This is an initial submission of a K23 application by Dr. Marciana Laster from the University of California, Los Angeles (UCLA). Candidate: Dr. Laster?s training objectives in this proposal include to: 1) develop expertise in the physiology and genetics of the PTH-Vitamin D axis, 2) gain further skills in the management of epidemiologic data, principles of genetic association studies and advanced bio-statistical approaches and 3) develop expertise in the assessment of bone turnover by bone histomorphometry. Dr. Laster will accomplish these activities through mentorship, coursework and participation in workshops. She has assembled a team of scientists including her primary mentor Dr. Isidro Salusky, an expert in pediatric CKD-MBD and co-mentor Dr. Ravi Thadhani, an expert in Vitamin D metabolism. Research: Pediatric CKD-MBD affects nearly all pediatric patients with CKD by the time they reach dialysis. Despite years of treatment with active Vitamin D sterols, skeletal morbidity and cardiovascular mortality remain unacceptably high. Dr. Laster?s long-term goal is to individualize the treatment of pediatric CKD-MBD in order to improve the health and quality of life of pediatric CKD patients. The first step toward accomplishing this goal involves the identification of genetic variants that predict PTH levels and skeletal response to PTH levels. Dr. Laster hypothesizes that the risk of secondary hyperparathyroidism and the degree of PTH responsiveness in CKD are predicted by genetic variation in the Vitamin D Receptor (VDR) gene, which mediates PTH release and osteoclast activity, and the Vitamin D Binding Protein (VDBP) gene, which mediates vitamin D transport and osteoclast activity. In Dr. Laster?s preliminary work she demonstrated clinical outcomes suggestive of underlying PTH resistance amongst African-Americans. A genetic basis of this PTH resistance is supported by studies demonstrating select genetic variants found frequently amongst African-Americans which are associated with a clinical picture suggestive of PTH resistance.
In Aim 1, Dr. Laster will identify SNPs within the VDR and VDBP genes that explain variation in PTH levels using a pre-dialysis CKD cohort of 1076 patients and a dialysis cohort of 100 patients.
This aim will establish how SNPs in the VDR and VDBP associate with serum PTH levels in the pediatric CKD population.
In Aim 2, Dr. Laster will identify SNPs in the VDR and VDBP that explain variation in PTH-adjusted bone turnover.
This aim will establish SNPs that are associated with a variable response of bone to elevations in PTH (i.e. PTH resistance).
In Aim 3, Dr. Laster will perform a genome wide association study in the 1076 pediatric pre-dialysis CKD patients in order to identify novel SNPs that explain variation in PTH levels. Dr. Laster?s aims will help to establish a phenotype of skeletal response that can then be used to individualize the intensity of pediatric CKD-MBD therapy.
Pediatric Chronic Kidney Disease-Mineral Bone Disorder is a comorbidity of CKD that impacts the skeletal and cardiovascular health of pediatric patients. Unfortunately, despite the importance of this entity, our current treatment guidelines do not enable individualized therapy despite evidence that a one-size fits all approach is inadequate. This proposal seeks to identify genetic variants that predict skeletal behavior in pediatric CKD- MBD and thereby allow the individualization of therapy.
