Associations between Plasma Choline Metabolites and Genetic Polymorphisms in One-Carbon Metabolism in Postmenopausal Women: The Women's Health Initiative Observational Study

ABSTRACT Background Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. Objectives This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. Methods We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993–1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. Results The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (−4.00% and −6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. Conclusions Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

Exploring effects of betaine-homocysteine methyltransferase (BHMT) gene polymorphisms on fatty acid traits and cholesterol in sheep

This study was aimed to explore the effects of Betaine-Homocysteine Methyltransferase (BHMT) gene polymorphisms on fatty acid traits and cholesterol in lambs. This study used a total of 147 blood samples for genotyping including 19 Javanese Fat-Tailed (JFT), 16 Javanese Thin-Tailed (JTT), 41 Composite Garut (CG), 35 Compass Agrinak (CA) and 36 Barbados Black Belly Cross (BC). A total of 61 rams as representative from five breed of sheep were selected for association study. Identification of BHMT single nucleotide polymorphisms was analyzed by PCR-RFLP method. Association of BHMT genotypes with fatty acid traits and cholesterol was performed by T-TEST. BHMT genotyping resulted into three genotypes (CC, CT and TT). Gene frequency of BHMT (g. 9947372 C>T) was in Hardy-Weinberg Equilibrium, excluding Javanese Fat-Tailed sheep. Association of BHMT genotypes with fatty acid traits resulted into a significant association (P<0.05) with C14:1, C17:1 and C18:0 fatty acids but not with cholesterol in sheep. SNP g. 9947372 (C>T) of BHMT gene might be a useful marker for selecting and producing sheep meat with desirable fatty acids.

P75 Relation between polymorphism of folic acid cycle genes and effectiveness of methotrexate in children with juvenile idiopathic arthritis

BackgroundMethotrexate (MTX) is the basic treatment of patient with Juvenile Idiopathic Arthritis (JIA), but effectiveness of this therapy is different. We aimed to study effectiveness of MTX in children with JIA with different genotypes of folic acid cycle genes.MethodsThe study included 8 patients with JIA. For determination of MTX effectiveness the American College of Rheumatology pediatric criteria (ACR-pedi) was used. Patients were divided into 2 groups according the effectiveness of MTX treatment. Group I included 4 patients, who were non-responders because ACR-pedi was less than 10%. Second group contained 4 patients, who had ACR-pedi more than 10%. The megerment of genotypes of genes of folate cycle, such as 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), 5,10methylenetetrahydrofolate reductase C677T and A1298C variants (MTHFR-677 and MTHFR129) by polymerase chain reaction (PCR) was performed for all patients.ResultsIn II group effectiveness of therapy according ACR-pedi was from 30% to 70% in 75% of children and more then 70% - in 25% of patients. In general, MTR gene indicated AA-genotype in 50% of patients, AG and GG-genotypes - in 25%; MTRR gene was performed with AA-genotype in 25%, AC-genotype in 12.5% and CC-genotype in 62.5%. MTHFR1298 gene was presented in 50% of patients with AA-alleles, in 25% - with AC and CC-genotypes. 50% of children had CC-genotype of MTHFR677 gene and other 50% - AC-genotype of MTHFR677 gene. CC-genotype of MTHFR1298 gene more frequently was determined in II group (p< 0.01). In group of non-responders AA-genotype of MTR gene was found more frequent in comparison with patients from group II (p< 0.01).ConclusionResponse to standard therapy in patients with JIA depends on time of prescription of MTX and genotype of MTHFR1298 and MTR genes.Disclosure(s)Nothing to disclose

Alleviation of paraquat-induced oxidative lung injury by betaineviaregulation of sulfur-containing amino acid metabolism despite the lack of betaine-homocysteine methyltransferase (BHMT) in the lung

Betaine regulates sulfur-containing amino acid metabolism in the lung despite the lack of BHMT and increases pulmonary antioxidant capacity.

Pathogenetic Justification for the Use of Folates for the Prevention of Congenital Malformations

The frequency and severity of congenital malformations (CMF) do not tend to decline in modern society. CMF for etiologic factors are referred to the pathologies of a multifactorial nature. Among the many causative factors of CMF there is a hereditary predisposition. The objective of the study was to increase the effectiveness of complex individualized prophylaxis of congenital malformations in women with polymorphic alleles of genes of folate cycle enzymes, the second phase of the detoxification system through the use of diagnostic, preventive, and therapeutic measures. Materials and methods. 120 women of reproductive age who live in the city of Odessa and the Odessa region were examined. The alleles of the genes of the folate cycle enzymes of methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR), glutathione-S-transferase M1 (GSTM1), folate acid, cyanocobalamin were determined. Results of the study and their discussion. The determination of the polymorphic alleles of the genes of the folate cycle enzymes of methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR), glutathione-S-transferase M1 (GSTM1), low folate, cyanocobalamin indicates the presence of a hereditary predisposition to the emergence of CMF, before and during pregnancy. Polymorphism of genes that control the synthesis of GSTM1 may alter the activity of detoxification enzymes. Expression of genes of GSTM1 enzymes begins in the embryonic period. Glutathione-dependent detoxification plays a key role in disinfecting of DNA peroxides. Mistakes of metabolism, functions of the corresponding enzymes are realized by chromosomal abnormalities and the risk of the occurrence of CMF, which requires the use of antioxidant therapy before and during pregnancy. Conclusions. It was found that a high (about 55%) frequency of the polymorphic alleles of the genes of folate cycle enzymes MTHFR (homozygous – 10.0%, heterozygous – 16.7%), 5 MTRR (homozygous 12.5%, heterozygous – 15.5%) , the second phase of the GSTM1 detoxification system (homozygous – 13.3%, heterozygous – 15.8%), the content below the reference values of folic acid in 26.7%, cyanocobalamin – in 63.4% of observations indicates a hereditary predisposition and may contribute the emergence of CMF, which explains the expediency of timely use of preventive measures including folates, antioxidants.