Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease
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....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-04-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00299-9 |
| _version_ | 1811272585875292160 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jiafen Gong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T22:42:59Z |
| format | Article |
| id | doaj.art-c9a883e6061748a2ad1bb0acfad420a2 |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-04-12T22:42:59Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-c9a883e6061748a2ad1bb0acfad420a22022-12-22T03:13:39ZengNature Portfolionpj Genomic Medicine2056-79442022-04-017111510.1038/s41525-022-00299-9Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung diseaseJiafen Gong0Gengming He1Cheng Wang2Claire Bartlett3Naim Panjwani4Scott Mastromatteo5Fan Lin6Katherine Keenan7Julie Avolio8Anat Halevy9Michelle Shaw10Mohsen Esmaeili11Guillaume Côté-Maurais12Damien Adam13Stéphanie Bégin14Candice Bjornson15Mark Chilvers16Joe Reisman17April Price18Michael Parkins19Richard van Wylick20Yves Berthiaume21Lara Bilodeau22Dimas Mateos-Corral23Daniel Hughes24Mary J. Smith25Nancy Morrison26Janna Brusky27Elizabeth Tullis28Anne L. Stephenson29Bradley S. Quon30Pearce Wilcox31Winnie M. Leung32Melinda Solomon33Lei Sun34Emmanuelle Brochiero35Theo J. Moraes36Tanja Gonska37Felix Ratjen38Johanna M. Rommens39Lisa J. Strug40Program in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Translational Medicine, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Translational Medicine, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Translational Medicine, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Alberta Children’s HospitalBritish Columbia Children’s HospitalThe Children’s Hospital of Eastern OntarioThe Children’s Hospital, London Health Science CentreFoothills Medical CentreKingston Health Sciences CentreDepartment of Medicine, Faculty of Medicine, Université de MontréalCentre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec-Université LavalIWK Health CentreIWK Health CentreFaculty of Medicine, Memorial University of NewfoundlandQueen Elizabeth II Health Sciences CentreDepartment of Pediatrics, University of SaskatchewanSt. Michael’s HospitalSt. Michael’s HospitalSt. Paul’s HospitalSt. Paul’s HospitalUniversity of Alberta HospitalRespiratory Medicine, Hospital for Sick ChildrenBiostatistics Division, Dalla Lana School of Public Health, University of TorontoCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Program in Translational Medicine, The Hospital for Sick ChildrenProgram in Translational Medicine, The Hospital for Sick ChildrenProgram in Translational Medicine, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Hospital for Sick ChildrenAbstract 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.https://doi.org/10.1038/s41525-022-00299-9 |
| spellingShingle | 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 Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease npj Genomic Medicine |
| title | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| title_full | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| title_fullStr | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| title_full_unstemmed | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| title_short | Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease |
| title_sort | genetic evidence supports the development of slc26a9 targeting therapies for the treatment of lung disease |
| url | https://doi.org/10.1038/s41525-022-00299-9 |
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