Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets

Abstract

BackgroundGenome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes.ResultsWe identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non-fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose.ConclusionsThese data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes.

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

“…47 It has measurable protein expression in normal human biliary epithelial cells, 48 and was identified in GWAS studies for type 2 diabetes. 49,50 Sox4 is a member of the SRY-related HMG-box family of transcription factors expressed in human hepatocytes 48 and is required for biliary tract development in mice. 51 It is overexpressed in and prognostic of several cancers, including cholangiocarcinoma and hepatocellular carcinoma.…”

Composite selection signals can localize the trait specific genomic regions in multi-breed populations of cattle and sheep

“…The associated gene pair has been known for its role in insulin-related metabolic traits [79]. In European cattle, these genes may be involved in several metabolic pathways for sufficient availability of energy for improved growth, production and maintaining body temperature in a temperate environment.…”

JAZF1, a relevant metabolic regulator in type 2 diabetes

“…The JAZF1 gene is present in a wide variety of tissues, but it is predominantly expressed in insulin responsive organs such as liver, fat, skeletal muscle, and pancreas . JAZF1 expression pattern is altered in certain pathological conditions such as obesity, diabetes, and hepatic steatosis .…”

“…Nutritional regulation plays an important role in regulating JAZF1 expression. Feeding behaviour significantly decreases mouse JAZF1 expression in the liver, but increases its expression in the hypothalamus . Future studies are needed to assess how food intake modulates JAZF1 expression in different tissues.…”