DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-L-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methyl-THF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-L-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography͞MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T͞T) and 187 homozygous for the wild-type (C͞C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T͞T genotypes had a diminished level of DNA methylation compared with those with the C͞C wild-type (32.23 vs.62.24 ng 5-methylcytosine͞g DNA, P < 0.0001). When analyzed according to folate status, however, only the T͞T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T͞T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.

A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) (5-methyltetrahydrofolate:(acceptor) oxidoreductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolism, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic method for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folates. An alteration was found as manifested by the presence of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofolate polyglutamates were the only folate form found in RBCs from individuals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity of the thermolabile variant of MTHFR and that this impairment results in an altered distribution of RBC folates.

BACKGROUND Disparities in healthcare access and delivery, caused by transportation and health workforce difficulties, negatively impact individuals living in rural areas. These challenges are especially prominent in older adults. DESIGN We systematically evaluated the feasibility, acceptability, and effectiveness in providing telemedicine (TMed), searching the English‐language literature for studies (January 2012 to July 2018) in the following databases: Medline (PubMed); Cochrane Library (Wiley); Web of Science; CINAHL; EMBASE (Ovid); and PsycINFO (EBSCO). PARTICIPANTS Older adults (mean age = 65 years or older, and none were younger than 60 years). INTERVENTIONS Interventions consisted of live, synchronous, two‐way videoconferencing communication in nonhospital settings. All medical interventions were included. MEASUREMENTS Quality assessment, using the Cochrane Collaboration's Risk‐of‐Bias Tool, was applied on all included articles, including a qualitative summary of all articles. RESULTS Of 6616 citations, we reviewed the full text of 1173 articles, excluding 1047 that did not meet criteria. Of the 17 randomized controlled trials, the United States was the country with the most trials (6 [35%]), with cohort sizes ranging from 3 to 844 (median = 35) participants. Risk of bias among included studies varied from low to high. Our qualitative analysis suggests that TMed can improve health outcomes in older adults and that it could be used in this population. CONCLUSIONS TMed is feasible and acceptable in delivering care to older adults. Research should focus on well‐designed randomized trials to overcome the high degree of bias observed in our synthesis. Clinicians should consider using TMed in routine practice to overcome barriers of distance and access to care. J Am Geriatr Soc 67:1737–1749, 2019