described in the last decade. This article highlights a case of a child with severe arterial thrombosis who was heterozygous for the factor V Leiden (FVL) and prothrombin G20210A mutations. The patient diagnosed with purpura fulminans was an 8-year-old boy who was referred to our hospital with purpuric lesions on the extremities and necrosis of the penis. We believe that the coexistence of more than one thrombophilic mutation contributed to the occurrence of severe thrombosis at a young age in this patient.

The genetic analysis of Turkish patients with Huntington's disease.

OBJECTIVE: Exploring the (CAG)n expansion within IT 15 gene in Turkish Huntington's disease (HD) patients and its relation to downstream (CCG)n repeat polymorphism to elucidate population specific haplotypic heterogeneity. METHODS: Twenty-seven patients with clinical diagnosis of HD from 19 families were sampled. The triplet repeats were evaluated by sizing the fluorescent PCR products on an ABI 310 capillary gel electrophoresis unit. RESULTS: The number of (CAG)n repeat expansions (range: 40-76, mean: 45.6+/-7) were inversely correlated with age of onset (r=-0.81, P<0.0001). The (CCG)n polymorphism in HD chromosomes was confined to (CCG)7 in all patients. In normal chromosomes CAG polymorphism was accumulated at a relatively higher range (mean: 19.3+/-2.9) together with the common occurrence of(CCG)7 and (CCG)10 alleles. CONCLUSION: The distribution range of the CAG and CCG repeat polymorphism in normal chromosomes and strong linkage disequilibrium between HD mutation and (CCG)7 haplotype provided a striking similarity to populations of western European descent.