Genetic Modifiers and Diagnostics for Bone Health in Cystic Fibrosis

PROJECT SUMMARY/ABSTRACT Osteoporotic fractures increase morbidity and mortality in people with CF; vertebral fractures are the most common osteoporotic fracture in people with CF. Diagnosing CF osteoporosis is hindered by two critical gaps: the current standard of care (use of dual energy X-ray absorptiometry, DXA) has poor sensitivity for fracture in people with CF and fracture risk strata have not been defined in this population. Beyond DXA, other genetic and imaging data are used to predict fracture risk in people without CF. Genetics explains 50% of variation in vertebral fractures; genetic modifiers alter non-CF osteoporosis risk, but genetic modifiers specific to CF osteoporosis have not yet been identified. Volumetric bone density (vBMD) by CT is superior to bone density by DXA in predicting vertebral fracture in non-CF populations, but has not yet been investigated in people with CF. Identification of genetic modifiers associated with CF osteoporosis and building prediction models for osteoporosis using quantitative measures of bone strength derived from CT imaging can address this critical knowledge gap in CF osteoporosis. To test the hypothesis that genetic modifiers and imaging biomarkers will identify people with CF at highest risk for vertebral fracture, I will conduct three aims: 1) discover genetic modifiers of CF osteoporosis through candidate and genome wide association study approaches, 2) examine the relationship of volumetric bone density and vertebral fracture in people with CF, and 3) explore the association of genetic modifiers, volumetric bone density and vertebral fracture. Data generated will enable identification of people with CF at highest risk for vertebral fracture and be preliminary data for future R01 applications. This proposal will support the training of Dr. Malinda Wu, a pediatric endocrinologist, who is dedicated to an academic career studying osteoporosis, using CF as the model. During the K23 award period, she will acquire requisite skills in clinical and translational investigation through formal coursework and workshops, attendance of conferences and seminars, personalized mentoring and hands-on research experience. Dr. Wu will be mentored by Dr. Scott Blackman, expert in genetic modifiers of CF complications, and Dr. Janet Crane, expert in bone biology. She has assembled a diverse team of experts with the skills, resources, and expertise to guide her to successfully complete this project. In summary, the research and training plan proposed in this K23 application will broaden our understanding of CF osteoporosis which has implications for non-CF osteoporosis and provide the necessary training and investigational niche for Dr. Wu to develop a successful, independent career in research.