@article{090ecb35b0b5455699e80dd5a0fde394,
title = "DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program",
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",
author = "Izquierdo, {Manuel E.} and Marion, {Chad R.} and Moore, {Wendy C.} and Raraigh, {Karen S.} and Taylor-Cousar, {Jennifer L.} and Cutting, {Gary R.} and E. Ampleford and Hawkins, {Gregory A.} and Joe Zein and M. Castro and Denlinger, {Loren C.} and Erzurum, {Serpil C.} and Fahy, {John V.} and Elliot Israel and Jarjour, {Nizar N.} and David Mauger and Levy, {Bruce D.} and Wenzel, {Sally E.} and Prescott Woodruff and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Ortega, {Victor E.}",
note = "Funding Information: X01 from the NHLBI for TOPMed whole‐genome sequencing and NIH grants R01 HL142992, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109250, U10 HL109250, U10 HL109168, U10 HL109152, U10 HL109086, and U10 HL109046. Funding Information: Dr. Izquierdo has nothing to disclose, Dr. C.R. Marion has nothing to disclose, Dr. Moore reports grants from NIH/NHLBI, grants from AstraZeneca, Boehringer‐Ingelheim, Genentech, GlaxoSmithKline, Sanofi‐Genzyme‐Regeneron, and Teva during the conduct of the study; grants and personal fees from AstraZeneca, and Sanofi Regeneron, grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Gossamer, and Cumberland Pharmaceuticals outside the submitted work; Karen S. Raraigh has nothing to disclose, Dr. Taylor‐Cousar: received grants from Vertex Pharmaceuticals Incorporated, Gilead, N30, Celtaxsys, Proteostasis, and Bayer; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design, participation on advisory boards, and speaking engagements; has received speaking fees from Celtaxsys; and has served on advisory boards and/or provided consultation for Novartis, Genentech, Gilead, Protalix, Santhera, 4DMT, AbbVie, and Proteostasis; Dr. Cutting has nothing to disclose; Dr. Ampleford has nothing to disoclose; Dr. Hawkins has nothing to disclose, Dr. Zein has nothing to disclose, Dr. Castro receives University Grant Funding from NIH, American Lung Association, PCORI, Pharmaceutical Grant Funding from AstraZeneca, Chiesi, Novartis, GSK, Sanofi‐Aventis; consultant fees for Genentech, Theravance, VIDA, Teva, Sanofi‐Aventis, is a speaker for AstraZeneca, Genentech, GSK, Regeneron, Sanofi, & Teva, and receives Royalties from Elsevier; Dr. Denlinger has grants from NIH/NHLBI and has consulted with AstraZeneca and Sanofi‐Regeneron during the conduct of the study; the extension of the longitudinal phase of the SARP cohort has also been supported by AstraZeneca, Boehringer‐Ingelheim, Genentech, GSK, Sanofi‐Genzyme‐Regeneron, and TEVA; Dr. Erzurum reports grants from National Institutes of Health (NIH), during the conduct of the study; and Chair of the ABIM Pulmonary Disease Board; Dr. Fahy reports grants from NIH/NHLBI, grants from Boehringer Ingelheim during the conduct of the study; personal fees from Boehringer Ingelheim, Pieris, Arrowhead Pharmaceuticals, and Gossamer outside the submitted work, in addition, Dr. Fahy has a patent US20110123530A1 ‐ “Compositions and methods for treating and diagnosing asthma” issued, a patent WO2014153009A2 ‐Thiosaccharide mucolytic agents. issued, and a patent WO2017197360 ‐ “CT Mucus Score” ‐ A new scoring system that quantifies airway mucus impaction using CT lung scans; Dr. Israel reports personal fees from AstraZeneca, Biometry, Entrinsic Health Solutions, Equillium, Genentech, GlaxoSmithKline, Merck, Novartis, 4D Pharma, Pneuma Respiratory, Regeneron Pharmaceuticals, Sanofi Genzyme, Sienna Biopharmaceutical, TEVA Specialty Pharmaceuticals, and Vitaeris, Inc; grants from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Merck, Novartis, Sanofi, TEVA and Vifor‐Pharma; nonfinancial support from Circassia, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Merck, TEVA Specialty Pharmaceuticals and Vifor‐Pharma; other from Vorso Corp, outside the submitted work; Dr. Jarjour has grants from NIH/NHLBI and has consulted with AstraZeneca and Boehringer Ingelheim, and during the extension of the longitudinal phase of the SARP cohort has also been supported, in part, by AstraZeneca, Boehringer‐Ingelheim, Genentech, GSK, Sanofi‐Genzyme‐Regeneron, and TEVA; Dr. Mauger reports grant support from the NIH, AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Sanofi‐Genzyme‐Regeneron, and Teva. L. C. Dr. Levy reports grants from NIH during the conduct of the study; other from Nocion Therapeutics, from Entrinsic Health, grants and personal fees from Sanofi, personal fees from Pieris Pharmaceuticals, Novartis, AstraZeneca, Corbus Pharmaceuticals, Gossamer Bio, Metera Pharmaceuticals, and Teva, and grants from Samsung Research America outside the submitted work; Dr. Wenzel reports grants from NIH and personal fees from AstraZeneca, grants and personal fees from GSK during the conduct of the study; grants and personal fees from Sanofi‐Regeneron, grants from Boehringer Ingelheim, Novartis, and TEVA, and personal fees from Pieris outside the submitted work; Dr. Woodruff is a consultant for Astra Zeneca, Theravance, Glenmark pharmaceuticals, Sanofi and Regeneron and has received funding from Genetech and the COPD Foundation, Dr. Bleecker reports other from NIH grant, clinical trials through his employer, Wake Forest School of Medicine and University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Johnson and Johnson (Janssen), Novartis, Regeneron, and Sanofi Genzyme, personal fees also serving as a paid consultant for AztraZeneca, MedImmune, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme outside the submitted work; Dr. Meyers has nothing to disclose; Dr. Ortega reports grants from NIH, personal fees from CSL Behring, outside the submitted work. Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC.",
year = "2022",
month = jul,
doi = "10.1002/ppul.25939",
language = "English (US)",
volume = "57",
pages = "1782--1788",
journal = "Pediatric Pulmonology",
issn = "8755-6863",
publisher = "Wiley-Liss Inc.",
number = "7",
}