Ali Sazci

Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk

Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of 136 healthy controls. The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were significantly higher in the total migraine population (33.82%, 33.82%) than in controls (25.38% and 24.26%), respectively. The genotypes T677T and C1298C were the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457; P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals with migraine with aura with C1298C and C677C/C1298C genotypes were even more profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320; P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However individuals with migraine without aura with T677T and C1298C genotypes showed the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with C1298C and C677C/C1298C genotypes may also predispose to tension-type headache (OR=8.375; 95% CI=0.685-102.458); P=0.049).

Polymorphisms in the MTHFR gene are associated with breast cancer.

The methylenetetrahydrofolate reductase (MTHFR) gene is a polymorphic gene involved in folate metabolism, DNA biosynthesis, methylation and genomic integrity in actively dividing cells. The MTHFR C677T and A1298C polymorphisms are likely to play an important role in the susceptibility to breast cancer. In this case-control study, we examined the role of MTHFR C677T and A1298C polymorphisms in breast cancer patients. We genotyped 118 premenopausal women with sporadic breast cancer and 193 controls, using a PCR-RFLP method. The allele frequencies of the MTHFR 677T were 31.36% in the breast cancer cases and 28.76% in the controls. The allele frequencies of the MTHFR 1298C were 37.29% in the breast cancer subjects and 31.35% in the controls. Frequencies of MTHFR C677C, C677T and T677T were 50.8, 33.9 and 14.4% in the breast cancer patients and 48.7, 45.1 and 6.2% in the controls, respectively. The results of a χ2 analysis indicated that the MTHFR 677T allele was significantly distributed (χ2 = 7.234; p = 0.027). Likewise, the MTHFR T677T genotype showed a 2.5-fold increased risk for breast cancer and the C1298C genotype showed a 1.9-fold increased risk for breast cancer. In the compound genotypes, T677T/A1298A and C677C/C1298C showed a 4.472- and a 2.301-fold increased risk for breast cancer (OR = 4.472, p = 0.001, and OR = 2.301, p = 0.024), respectively. In conclusion, our data suggest that the MTHFR 677T, 1298C alleles, T677T, C1298C genotypes, and C677C/C1298C and T677T/A1298A compound genotypes are genetic risk factors for premenopausal women with sporadic breast cancer.

Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C.

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both stroke subtypes in patients with methylenetetrahydrofolate reductase gene polymorphisms. Therefore, we examined whether the C677T and A1298C polymorphisms of MTHFR gene are genetic risk factors for both ischemic and hemorrhagic stroke in a Turkish Caucasian population. In a case-control study, 120 total unrelated stroke patients (92 ischemic stroke, 28 hemorrhagic stroke), and 259 healthy controls were genotyped for C677T and A1298C polymorphisms of the MTHFR gene using a PCR-RFLP based-method. The MTHFR 1298C allele (chi(2)=8.589; P=0.014), C1298C genotype (OR=2.544; P=0.004), and C677C/C1298C compound genotype (OR=3.020; P=0.001) were associated with overall stroke. The MTHFR 1298C allele (chi(2)=11.166; P=0.004), C1298C genotype (OR=2.950; P=0.001), and C677C/C1298C compound genotype (OR=3.463, P=0.0001) were strongly associated with ischemic stroke. Interestingly however, the MTHFR 677T allele (chi(2)=6.033; P=0.049), T677T genotype (OR=3.120; P=0.014), and T677T/A1298A compound genotype (OR=4.211; P=0.002) were associated with hemorrhagic stroke. In conclusion, the C677T and A1298C polymorphisms of the MTHFR gene are genetic risk factors for hamorrhagic and ischemic stroke respectively, independent of other atherothrombotic risk factors.

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: Association is significant in men but not in women

Schizophrenia is a complex and common psychiatric disorder with a polygenic inheritance. In our previous report, we showed an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy in Istanbul, Turkey [Sazci, A., Ergul, E., Guzelhan, Y., Kaya, G., Kara, I., 2003. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol. Brain Res. 117, 104-107]. We wanted also independently to confirm this study in a gender-specific manner with schizophrenic patients from Erenkoy in Istanbul, Turkey. To investigate the role of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene in schizophrenia in a gender-specific manner, we analyzed the genotypes of MTHFR677 and MTHFR1298 of 297 schizophrenic patients and 341 healthy controls, using a polymerase chain reaction restriction fragment length polymorphism method. The MTHFR 677T allele was significantly distributed (chi2=7.312; P=0.026), between schizophrenic patients and healthy controls. The T677T genotype was overrepresented in the total schizophrenic patients (OR=1.938; 95%CI=1.133-3.315; chi2=5.996; P=0.014). Similarly, the T677T/A1298A compound genotype was the most significant one in the total schizophrenic patients (OR=2.397; 95% CI=1.327-4.330; chi2=8.821; P=0.003). The C1298C genotype was overrepresented in the total schizophrenic patients (OR=1.706; 95%CI=1.014-2.870; chi2=4.126; P=0.042). Likewise, the C677C/C1298C compound genotype was significant in the total schizophrenic patients (OR=1.689; 95%CI=0.985-2.894; chi2=3.695; P=0.055). When schizophrenic patients and healthy controls were stratified according to gender difference, the T677T genotype and T677T/A1298A compound genotype were significantly overrepresented (OR=2.184; 95% CI=1.069-4.462; chi2=4.767; P=0.029; OR=2.748; 95% CI=1.215-6.214; chi2=6.301; P=0.012, respectively) in men schizophrenic patients. However, neither the MTHFR C677T nor the A1298C polymorphisms are associated with schizophrenia in women. In conclusion, the MTHFR 677T allele and T677T, C1298C genotypes, and T677T/A1298A, C677C/C1298C compound genotypes are genetic risk factors for schizophrenia in men but not in women in a gender-specific manner.

Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia.

To investigate the role of methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, we analyzed the genotypes of MTHFR677 and MTHFR1298 of 130 schizophrenic patients and 226 controls, using a polymerase chain reaction restriction fragment length polymorphism method. The MTHFR T677 allele was significantly distributed (chi(2)=7.900; P=0.019), between schizophrenic cases and healthy controls. The T677T genotype was overrepresented in the schizophrenic patients (OR=2.504; 95% CI=1.276-4.915; chi(2)=7.477; P=0.006). The T677T/A1298A, and C677T/C1298C compound genotypes were greater in the schizophrenic patients (OR=3.157; 95% CI=1.522-6.545; chi(2)=10.336; P=0.001 and OR=1.744; 95% CI=0.108-28.121; chi(2)=0.158; P=0.691, respectively). The MTHFR T677 allele and T677T and T677T/A1298A genotypes are genetic risk factors for schizophrenia.

Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of alcohol abuse worldwide. Non-alcoholic steatohepatitis (NASH) is the most progressive form of NAFLD. The aim of this study was to investigate the role of apolipoprotein E (APOE) polymorphisms in the development of NASH. We analysed 57 NASH patients and 245 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a case–control study. The diagnosis of the patients was based on liver biopsy. The serum levels of glucose, lipids, vitamin B12, folic acid, homocysteine, insulin, total biluribin, total protein, albumin, ferritin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined in all of the subjects. Body mass index (BMI), waist circumference (WC), AST, ALT, fasting blood sugar (FBS), total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, insulin and ferritin levels were significantly higher in the 57 patients with NASH compared with the 245 healthy controls. The APOE ε3 allele was overrepresented in the whole group of NASH patients (ε3=97.37% in NASH versus 82.45% in controls). The APOE polymorphism was statistically significantly associated with NASH (χ2=15.741; p=0.008). The APOE3/3 genotype (odds ratio [OR]=7.941; p=0.000) was strongly associated with increased risk for NASH in all NASH patients. Consequently, the APOE3/3 genotype may play a role in the aetiopathogenesis of NASH.

Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke.

Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with increased incidence of stroke in some populations, although contradictory results have been reported. The aim of this study was to determine the allelic frequency and the genotypic distribution for ACE gene polymorphism in Turkish patients with ischemic stroke compared to appropriate healthy controls and to correlate the genetic findings with stoke type. One hundred and eight patients with ischemic stroke versus 79 healthy controls were studied for the presence of ACE gene polymorphism detected by PCR. Genotypes were defined as DD, II and ID according to the presence of the D (deletion) and I (insertion) alleles. There was no statistically significant difference in either the genotypic distribution or allelic frequency between the patients versus healthy controls (chi2 = 0.105; df = 1; p = 0.430). There was also no significant difference for ACE genotype distribution and allelic frequency within the stroke group classified according to Bamford criteria (chi2 = 4.827; df = 3; p = 0.185). Our data supports lack of association between DD genotype and/or D allele and ischemic stroke or subtypes of ischaemic stroke in the Turkish population.

Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives

We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and 238 controls. tHcy and folate and vitamin B12 levels were measured by Fluorescence Polarization Immunoassay and Electrochemiluminescence, respectively. The tHcy was significantly increased in patients and relatives. In contrast, folate and B12 were significantly lower in patients and relatives. Gender was not considered as a significant determinant in the multivariate analysis. Genotypes of c.1298A>C and c.677C>T were correlated with tHcy, folate and B12. Patients and relatives carrying TT and/or AA and AC genotypes had elevated tHcy and reduced folate and B12 levels. High tHcy but low folate and vitamin B12 levels may be a risk factor for development of bipolar disorder.

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene in patients with essential tremor in Turkey

Essential tremor (ET) is a most common human movement disorder of unknown etiology. Previous reports have shown that the C677T polymorphism of methylenetetrahydrofolate reductase gene has been associated with neurodegenerative disorders. To investigate the role of methylenetetrahydrofolate reductase gene polymorphisms in essential tremor, we analyzed the alleles and genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in a total of 158 unrelated essential tremor patients and compared them with those of 246 unrelated healthy control subjects, using a polymerase chain reaction restriction fragment length polymorphism method. The allele frequency of MTHFR 677T was 35.76% in the essential tremor cases and 30.08% in the controls. We obtained statistically significant results for MTHFR677 and also for MTHFR1298. The MTHFR T677T genotype was overrepresented and was statistically significant. The T677T/A1298A and C677C/C1298C compound genotypes were similarly statistically significant. The C677C/A1298A compound genotype provided protection for essential tremor. In conclusion, the MTHFR 677T, 1298C alleles and MTHFR T677T genotype and T677T/A1298A, and C677C/C1298C compound genotypes are genetic risk factors for essential tremor in Turkey.

A de novo complex chromosome rearrangement involving three chromosomes (2, 13, and 18) in an oligospermic male

OBJECTIVE To determine an unusual complex chromosome rearrangement found in a man with oligospermia with a normal phenotype. DESIGN Case report with a review of the literature. SETTING Academic research environment. PATIENT(S) A man with oligospermia but otherwise apparently healthy. INTERVENTION(S) Peripheral blood lymphocytes were used for karyotyping, and metaphases were analyzed by the fluorescence in situ hybridization (FISH) procedure. Further characterization of the karyotype was done by using multicolor banding (MCB) probes. MAIN OUTCOME MEASURE(S) Physical examination, semen analysis, GTG banding, FISH, MCB. RESULT(S) The semen analysis revealed oligospermia. The lymphocytic karyotype detected an unusual complex chromosome rearrangement involving chromosomes 2, 13, and 18 determined by banding cytogenetics. Karyotype was established as 46,XY,t(2;13;18)ins(2;13)(2qter-->2p25.1::13q13-->13q22::18q12.3-->18qter;13pter-->13q13::2p25-->2pter;18pter-->18q12.3::13q22-->13qter) after MCB analysis. CONCLUSION(S) The association of an unusual complex chromosome rearrangement with three recurrent spontaneous abortions was reported.