Investigators at the Hebrew University of Jerusalem (Israel) designed a stepwise study to search for disease-contributing DNA methylation variations. First, a pool based, genome-scale screen was carried out among 1169 type II diabetes cases and control individuals. Next, in-depth analyses were performed at selected top-ranking regions.
Results published in the January 15, 2012, online edition of the journal Human Molecular Genetics revealed an excess of differentially methylated sites in genomic regions that were previously associated with type II diabetes through genetic studies. A clear-cut region of hypomethylation was identified in the DNA of the type II diabetes cases relative to controls. The effect was independent of the sequence polymorphism in the region and persisted among individuals carrying the sequence-risk alleles. The odds of belonging to the type II diabetes group were increased by 6.1% for every 1% decrease in methylation.
A prospective study carried out in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to type II diabetes, relative to the individuals who stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators.
The data uncovered by this study showed that, “Low methylation levels at the analyzed sites were an early marker of type II diabetes and pointed to a novel mechanism by which early-onset, interindividual methylation variation at isolated nonpromoter genomic sites predisposes to type II diabetes.”
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