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.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

“…Serum TMAO accumulates after a single meal rich in precursor nutrients and remains elevated for the duration of the diet [ 13 , 16 , 87 , 90 , 91 ]. Despite variability among diets and patients, serum TMAO levels are typically low in healthy subjects, ranging from 1 to 3 µM, which increases to 15 µM with old age [ 8 , 16 , 67 , 87 , 88 , 89 ]. The onset of Western-diet-driven chronic diseases elevates TMAO to concentrations from 7 and 170 µM, with kidney disease patients showing the highest levels and T2D or CVD patients showing levels at or above 20 µM [ 5 , 25 , 68 , 70 , 72 , 74 , 75 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ].…”

“…T2D or CVD patients present levels at or above 20 µM [ 5 , 25 , 68 , 70 , 72 , 74 , 75 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Alternatively, healthy patients present low levels from 1 to 3 µM [ 8 , 16 , 67 , 87 , 88 , 89 ]. Therefore, to represent these variable clinical TMAO concentrations, we investigated the 0.3 and 160 µM range of TMAO in both the SCC and GLT conditions.…”

Interaction analysis of gene variants related to one‐carbon metabolism with chronic hepatitis B infection in Chinese patients

“…23 BHMT rs492842 and rs490268 were found to be statistically significant in right-sided and left-sided obstructive heart defects risk in 10 US state populations. 32 As a susceptibility gene polymorphism site, rs3733890 was correlated with dimethylglycine concentration in postmenopausal women from the USA, 33 telomere length in non-Hispanic white participants, 34 omphalocele in African-Americans 35 and neural tube defects in Caucasian Americans. 36 It was also found that rs3733890 was a significant predictor of homocysteine concentration in healthy Caucasian adults in the Washington area of the USA, 37 and similar results were obtained in Chinese population.…”

Mild Choline Deficiency and MTHFD1 Synthetase Deficiency Interact to Increase Incidence of Developmental Delays and Defects in Mice

“…Unfortunately, current choline intakes in most pregnant women and women of child-bearing age fail to meet the AI [ 22 , 23 , 24 , 25 ]. Furthermore, dietary requirements for choline may be increased by genetic variants, such as the common MTHFD1 R653Q polymorphism in the synthetase domain of this trifunctional enzyme [ 8 , 9 , 10 , 11 , 12 , 26 ]. In this study, we used the MTHFD1-synthetase-deficient mouse model to examine the hypothesis that pregnant 653QQ women may be more sensitive to choline deficiency with respect to reproductive outcomes.…”

“…The common R653Q variant ( MTHFD1 c.1958 G > A; rs2236225, ~20% QQ in European populations) compromises the synthetase activity of MTHFD1 [ 4 ] and has been identified as a risk factor for neural tube defects (NTD), heart defects, intrauterine growth restriction, and pregnancy loss [ 4 , 5 , 6 , 7 ]. In addition to its effects on folate metabolism, MTHFD1 R653Q has been found to alter choline metabolism in human studies [ 8 , 9 , 10 , 11 , 12 ]. Folate and choline metabolism intersect in the liver, the major site of both folate and choline metabolism.…”