| Title: | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| Journal: | npj Genomic Medicine |
| Published: | 8 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35396391/ |
| DOI: | https://doi.org/10.1038/s41525-022-00299-9 |
| URL: | https://www.nature.com/articles/s41525-022-00299-9.pdf |
| Citations: | 10 (8 in last 2 years) as of 8 Aug 2024 |
Publication 12421
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Abstract
Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.</p>
41 Authors
- Jiafen Gong
- Gengming He
- Cheng Wang
- Claire Bartlett
- Naim Panjwani
- Scott Mastromatteo
- Fan Lin
- Katherine Keenan
- Julie Avolio
- Anat Halevy
- Michelle Shaw
- Mohsen Esmaeili
- Guillaume Côté-Maurais
- Damien Adam
- Stéphanie Bégin
- Candice Bjornson
- Mark Chilvers
- Joe Reisman
- April Price
- Michael Parkins
- Richard van Wylick
- Yves Berthiaume
- Lara Bilodeau
- Dimas Mateos-Corral
- Daniel Hughes
- Mary J. Smith
- Nancy Morrison
- Janna Brusky
- Elizabeth Tullis
- Anne L. Stephenson
- Bradley S. Quon
- Pearce Wilcox
- Winnie M. Leung
- Melinda Solomon
- Lei Sun
- Emmanuelle Brochiero
- Theo J. Moraes
- Tanja Gonska
- Felix Ratjen
- Johanna M. Rommens
- Lisa J. Strug
1 Application
| Application ID | Title |
|---|---|
| 40946 | Understanding the Pathophysiology of Cystic Fibrosis Gene Modifiers |
Enabling scientific discoveries that improve human health