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CFTR2 – Part 2 Using CFTR2 to examine how CFTR mutations affect clinical outcome

CFTR2 – Part 2 Using CFTR2 to examine how CFTR mutations affect clinical outcome. Patrick Sosnay on behalf of the CFTR2 team Johns Hopkins University Perdana University Graduate School of Medicine. CFTR Mutations. Cystic Fibrosis. Genotype. Phenotype. CFTR Mutations. Cystic Fibrosis.

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CFTR2 – Part 2 Using CFTR2 to examine how CFTR mutations affect clinical outcome

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  1. CFTR2 – Part 2Using CFTR2 to examine how CFTR mutations affect clinical outcome Patrick Sosnay on behalf of the CFTR2 team Johns Hopkins University Perdana University Graduate School of Medicine

  2. CFTR Mutations Cystic Fibrosis Genotype Phenotype

  3. CFTR Mutations Cystic Fibrosis

  4. Pancreatic status differs by the type of mutation Kristidis P, Bozon D, Corey M et al. Am J Hum Genet. 1992

  5. Pancreatic status can be predicted from mutation class CFTR V. Reduced expression PS IV. Channel function III. Channel activation Golgi PI II. Folding and modification Rough endoplasmic reticulum I. RNA Expression Nucleus Welsh and Smith, Cell, 1993

  6. Incomplete correlation between genotype and phenotype • Good correlation with pancreatic status (insufficient vs. sufficient) • Moderate correlation with sweat chloride concentration when patients are grouped according to pancreatic status • Weak correlation with lung function

  7. Individual mutations do not appear to correlate with lung function NS The Cystic Fibrosis Genotype-Phenotype Consortium NEJM 1993

  8. Specific Genotype Specific Trait Discrete variable: Pancreatic sufficient or pancreatic insufficient Mutations grouped by type or class

  9. Specific Genotype Specific Trait ? Continuous variable: Sweat chloride or lung function Individual mutations

  10. Clinical Data from CFTR2

  11. Specific Genotype Specific Trait Use CFTR function measurements in cell lines as a way of describing genotype Continuous variable: Sweat chloride or lung function 1100 mutations in CFTR2

  12. CFTR chloride channel function correlates with sweat chloride concentration of patients that carry the same mutations R1070Q M470V I148T

  13. CFTR chloride channel function correlates with sweat chloride concentration of patients that carry the same mutations

  14. The relationship between log10 CFTR function and sweat chloride is linear r=0.78, p<0.001

  15. The relationship between log10 CFTR function and lung function is linear r=0.56, p<0.001

  16. Consequences of exponential relationship on lung function and sweat chloride concentration Mean lung function increases 8% predicted (95% CI 4-12) Mean sweat Chloride decreases 27 mEq/L (95% CI 20-33) 0- 5% function

  17. Consequence of exponential relationship on lung function and sweat chloride concentration Mean lung function increases 1.4% predicted (95% CI 0.7-2.1) Mean sweat chloride decreases 4.7 mEq/L (95% CI 3.6-5.8) 5- 10% function

  18. Why is there greater change in sweat chloride than in lung function with restoration of CFTR function? Environment Other genes • CFTR channel function plays a greater role in determining sweat chloride concentration than FEV1

  19. Opportunities for future studies • Collection of clinical data from patients in other regions • To examine global variability • To inform disease liability of rare variants • Correlate genotype with longitudinal measures of lung function and other complications of CF (e.g. lung infection) • Examine the relationship of other CFTR functions (e.g. ENaC regulation, HCO3- transport) with sweat chloride concentration, pancreatic status, and lung function

  20. Summary Data from nearly 40,000 CF patients in the CFTR2 database has been instrumental in: • Increasing the list of clinically, functionally and genetically vetted ‘CF-causing’ mutations from 23 to ~160 (more to follow..) • Demonstrating that CFTR chloride channel function displays an exponential relationship with sweat chloride concentration and lung function. • Revealing that improvement in low function CFTR mutations will have the greatest effect on CF phenotype.

  21. With tremendous gratitude CFTR2 Team: Michelle Lewis Karen Siklosi Johanna Rommens Mary Corey Ruslan Dorfman Julian Zielenski Carlo Castellani Fred Van Goor Phil Thomas, Margarida Amaral, Claude Ferec, Milan Macek, Phil Farrell Adi Gherman, Kyle Kaniecki, Jessica LaRusch, Darci Ferrer, Dave Masica, Kathleen Naughton, Neeraj Sharma Chris Penland Preston Campbell Bruce Marshall Leslie Hazle Cindy George Bob Beall Mentors: Garry Cutting Rachel Karchin Charlie Wiener JHH CF Team: Michael Boyle, Noah Lechtzin, Christian Merlo, Meghan Ramsay, Sue Sullivan, Marsha Davis, Rebecca Smith, Karen VonBerg, Kathie Bukowski

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