Significance: We provide a comprehensive catalog of novel genetic variants influencing gene expression and metabolic phenotypes in human pancreatic islets. The data also show that the path from genetic variation (SNP) to gene expression is more complex than hitherto often assumed, and that we need to consider that genetic variation can also influence function of a gene by influencing exon usage or splice isoforms (sQTL), allelic imbalance, RNA editing, and expression of noncoding RNAs, which in turn can influence expression of target genes.

To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH⁺) or without (FH⁻) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH⁺ compared with FH⁻ men. We further validated our findings from FH⁺ men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH⁺ men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH⁺ and FH⁻ individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10⁻⁶) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

Ratting Out a Diabetes Gene: Inbred animals with inherited susceptibility to disease can be especially informative regarding pathogenetic mechanisms because they carry naturally occurring genetic variants of the same type that cause disease in humans. This principle is illustrated byRosengrenet al.(p.217; published online 19 November), whose analysis of an inbred strain of rats prone to develop type 2 diabetes led to the discovery of a gene whose aberrant overexpression suppresses pancreatic insulin secretion in both rats and humans. The culprit gene, ADRA2A, encodes the alpha2A adrenergic receptor and is potentially a valuable lead for diabetes therapy because it can be targeted pharmacologically.