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

• Published in: PloS one 2020-06, Vol.15 (6), p.e0234578-e0234578
• Main Authors: Sae-Lee, Chanachai, Biasi, Julien De, Robinson, Natassia, Barrow, Timothy M, Mathers, John C, Koutsidis, Georgios, Byun, Hyang-Min
• Format: Article
• Language: English
• Subjects: Age; Alu elements; Alzheimer's disease; Biology and life sciences; Biomarkers; Cancer; Carbon; Cognitive ability; Complications and side effects; Cyanocobalamin; Datasets; Dementia; Dementia disorders; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diet; Dietary supplements; DNA; DNA methylation; DNA probes; DNA sequencing; Epigenetics; Folic acid; Gene mapping; Gene regulation; Genes; Genetic aspects; Genomes; Genomic instability; Genotypes; Health aspects; Health sciences; Homocysteine; Life sciences; Loci; Long interspersed nucleotide elements; Mapping; Medicine and Health Sciences; Metabolism; Methylation; Methylenetetrahydrofolate reductase; Nervous system; Neurodegenerative diseases; Older people; Physical Sciences; Probes; Risk; Risk factors; Studies; Type 2 diabetes; Vitamin B; Vitamin B12
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0234578

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 B.sub.12 . 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 [mu]g/day) and vitamin B.sub.12 (500 [mu]g/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 (P.sub.FDR < 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 B.sub.12, 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.