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DNA Sequencing Analysis of Cystic Fibrosis Transmembrane Regulator Gene Identifies Cystic Fibrosis-Associated Variants in the Severe Asthma Research Program.
  • +19
  • Manuel E. Izquierdo,
  • Chad R. Marion,
  • Wendy Moore,
  • Karen Raraigh,
  • Jennifer Taylor-Cousar L,
  • Gary Cutting,
  • E. Ampleford,
  • Gregory A. Hawkins,
  • Joe Zein,
  • Mario Castro,
  • Loren C. Denlinger,
  • Serpil Erzurum,
  • John Fahy,
  • Elliot Israel,
  • Nizar Jarjour,
  • David Mauger,
  • Bruce D. Levy,
  • Sally Wenzel,
  • Prescott Woodruff,
  • Eugene Bleecker,
  • Deborah A. Meyers,
  • Victor E. Ortega
Manuel E. Izquierdo
Wake Forest Baptist Medical Center
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Chad R. Marion
Wake Forest University Section of General Internal Medicine
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Wendy Moore
Wake Forest University School of Medicine
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Karen Raraigh
Johns Hopkins Medicine Office of Johns Hopkins Physicians
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Jennifer Taylor-Cousar L
National Jewish Health Department of Medicine
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Gary Cutting
Johns Hopkins University School of Medicine
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E. Ampleford
Wake Forest University Section of General Internal Medicine
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Gregory A. Hawkins
Wake Forest Baptist Medical Center
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Joe Zein
Cleveland Clinic
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Mario Castro
The University of Kansas Hospital
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Loren C. Denlinger
University of Wisconsin-Madison Department of Medicine
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Serpil Erzurum
Cleveland Clinic
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John Fahy
University of California San Francisco
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Elliot Israel
Brigham and Women's Hospital Channing Division of Network Medicine
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Nizar Jarjour
University of Wisconsin Hospitals and Clinics
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David Mauger
The Pennsylvania State University - University Park Campus
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Bruce D. Levy
Brigham and Women's Hospital Channing Division of Network Medicine
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Sally Wenzel
University of Pittsburgh School of Medicine
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Prescott Woodruff
University of California San Francisco
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Eugene Bleecker
The University of Arizona College of Medicine Tucson
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Deborah A. Meyers
The University of Arizona College of Medicine Tucson
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Victor E. Ortega
Mayo Clinic Scottsdale
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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 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;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.
16 Apr 2022Submitted to Pediatric Pulmonology
19 Apr 2022Assigned to Editor
19 Apr 2022Submission Checks Completed
20 Apr 2022Editorial Decision: Accept
21 Apr 2022Published in Pediatric Pulmonology. 10.1002/ppul.25939