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Lookup NU author(s): Chanachai Sae-Lee, Natassia Robinson, Professor John Mathers, Dr Hyang-Min ByunORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) and Alu, comprise ~40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 and Alu methylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 and Alu elements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 μg/day) and vitamin B12 (500 μg/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (PFDR < 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of all Alu probes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, including GNB5, GNG7 and PKN3 (p < 0.05). In older individuals supplemented with folate/vitamin B12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with the MTHFR CC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 and Alu elements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.
Author(s): Sae-Lee C, Biasi J, Robinson N, Barrow TM, Mathers JC, Koutsidis G, Byun H-M
Publication type: Article
Publication status: Published
Journal: PLoS ONE
Year: 2020
Volume: 15
Issue: 6
Online publication date: 11/06/2020
Acceptance date: 28/05/2020
Date deposited: 23/06/2020
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pone.0234578
DOI: 10.1371/journal.pone.0234578
Data Access Statement: All data files are available in Gene Expression Omnibus with the identifiers 10.1016/j.neurobiolaging.2014.12.023 and 10.1186/s13148-015-0154-5 (GSE62300 and GSE74548).
PubMed id: 32525932
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