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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.
Highlights
Type 2 diabetes mellitus (T2D) is a metabolic disease affecting more than 200 million people worldwide in 2010, and global prevalence is predicted to increase to more than 400 million people by 2030 [1]
A total of 9,139 probes mapping to long interspersed nuclear element 1 (LINE-1) elements and 12,339 probes mapping to Alu sequences on the 450K array were analysed in relation to pre-symptomatic dementia (PSD)
We identified 714 loci mapping to retrotransposons (LINE-1 and Alu) that were differentially methylated in T2D patients with PSD compared to those with normal cognitive function, with such changes enriched within older families (L1M, AluJ, and AluS)
Summary
Type 2 diabetes mellitus (T2D) is a metabolic disease affecting more than 200 million people worldwide in 2010, and global prevalence is predicted to increase to more than 400 million people by 2030 [1]. Epigenetic changes occur during cognitive dysfunction and the development of dementia in T2D patients and, have potential as disease biomarkers. LINE-1 and Alu methylation has been widely measured as surrogate marker for global DNA methylation [15, 21,22,23,24,25]. Hypomethylation of these elements is associated with genomic instability [26] and occurs in multiple diseases including cancer [15, 22, 27] and AD [28]. We hypothesise that DNA methylation changes within LINE-1 or Alu elements are potential novel markers of early-stage dementia in T2D
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