Impact of Genetics on Endocrine Manifestations of Cystic Fibrosis

Cystic fibrosis (CF) is a monogenic multisystem disorder. Endocrine complications of CF are common and include diabetes, growth disorders, and bone disease among others. CF endocrinopathies may be influenced by 2 classes of genetic factors: (1) disease-causing cystic fibrosis transmembrane receptor (CFTR) variants that determine the level of CFTR dysfunction, and (2) variants in other genes throughout the genome known as genetic modifiers. This review highlights the impact of these genetic factors on selected endocrine manifestations of CF. CF-related diabetes (CFRD): CFRD is dependent on both variation at CFTR and genetic modifiers. Some genetic modifiers identified for CFRD influence non-CF forms of diabetes, eg, type 2 diabetes, highlighting overlapping pathophysiology, while others appear to be unique to CFRD. Other CFRD modifiers influence multiple CF manifestations, suggesting influence of the CF disease process itself. Growth disorders: Genetic investigations of growth and nutritional status have likewise identified both CFTR and non-CFTR genetic influences, with the latter revealing overlapping as well as distinct pathophysiological mechanisms involved in weight regulation in the general population. CF-related bone disease: Fewer CF-related bone disease studies have been conducted, but osteoporosis in the general population is a highly heritable trait with more than 1000 genetic modifiers already identified. Like studies of diabetes and growth, identifying genetic modifiers of osteoporosis-related traits in CF will likely reveal how pathophysiology of CF and non-CF bone disease is overlapping or distinct. Consideration of genetic influences on CF endocrinopathy can lead to better understanding for these endocrine manifestations in and outside of CF.