Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

Authors

Jiafen Gong, Hospital for Sick Children University of Toronto
Gengming He, Hospital for Sick Children University of Toronto
Cheng Wang, Hospital for Sick Children University of Toronto
Claire Bartlett, Hospital for Sick Children University of Toronto
Naim Panjwani, Hospital for Sick Children University of Toronto
Scott Mastromatteo, Hospital for Sick Children University of Toronto
Fan Lin, Hospital for Sick Children University of Toronto
Katherine Keenan, Hospital for Sick Children University of Toronto
Julie Avolio, Hospital for Sick Children University of Toronto
Anat Halevy, Hospital for Sick Children University of Toronto
Michelle Shaw, Hospital for Sick Children University of Toronto
Mohsen Esmaeili, Hospital for Sick Children University of Toronto
Guillaume Côté-Maurais, Centre Hospitalier de L'Universite de Montreal
Damien Adam, Centre Hospitalier de L'Universite de Montreal
Stéphanie Bégin, Centre Hospitalier de L'Universite de Montreal
Candice Bjornson, Alberta Children's Hospital
Mark Chilvers, BC​ Children​'​​s Hospital
Joe Reisman, Children's Hospital of Eastern Ontario, Ottawa
April Price, London Health Sciences CentreFollow
Michael Parkins, Foothills Medical Centre
Richard van Wylick, Kingston Health Sciences Centre
Yves Berthiaume, Université de Montréal, Faculté de Médecine
Lara Bilodeau, Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval
Dimas Mateos-Corral, IWK Health Centre
Daniel Hughes, IWK Health Centre
Mary J. Smith, Memorial University of Newfoundland, Faculty of Medicine

Document Type

Article

Publication Date

12-1-2022

Journal

npj Genomic Medicine

Volume

7

Issue

1

URL with Digital Object Identifier

10.1038/s41525-022-00299-9

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.