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DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes

Lookup NU author(s): Chanachai Sae-Lee, Natassia Robinson, Professor John Mathers, Dr Hyang-Min Byun

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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 Source Location: https://doi.org/10.1016/j.neurobiolaging.2014.12.023 https://doi.org/10.1186/s13148-015-0154-5

PubMed id: 32525932


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