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Understanding the Genetic Risk for Type 2 Diabetes

Analyses of genetic variations associated with type 2 diabetes provide insight into how these variations affect an individual’s risk for this disease. An explosion of technologies and tools has enabled researchers to conduct large studies to compare the genomes of thousands of people with and without type 2 diabetes to identify genetic variants that affect the likelihood of developing the disease. Whereas genetic risk for some diseases can be accounted for by a few variants with large effects, the current set of over 60 risk variants for type 2 diabetes only explains a small percentage of the genetic risk for the disease. In addition, how most of these variants alter the risk of type 2 diabetes is unknown. Toward the goal of elucidating the effects of these variants on disease risk, researchers are utilizing a number of different approaches, taking advantage of the latest developments in tools and technologies, as evidenced by two recent studies.

In the first study, scientists hypothesized that identification of additional risk variants and the function of the genes they affect will illuminate a limited set of molecular pathways that influence development of type 2 diabetes. By conducting a meta-analysis in which they pooled data from over 34,000 people with type 2 diabetes and nearly 115,000 people without the disease, the researchers identified 10 previously unreported type 2 diabetes risk variants. Two of the newly discovered associated variants showed sex-differentiated associations; one was more significantly associated with type 2 diabetes in males, and the other in females. The researchers used several analytical approaches to identify pathways and networks that may be involved in the development of type 2 diabetes. The investigators found that some of the key processes influenced by type 2 diabetes risk genes include regulation of cell division, signaling by proteins secreted by fat cells, and regulation of gene activity (whether a gene is turned “on” or “off”) by a protein called CREBBP.

In another study, the researchers focused on assessing the extent to which the previously identified type 2 diabetes genetic risk variants affected the activity of genes that are either nearby or distant from them (often on a different chromosome). Genes are typically regulated in the sense that they can be kept inactive, when not needed, or utilized to varying degrees. The regulatory elements—which typically include DNA near the gene and the proteins that interact with that DNA—are thus analogous to the components of a dimmer switch: they control the extent to which a gene is activated (or “expressed”) in any given cell. The investigators sought to determine which of the known type 2 diabetes risk variants affect expression levels of nearby genes, which affect expression of distant genes, and which have little impact on gene expression. They found that, in general, genetic variants associated with type 2 diabetes affected genes at a distance from the genetic variation itself— either on a different chromosome than that containing the variant or on the same chromosome, but not nearby.

This result is surprising because many researchers assumed that the identified genetic variants altered the activity of a gene or genes in the same chromosomal neighborhood as the variant. Because specific genes are often more active in one tissue than in another, the investigators examined the impact of the type 2 diabetes risk genes on gene expression in multiple tissues involved in the disease. The data revealed many tissue-specific effects, which may eventually help uncover how specific genetic variants exert their effects on disease risk. By increasing understanding of the genetic factors that influence development of type 2 diabetes, researchers hope to use this knowledge to tailor prevention and treatment strategies to individuals and to develop new therapeutic approaches.