ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Diabetes 2017;66:1713-1722

This study examined whether genetic variants predisposing to T2DM exert their influence on disease via changes in DNA methylation in a young, non-diabetic, cross-sectional cohort. The examination of young subjects who are disease-free enables exploration of SNP-methylation relationships without assessing methylation differences that result from reverse causation. About half of known T2DM SNPs were found to be associated with variation in DNA methylation. To understand whether methylation is a causal pathway to future disease or a non-causal biomarker, the association between the mQTL and diabetes was extracted from 26,488 T2DM cases and 83,964 controls (from DIAGRAM consortium data). For almost all T2DM SNP associations, no evidence was found that methylation is a key pathway for SNP effects on T2DM.

Only one methylation site, that associated with a T2DM risk variant in KCNQ1 (encoding potassium voltage-gated channel KQT-like subfamily, member 1), was found likely to be on the causal pathway to disease in later life. KCNQ1 is a gene encoding the pore-forming subunit of a voltage-gated K+ channel that plays a key role in the repolarization of the cardiac action potential, as well as in water and salt transport in epithelial tissues. Mutations in the KCNQ1 gene cause the long QT syndrome and deafness. KCNQ1 is also expressed in pancreatic islets, and blockade of the channel with KCNQ1 inhibitors stimulates insulin secretion. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. The KCNQ1 gene is located on chromosome 11 in a region containing several imprinted genes that are linked to Beckwith-Wiedemann syndrome. Intronic SNPs in the KCNQ1 genomic region have been associated with lower pancreatic β-cell insulin secretion in individuals with T2DM in a manner dependent on parental origin and hypermethylation of the maternal allele of KCNQ1 is suggested to affect early pancreas development.