Genome-wide association studies have identified at least 9 genetic loci whose variation influences risk for type 2 diabetes. The mechanisms by which they cause disease remain to be elucidated. However, diabetes occurring as a complication of other diseases may involve some of the same mechanisms as type 2 diabetes, allowing studies of one disease to inform the other. Cystic fibrosis (CF) is a genetic disease involving the exocrine pancreas in which patients develop diabetes at a high rate as they reach adolescence and young adulthood. Using data from the U.S. CF Twin and Sibling study, we have shown that genetic modifiers (other than the gene that causes CF) are the primary cause of diabetes in CF. Also, we showed that CF patients with a family history of type 2 diabetes have a three-fold greater risk of developing diabetes themselves. These findings indicate that the same genes may affect diabetes susceptibility in both CF patients and in the general population. Indeed, we have shown that a susceptibility gene for type 2 diabetes, TCF7L2, is associated with increased risk for diabetes in CF in two independent study groups. Thus, diabetes susceptibility genes of low effect in the general population may play a key role in this important complication of CF. The overall goals of this proposal are to identify genetic modifiers for diabetes in CF, assess their role in type 2 diabetes, and delineate important factors influencing their impact on disease. These goals will be met by performing a high-density genome-wide scan for association with diabetes in C Fin a large group of recruited CF patients and families. Variants associated with diabetes in CF will be tested in already characterized type 2 diabetes study groups, and previously identified type 2 diabetes variants will be tested in CF patients. Finally, we will identify the impact of clinical and environmental factors on the effect of TCF7L2 and other identified variants, using study groups recruited specifically for high-quality diabetes-related information such as BM1, steroid use, and oral glucose tolerance test results. This information will allow early identification of CF patients at high risk for diabetes, will allow testing of therapies with regards to underlying genetic profile, and will improve our understanding of diabetes not only for CF patients but for diabetes in the general population. PUBLIC HEALTH RELEVANCE: Characterization of modifier genes for diabetes in CF will improve targeting and individualization of diabetes screening and therapy for CF patients, will allow tests of new therapies to be interpreted in light of a patient's underlying genetic profile, and will improve our understanding of diabetes not only for CF patients but for diabetes in the general population.