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) 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.© 2022. The Author(s).
About The Expert
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
References
PubMed