January 15, 2010
On a mid-May morning last year, pediatric endocrinologist Scott Blackman raised a number of questions regarding the relationship of diabetes and cystic fibrosis. Are CF patients susceptible to diabetes? If so, how? Do treatments for CF put them more at risk for diabetes? And do treatments for diabetes affect the status of their CF? Does diabetes increase the severity of lung disease in CF patients?
The questions seemed endless and critically important, Blackman suggested, noting that 25 percent of CF patients ages 10-19 – and 40 percent of CF patients over age 40 – have diabetes. But the answers may have more to do with so-called modifier genes – genes other than the CF gene, CFTR – that may affect how the body responds to conditions that develop as the result of the defective CFTR. That ground, Blackman added, has been broken by Johns Hopkins geneticist Garry Cutting, who showed in twin and sibling studies that modifier genes, rather than CFTR, are responsible for most of the variability in severity of lung disease in CF patients. Building on those findings, Blackman is seeking out modifier genes related to diabetes in CF patients.
“By studying twins and siblings with cystic fibrosis, we are able to test which features of CF are influenced by modifier genes and which are not,” Blackman reported last May. “Identifying and understanding modifier genes will help us identify new pathways and more effective treatments for CF-related diabetes.”
With Cutting and other collaborators in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, Blackman has found that modifier genes do indeed play a substantial role in diabetes complicating cystic fibrosis (Journal of Clinical Endocrinology Metabolism, April 2009). The first such example, Blackman said, is a variant in TCF7L2, a susceptibility gene for type 2 diabetes in people who do not have CF, which has a significant effect on diabetes risk in CF patients (see Diabetologia, September 2009).
“Although non-genetic factors contribute to risk of worse outcomes,” Blackman said, “genetic modifiers are the primary cause of diabetes in CF.”
In time, such findings should translate into improved health and survival and quality of life for CF patients with CF, as outcomes studies show they have worse lung function and shorter survival than CF patients who do not have diabetes. What modifier genes reveal will also likely influence when and how to treat – or not treat – CF patients with diabetes.
“Maybe we want to give insulin to patients we normally wouldn’t give insulin? Or maybe there’s a benefit in treating diabetes in the CF patient earlier?” Blackman concluded. “By identifying new pathways and increasing our understanding of the relationship between diabetes and CF, we can better identify at-risk patients and individualize therapy.”