loading page

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

Corresponding Author:[email protected]

Author Profile
Chad R. Marion
Wake Forest University Section of General Internal Medicine
Author Profile
Wendy Moore
Wake Forest University School of Medicine
Author Profile
Karen Raraigh
Johns Hopkins Medicine Office of Johns Hopkins Physicians
Author Profile
Jennifer Taylor-Cousar L
National Jewish Health Department of Medicine
Author Profile
Gary Cutting
Johns Hopkins University School of Medicine
Author Profile
E. Ampleford
Wake Forest University Section of General Internal Medicine
Author Profile
Gregory A. Hawkins
Wake Forest Baptist Medical Center
Author Profile
Joe Zein
Cleveland Clinic
Author Profile
Mario Castro
The University of Kansas Hospital
Author Profile
Loren C. Denlinger
University of Wisconsin-Madison Department of Medicine
Author Profile
Serpil Erzurum
Cleveland Clinic
Author Profile
John Fahy
University of California San Francisco
Author Profile
Elliot Israel
Brigham and Women's Hospital Channing Division of Network Medicine
Author Profile
Nizar Jarjour
University of Wisconsin Hospitals and Clinics
Author Profile
David Mauger
The Pennsylvania State University - University Park Campus
Author Profile
Bruce D. Levy
Brigham and Women's Hospital Channing Division of Network Medicine
Author Profile
Sally Wenzel
University of Pittsburgh School of Medicine
Author Profile
Prescott Woodruff
University of California San Francisco
Author Profile
Eugene Bleecker
The University of Arizona College of Medicine Tucson
Author Profile
Deborah A. Meyers
The University of Arizona College of Medicine Tucson
Author Profile
Victor E. Ortega
Mayo Clinic Scottsdale
Author Profile

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