DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program

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

Affiliations

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.

PMID: 35451201
PMCID: PMC9443928
DOI: 10.1002/ppul.25939

DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program

Manuel E Izquierdo et al. Pediatr Pulmonol. 2022 Jul.

. 2022 Jul;57(7):1782-1788.

doi: 10.1002/ppul.25939. Epub 2022 May 5.

Authors

Affiliations

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.

PMID: 35451201
PMCID: PMC9443928
DOI: 10.1002/ppul.25939

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.

Keywords: Asthma; CF-Asthma Overlap; CFTR; cystic fibrosis; heterozygote carriers.

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Figures

**Figure 1.. Flow diagram for methods**
Flow diagram for characterization, selection, and analyses of individuals. Definition of abbreviations are as follows: CFTR=cystic fibrosis transmembrane regulator gene, CFTR2=clinical and functional translation of CFTR project, SARP=severe asthma research program, ED=emergency department, in-del-insertion deletion, CF-C=cystic fibrosis causing, VVCC=variants of varying clinical consequences, ACMG=American College of Medical Genetics, MAF=Minor allele frequency, AA=African American, NHW=non-Hispanic white.

See this image and copyright information in PMC

References

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DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program

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DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program

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