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Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood

ABSTRACT: Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1,169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranked regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (p=0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR=1.061, 95% CI: 1.032-1.090), and the sensitivity (AUC = 0.638, 95% CI: 0.586-0.690), (Males=0.675, Females=0.609), was better than of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals that stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM, and suggest a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33032 | GEO | 2011/10/18

SECONDARY ACCESSION(S): PRJNA149541

REPOSITORIES: GEO

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Project description:Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1,169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranked regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (p=0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR=1.061, 95% CI: 1.032-1.090), and the sensitivity (AUC = 0.638, 95% CI: 0.586-0.690), (Males=0.675, Females=0.609), was better than of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals that stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM, and suggest a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM. Five pools of DNA samples consist of 710 T2DM patients and 459 control individuals were analyzed for average methylation levels at 1,461,753 DNA genomic fragments containing 3,359,645 CpG methylation sites using four SNP arrays for each sample, two 'genomic' (before treatment) replicates and two MSRE (treatment with a cocktail of five methyl-sensitive-restriction-enzyme) replicates. The analysis was done using the Affymetrix SNP 6.0 array.

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Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood

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