Elena N. Voronina

Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level

Methionine synthase (MTR) and methylenetetrahydrofolate reductase (MTHFR) enzymes are involved in the metabolism of methyl groups, and thus have an important role in the maintenance of proper DNA methylation level. In our study we aimed to evaluate the effect of the polymorphism A2756G (rs1805087) in the MTR gene on the level of human leukocyte genomic DNA methylation. Since the well-studied polymorphism C677T (rs1801133) in the MTHFR gene has already been shown to affect DNA methylation, we aimed to analyze the effect of MTR A2756G independently of the MTHFR C677T polymorphism. For this purpose, we collected the groups of 80 subjects with the MTR 2756AA genotype and 80 subjects with the MTR 2756GG genotype, having equal numbers of individuals with the MTHFR 677CC and the MTHFR 677TT genotypes, and determined the level of DNA methylation in each group. Individuals homozygous for the mutant MTR 2756G allele showed higher DNA methylation level than those harboring the MTR 2756AA genotype (5.061 ± 1.761% vs. 4.501 ± 1.621%, P=0.0391). Individuals with wild-type MTHFR 677СC genotype displayed higher DNA methylation level than the subjects with mutant MTHFR 677TT genotype (5.103 ± 1.767% vs. 4.323 ± 1.525%, P=0.0034). Our data provide evidence that the MTR A2756G polymorphism increases the level of DNA methylation and confirm the previous reports that the MTHFR C677T polymorphism is associated with DNA hypomethylation.

Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin's lymphoma.

We investigated the role of single nucleotide polymorphisms (SNPs) in the folate-metabolizing genes MTHFR, MTR, MTRR, MTHFD, CBS and SHMT in regulating genetic susceptibility to Non-Hodgkins lymphoma (NHL). We determined the allele and genotype frequencies in the case group (146 patients with NHL) and the control group (540 blood donors). A significant association with NHL was observed only for MTHFD1 G1958A (allele G OR=1.382, P=0.05; genotype GA OR=2.316, P=0.01; genotype GG OR=2.153, P=0.03). After additional stratification of case and control groups according to sex and tumor type association of MTHFD1 G1958A with NHL was observed only in high-grade NHL subgroup (allele G OR=1.664, P=0.01) and in women subgroup (allele G OR=2.043, P=0.009). Meta-analysis for SNPs in the MTHFR, MTR, MTRR and SHMT revealed a reducing effect of the MTR 2756G allele on the risk of NHL (OR=0.902; 95% CI 0.821-0.991, P=0.03).

Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk

Alterations in the nucleotide sequences of folate-metabolizing genes can increase the risk of malignant transformation. The aim of our study was to investigate the association of three single-nucleotide polymorphisms (SNPs) in the folate-metabolizing genes - A2756G MTR, A66G MTRR, and 844ins68 CBS - which have putative functional significance in breast cancer risk. The allele and genotype frequencies of the SNPs were determined in a case group (840 women with sporadic breast cancer) and a control group (770 women). No statistically significant association of studied SNPs with breast cancer was revealed. A meta-analysis, which included data obtained from the literature and the present research, did not reveal any statistically significant associations of these SNPs with breast cancer. The results obtained provide evidence that these SNPs are not involved in the development of breast cancer.

Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of West Siberia.

Polymorphisms within intron 2 of the FGFR2 gene have been associated with increased risk of breast cancer (BC) in European and Asian populations. The study by Easton et al reported two FGFR2 SNPs, rs2981582 and rs7895676, to be among those most strongly associated with BC risk. Statistical modeling suggested that rs7895676 was the variant responsible for the association observed in the region. In this work, we studied the association between seven FGFR2 SNPs, including rs2981582 and rs7895676, and BC risk in the Russian population of 766 case and 665 control women from Siberia, Russian Federation. In our population, allelic frequencies and the magnitude of linkage disequilibrium (LD) were different from those observed in European and Asian populations. The following three SNPs were significantly associated with BC in our study: rs7895676[C] (odds ratio (OR)=1.28 (1.12–1.43), P=1.7 × 10−3), rs2981582[T] (OR=1.46 (1.30–1.62), P=2 × 10−6) and rs3135718[G] (OR=1.43 (1.27–1.58), P=6 × 10−6). The latter two SNPs were in strong (r2=0.95) LD in our sample. Maximum likelihood analysis showed that the model, including rs7895676, only explains that the association is significantly (P<0.001) worse than any of the models, including either rs2981582 or rs3135718. Thus, in addition to the confirmation of association of FGFR2 with the BC risk in this new population, our study has suggested that rs7895676 is not likely to represent the causative variant.

Polymorphisms in folate-metabolizing genes and risk of idiopathic male infertility: a study on a Russian population and a meta-analysis.

OBJECTIVE To investigate the association of polymorphisms in the folate-metabolizing genes with idiopathic male infertility in a Russian population and to perform a meta-analysis. DESIGN A case-control study. SETTING Research laboratory. PATIENT(S) 275 men with idiopathic male infertility and a population sample of 349 men. INTERVENTION(S) Determining the genotypes of polymorphisms MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, SHMT1 C1420T, MTHFD1 G1958A, and CBS 844ins68. MAIN OUTCOME MEASURE(S) Semen analyses performed according to the World Health Organization guidelines (WHO, 1999) and Kruger strict morphology test. RESULT(S) None of the polymorphisms were significantly associated with idiopathic male infertility after the implementation of Bonferroni correction for multiple testing, although the MTHFD1 G1958A and MTR A2756G polymorphisms showed an association before the Bonferroni correction. Meta-analysis revealed an association by use of fixed-effects model of MTHFR C677T with the risk of azoospermia. CONCLUSION(S) These findings suggest that polymorphisms in folate-metabolizing genes could be involved in the etiology of male infertility. Additional studies performed on larger groups are necessary to investigate the possible associations.

Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms

A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits.

Association of the MTHFR 1298A>C (rs1801131) polymorphism with speed and strength sports in Russian and Polish athletes

Abstract It has been suggested that DNA hypomethylation because of poorer effectiveness of the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme induces muscular growth. We hypothesised that the common, functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. To test this hypothesis, we investigated the distribution of the 1298A>C variant in Polish (n = 302) and Russian (n = 842) athletes divided into four groups: endurance, strength-endurance, sprint-strength and strength-endurance, as well as in 1540 control participants. We found different genotypes (the AC heterozygote advantage) and allele distributions among sprint-strength athletes and strength athletes than the groups of sedentary controls for each nationality. In the combined study, the allelic frequencies for the 1298C variant were 35.6% in sprint-strength athletes (OR 1.18 [1.02–1.36], P = 0.024 vs. controls) and 38.6% in strength athletes (OR 1.34 [1.10–1.64], P = 0.003 vs. controls). The results of the initial and repetition studies as well as the combined analysis suggest that the functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. The presence of the C allele seems to be beneficial in sprint-strength and strength athletes. It needs to be established whether and to what extent this effect is mediated by alteration in DNA methylation status.

Allele Frequency and Genotype Distribution of 9 SNPs in the Kazakh Population

Background: Determining the allelic variants of xenobiotic biotransformation genes is important, especially for prescribing personalised drugs. Knowledge of the allele distribution in different populations may be considered when selecting the preferred medication regimen. The frequency of CYP2C9, VKORC1, CYP4F2, GGCX, CYP2D6 and CYP1A2 genes has been studied in many populations, but the populations in Central Asia have not yet been investigated. Methods and materials: Using real-time PCR and direct sequencing-based methods, the current study assessed the frequencies of 9 polymorphisms of genes encoding enzymes involved in drug metabolism in 450 healthy individuals from different regions of Kazakhstan and 575 healthy individuals from the West-Siberian region of Russia. Results: The allele frequencies in the Kazakh population were determined for CYP2C9*2 (0.02), CYP2C9*3 (0.03), VKORC1 c. 173+1369G>C, VKORC1 c. 173+1000C>T (0.72, СYP4F2 (0.31), GGCX (0.04), CYP2D6*4 (0.07), CYP2D6*3 (0.01) and CYP1A2*1F (0.35). All alleles were in Hardy–Weinberg equilibrium (p > 0.05). The allele frequencies in the Russian population were as follows: CYP2C9*2, 0.08; CYP2C9*3, 0.08; VKORC1 (c. 173+1000C>T), 0.40; VKORC1 (c. 173+1369G>C), 0.41; СYP4F2 (c. 1297G>A), 0.24; GGCX (c. 1913+45G>C), 0.08; CYP2D6*3, 0.15; CYP2D6*4, 0.22; and CYP1A2*1F (c. -9-154C>A), 0.31. All alleles were in Hardy–Weinberg equilibrium (p>0.05), except GGCX (p=0.04). Conclusion: The Kazakh population allele frequency was between the Caucasian and Asian populations for nearly all of the studied gene allele variants.

Polymorphisms in folate‐metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: a case–control study

Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate‐metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group.

Personalized approach of medication by indirect anticoagulants tailored to the patient-Russian context: what are the prospects?

Indirect anticoagulants such as warfarin are the ‘gold standard’ for prevention and treatment of thromboembolic complications in patients at risk (in atrial fibrillation of valvular and nonvalvular etiology, the presence of artificial heart valves, orthopedic and trauma interventions, and other pathological conditions). A wide range of doses required to achieve a therapeutic effect indicates the need for a personalized approach to the appointment of warfarin. In addition to the dependence on the patients clinical characteristics (sex, age, smoking status, diagnosis), there is a clear association between the warfarin dose and the carriage of certain allelic variants of key genes that makes it possible to apply molecular genetic testing for individual dose adjustment. This provides a more rapid target anticoagulant effect and also reduces the risk of bleeding associated with a possible overdose of warfarin. Implementation of this approach will allow more wide and safe application of indirect anticoagulants in Russia for needy patients.