Dataset Information

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.

SUBMITTER: Izquierdo ME

PROVIDER: S-EPMC9443928 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Izquierdo Manuel E ME Marion Chad R CR Moore Wendy C WC Raraigh Karen S KS Taylor-Cousar Jennifer L JL Cutting Gary R GR Ampleford E E Hawkins Gregory A GA Zein Joe J Castro M M Denlinger Loren C LC Erzurum Serpil C SC Fahy John V JV Israel Elliot E Jarjour Nizar N NN Mauger David D Levy Bruce D BD Wenzel Sally E SE Woodruff Prescott P Bleecker Eugene R ER Meyers Deborah A DA Ortega Victor E VE

Pediatric pulmonology 20220505 7

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>We ...[more]

PMID: 35451201

Similar Datasets

Project description:Background: Most cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to protein misfolding and degradation by the ubiquitin-proteasome system. Previous studies demonstrated that PIAS4 facilitates the modification of wild-type (WT) and F508del CFTR by small ubiquitin-like modifier (SUMO)-1, enhancing CFTR biogenesis by slowing immature CFTR degradation and producing increased immature CFTR band B. Methods: We evaluated two correction strategies using misfolding mutants, including the common variant, F508del. We examined the effects on mutant expression of co-expression with PIAS4 (E3 SUMO ligase), and/or the corrector, C18. To study the impact of these correction conditions, we transfected CFBE410- cells, a bronchial epithelial cell line, with a CFTR mutant plus: (1) empty vector, (2) empty vector plus overnight 5 μM C18, (3) PIAS4, and (4) PIAS4 plus C18. We assessed expression at steady state by immunoblot of CFTR band B, and if present, band C, and the corresponding C:B band ratio. The large PIAS4-induced increase in band B expression allowed us to ask whether C18 could act on the now abundant immature protein to enhance correction above the control level, as reported by the C:B ratio. Results: The data fell into three mutant CFTR categories as follows: (1) intransigent: no observable band C under any condition (i.e., C:B = 0); (2) throughput responsive: a C:B ratio less than control, but suggesting that the increased band C resulted from PIAS4-induced increases in band B production; and (3) folding responsive: a C:B ratio greater than control, reflecting C18-induced folding greater than that expected from increased throughput due to the PIAS4-induced band B level. Conclusion: These results suggest that the immature forms of CFTR folding intermediates occupy different loci within the energetic/kinetic folding landscape of CFTR. The evaluation of their properties could assist in the development of correctors that can target the more difficult-to-fold mutant conformations that occupy different sites within the CFTR folding pathway.

Dataset Information

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

Background

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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