Genetic Modifiers of Cystic Fibrosis-Related Diabetes

Adolescents and adults with cystic fibrosis (CF) are at high risk to develop an insulin-deficient form of diabetes (CF-related diabetes, or CFRD) over time, and having CFRD worsens lung disease and shortens lifespan in CF. The age of onset of CFRD varies widely, essentially from 10 to 60 years of age, and our group demonstrated that this variation is caused by genes other than CFTR.

We identified five risk genes, a.k.a., genetic modifiers of CFRD, including four genes associated with type 2 diabetes (T2D), which identify areas of overlapping pathophysiology for CFRD and T2D. One modifier gene encodes a channel protein known to associate with CFTR, suggesting that it could affect multiple aspects of CF disease. Multiple follow-up projects include:

  1. To better understand how genetic modifiers influence the underlying metabolic abnormalities (such as insulin deficiency or insulin resistance), we are measuring profiles of multiple hormones during glucose tolerance testing in people with CF.
  2. We are conducting a follow-up genome-wide association study to identify new CFRD risk genes.
  3. We are also investigating how gene variants affect other metabolic problems in CF, such as poor weight gain (or obesity).
  4. We are analyzing the relationship between the CF-causing mutations in CFTR with the risk of diabetes using data from the CFTR2 study, a study of >90,000 individuals with CF.
  5. Other research projects are aimed at understanding the relationship between CF-related liver disease and CFRD, and the effect of prediabetes (including impaired fasting glucose) on outcomes in CF.