Citations 1
DNA Sequencing Analysis of Cystic Fibrosis Transmembrane Regulator Gene Identifies Cystic Fibrosis-Associated Variants in the Severe Asthma Research Program.
Izquierdo, Manuel, Marion, Chad R. , Moore, Wendy C. , Raraigh, Karen S. , L, Jennifer Taylor-Cousar, Cutting, Garry R. , Ampleford, Elizabeth J., Hawkins, Gregory A., Zein, Joe , Denlinger, Loren C. , Erzurum, Serpil C. , Israel, Elliot , Jarjour, Nizar N. , Mauger, David, Woodruff, Prescott G. , Bleecker, Eugene R. , Meyers, Deborah A. , Ortega, Victor E. , Cutting, Gary R , Taylor‐Cousar, Jennifer L. , Castro, Mario , Fahy, John V. , Levy, Bruce David , Wenzel, Sally E.
No container title available | April 19, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
10.22541/au.165037325.52611651/v1
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.