Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study

Abstract

Background Genetic variation in one-carbon metabolism may affect nutrient levels and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in U.S. postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. Objective We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. Methods In 1,573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50–79 years, 288 non-synonymous and tagging single-nucleotide variants (SNVs) were genotyped. Red blood cell (RBC) folate, plasma folate, pyridoxal-5′-phosphate (PLP), vitamin B-12, homocysteine, and cysteine levels were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. Results After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (–13.0%, 95% CI = –17.3% to –8.6%) and higher plasma homocysteine (3.5%, 95% CI = 1.7% to 5.3%) concentrations. Other associations for non-synonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G) and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest vs. lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. Conclusions Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

Coronary Artery Disease Is Related to Methylation Disorders Caused by the c.1286A>C MTHFR Polymorphism and to Low Serum 5-MTHF and Folic Acid Concentrations—Preliminary Results

“…Our results, showing that 5-MTHF and folic acid concentrations were lower in heterozygotes and in homozygotes with methylation disorders caused by MTHFR c.665C>T and c.1286A>C polymorphisms, were consistent with outcomes regarding folic acid provided by other researchers [34,35]. However, in a whole-genome sequencing study it appeared that the other gene located on the same chromosome as MTHFR was responsible for folic acid concentration [36].…”

The Correlation between Methylation Disorders Caused by the <em>MTHFR</em> Polymorphism and the Folates (Folic Acid, 5-MTHF) Metabolism, in Coronary Artery Disease Patients Diagnosed by Invasive Coronary Angiography—Preliminary Results

“…Our results were not statistically significant, however they are consistent with the 2022 study conducted on the population of 1712 obese people, where it was found that in the case of MTHFR gene polymorphisms (in homozygotes c.665C>T) the concentration of folic acid was significantly lower than in heterozygotes and in the wild type [33]. Our results are consistent with the results of the 2022 study conducted on 1855 postmenopausal women, where lower folic acid concentration and higher homocysteine concentration were found in the homozygous c.665C>T variant of the MTHFR gene [34]. However, in a whole-genome sequencing multicenter study no influence of the c.665C>T MTHFR polymorphism on the concentration of folic acid was found.…”

Common Variants in One-Carbon Metabolism Genes (MTHFR, MTR, MTHFD1) and Depression in Gynecologic Cancers

“…N-acetylcysteine (NAC) is a precursor of cysteine; given as a supplement, it appears to be promising in the treatment of several psychiatric disorders [ 36 , 37 ]. Recently, Cheng et al [ 38 ] analyzed, in a large study, the association of OCM genetic variants with blood biomarkers in postmenopausal women. They observed that significantly lower plasma cysteine concentrations were associated with MTHFD1 polymorphisms rs2236224 (G>A) and rs2236225 (R653Q, G>A) in non-Hispanic white women (−1.0%; 95% CI: −1.9%, −0.2%, per variant allele A; FDR-adjusted p = 0.078) [ 38 ].…”