GARRY R. CUTTING, MD PROFESSOR OF MEDICAL GENETICS DIRECTOR OF THE DNA DIAGNOSTIC LABORATORY THE JOHNS HOPKINS UNIVERSITY BALTIMORE, MARYLAND

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1 GARRY R. CUTTING, MD PROFESSOR OF MEDICAL GENETICS DIRECTOR OF THE DNA DIAGNOSTIC LABORATORY THE JOHNS HOPKINS UNIVERSITY BALTIMORE, MARYLAND

2 MODIFIERS OF CYSTIC FIBROSIS

3 LUNG FUNCTION MEASURES IN CF PATIENTS WITH IDENTICAL CFTR GENOTYPES Kerem et al NEJM 1990

4 COMPONENTS CONTRIBUTING TO VARIATION IN CF LUNG DISEASE Variation in = Genes + Environment + Stochastic lung function CFTR Modifier genes Shared Unique

5 APPROACH MZ twins (same genes) DZ twins and siblings (50% different genes) Together (shared environment) Apart (different environment) Unique Env Stochastic Genes and Genes Environment Environment

6 LUNG FUNCTION MEASURES ARE MORE SIMILAR IN MZ TWINS THAN DZ TWINS AND SIBLINGS Twin B Twin or Sibling B Monozygous Twins Same Sex DZ Twins & Siblings <3 Years Difference in Age Twin A r = 0.88, p < Twin or Sibling A r = 0.54, p < Vanscoy et al AJRCCM 2007

7 ARS QUESTION #11 Why might monozygous (ie. identical) twins differ in their severity of CF? 1. Different exposures to viruses 2. Different exposures to second hand smoke 3. Different timing of treatment 4. Different level of compliance 5. All of the above

9 LUNG FUNCTION MEASURES OVER 30 YEARS FOR A PAIR OF MZ TWINS WITH CF Age (Years)

10 LUNG FUNCTION MEASURES ARE MORE SIMILAR IN MZ TWINS THAN DZ TWINS AND SIBLINGS EVEN AFTER LIVING APART FOR 5 YEARS MZ twins Together (r = 0.94) Apart (r = 0.87) Together (r = 0.51) DZ twins/ siblings Apart (r = 0.52)

11 GENETIC AND NON-GENETIC CONTRIBUTIONS TO VARIATION IN CF LUNG FUNCTION 50% 50% Collaco et al J Peds 2010

12 Lung Function ENVIRONMENTAL FACTORS: SECONDHAND SMOKE IS ASSOCIATED WITH WORSE LUNG FUNCTION IN CF < Maximum FEV1CF% Most recent year of data (n = 812) Average FEV1CF%. Minimum 4 yrs (n = 581) Secondhand Smoke No Secondhand Smoke Collaco, JM et al JAMA 2008

ENVIRONMENTAL MODIFIER: MEAN ANNUAL AMBIENT TEMPERATURE 7.4 percentile point increase in FEV 1 (NHANES) Clinic Site B Clinic Site A P. aeruginosa Prevalence: 85.3% Age of Acquisition: 7.6 yrs P.

13 ENVIRONMENTAL MODIFIER: MEAN ANNUAL AMBIENT TEMPERATURE 7.4 percentile point increase in FEV 1 (NHANES) Clinic Site B Clinic Site A P. aeruginosa Prevalence: 85.3% Age of Acquisition: 7.6 yrs P. aeruginosa Prevalence: 92.9% Age of Acquisition: 6.3 yrs Effects of temperature on lung function and infection are largely independent Collaco, M et al, in review

14 ENVIRONMENT-ENVIRONMENT INTERACTION: SECONDHAND SMOKE & AMBIENT TEMPERATURE Lung Function No Secondhand Smoke Secondhand Smoke <50 F F >60 F 40 F 50 F Temperature

15 ARS QUESTION #12 How many genes do humans have? 1. 1 (CFTR) 2. <20, ,000-30, >30,000

16 HOW MANY GENES DO HUMANS HAVE?

17 IDENTIFICATION OF GENETIC MODIFIERS OF LUNG FUNCTION BY CANDIDATE APPROACHES Mannose binding lectin 2 (MBL2) MBL deficiency ( 0 alleles) associated with reduced lung function (Garred JCI 1999), reduced survival (Buranawuti JMG 2006) and early age of infection (Dorfman JCI 2008) Transforming growth factor beta 1 (TGFB1) -509 (TT) and codon 10 (CC) genotypes associated with lower cross-sectional and longitudinal measures of lung function and BMI (Drumm ML, et al. NEJM 2005) Haplotype composed of -509 C, codon 10 T and intron 5 C associated with improved lung function (Bremer et al HMG 2008)

18 TGFB1 SIGNIFICANTLY INCREASES THE DELETERIOUS EFFECT OF EXPOSURE TO SECONDHAND SMOKE Lung function Error bars represent the 95% confidence intervals. The P values refer to t test comparisons between those exposed to secondhand smoke and those who were not exposed. Collaco et al JAMA 2008

19 FINDING NEW MODIFIER GENES

20 QUANTITATIVE LUNG PHENOTYPE: DISTRIBUTION (F508del/F508del = 841)

21 QUANTITATIVE LUNG PHENOTYPE: DISTRIBUTION

22 QUANTITATIVE LUNG PHENOTYPE: DISTRIBUTION

23 A REGION ON CHROMOSOME 11 BETWEEN THE EHF AND APIP GENES MODIFY CF LUNG DISEASE SEVERITY rs286873

24 PREDICTED EFFECT OF MODIFIER LOCI: EHF-APIP REGION Per allele: increase in 0.2 units of the quantitative lung disease phenotype equivalent to % increase FEV 1 percent predicted as calculated as recommended by the U.S. Cystic Fibrosis Foundation or an increase of years. 86mL in subjects older than

25 LOD score A REGION ON CHROMOSOME 20 MODIFIES CF LUNG DISEASE SEVERITY X Chromosome A QTL with a genome-wide significant LOD=5.04 was found on 20q13.2.

26 sib1 lung function sib1 lung function SIBLINGS WHO INHERITED THE SAME VERSIONS OF CHROMOSOME 20 FROM EACH PARENT HAD VERY SIMILAR LUNG FUNCTION MEASUREMENTS Neither chr 20 in common One chr 20 in common Both chr 20 in common sib2 lung function sib2 lung function sib2 lung function

27 SUMMARY Variation in lung function 50% 50% = Genes + Environment + Stochastic CFTR TGFB1 MBL2 IFRD1 EHF-APIP Chr 20 SHS Air Temp

28 VIELEN DANK!

Dan Koller, Ph.D. Medical and Molecular Genetics

Dan Koller, Ph.D. Medical and Molecular Genetics Design of Genetic Studies Dan Koller, Ph.D. Research Assistant Professor Medical and Molecular Genetics Genetics and Medicine Over the past decade, advances from genetics have permeated medicine Identification