Manuel E Izquierdo1, Chad R Marion2, Wendy C Moore3, Karen S Raraigh4, Jennifer L Taylor-Cousar5, Gary R Cutting6, E Ampleford7, Gregory A Hawkins8, Joe Zein9, M Castro10, Loren C Denlinger11, Serpil C Erzurum12, John V Fahy13, Elliot Israel14, Nizar N Jarjour15, David Mauger16, Bruce D Levy14, Sally E Wenzel17, Prescott Woodruff18, Eugene R Bleecker19, Deborah A Meyers20, Victor E Ortega21. 1. Wake Forest Baptist Medical Center, Winston Salem, North Carolina, USA. 2. Department of Internal Medicine, Wake Forest University, Winston Salem, North Carolina, USA. 3. Wake Forest Sch of Med, Winston-Salem, North Carolina, USA. 4. Johns Hopkins, Baltimore, Maryland, USA. 5. Department of Medicine and Pediatrics, National Jewish Health, Denver, Colorado, USA. 6. Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA. 7. Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 8. Center for Precision Medicine, Wake Forest Baptist Health, Winston Salem, North Carolina, USA. 9. Departments of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA. 10. Pulmonary Critical Care & Sleep Medicine, University of Kansas, Kansas City, Missouri, USA. 11. Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA. 12. Cleveland Clinic Foundation, Cleveland, Ohio, USA. 13. Pulmonary and Critical Care Medicine, University of California At San Francisco, San Francisco, California, USA. 14. Brigham and Womens Hospital, Boston, Massachusetts, USA. 15. University of Wisconsin Hospitals & Clinics, Madison, Wisconsin, USA. 16. Pennsylvania State University, Pennsylvania, USA. 17. Medicine PACCM, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 18. Department of Medicine, University of California, San Francisco, San Francisco, California, USA. 19. Department of Medicine, University of Arizona, Tucson, Arizona, USA. 20. Department of Genetics, Genomics, and Precision Medicine, University of Arizona, Tucson, Arizona, USA. 21. Mayo Clinic, Scottsdale, Arizona, USA.
Abstract
BACKGROUND: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. OBJECTIVE: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort. METHODS: We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency < 0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2. org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. RESULTS: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5 T; TG12[c.1210-11 T > G] and one Arg1070Trp) and a homozygote for the VVCC, 5 T; TG12. CONCLUSIONS: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort, including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.
BACKGROUND: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. OBJECTIVE: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort. METHODS: We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency < 0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2. org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. RESULTS: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5 T; TG12[c.1210-11 T > G] and one Arg1070Trp) and a homozygote for the VVCC, 5 T; TG12. CONCLUSIONS: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort, including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.
Authors: Peter G Middleton; Marcus A Mall; Pavel Dřevínek; Larry C Lands; Edward F McKone; Deepika Polineni; Bonnie W Ramsey; Jennifer L Taylor-Cousar; Elizabeth Tullis; François Vermeulen; Gautham Marigowda; Charlotte M McKee; Samuel M Moskowitz; Nitin Nair; Jessica Savage; Christopher Simard; Simon Tian; David Waltz; Fengjuan Xuan; Steven M Rowe; Raksha Jain Journal: N Engl J Med Date: 2019-10-31 Impact factor: 91.245
Authors: Anne Orholm Nielsen; Sadaf Qayum; Pierre Nourdine Bouchelouche; Lars Christian Laursen; Ronald Dahl; Morten Dahl Journal: J Cyst Fibros Date: 2016-06-17 Impact factor: 5.482
Authors: H G de Vries; J M Collée; H E de Walle; M H van Veldhuizen; C T Smit Sibinga; H Scheffer; L P ten Kate Journal: Hum Genet Date: 1997-01 Impact factor: 4.132