Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.
Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector.

In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
Lisa J
LJ
Strug
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada|Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada|Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
Tanja
T
Gonska
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Gengming
G
He
Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Katherine
K
Keenan
Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Wan
W
Ip
Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris, France|Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital St. Antoine, Biostatistics Department; Inserm U1136, Paris, France
Pierre-Yves
PY
Boëlle
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Fan
F
Lin
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Naim
N
Panjwani
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jiafen
J
Gong
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
Weili
W
Li
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada
David
D
Soave
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bowei
B
Xiao
Department of Respiratory Medicine and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Elizabeth
E
Tullis
Department of Medicine, University of Calgary, Calgary, Alberta, Canada|The Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada
Harvey
H
Rabin
Department of Medicine, University of Calgary, Calgary, Alberta, Canada|The Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada
Michael D
MD
Parkins
Division of Paediatric Respirology, Department of Paediatrics, Children's Hospital at London Health Sciences Centre, London, Ontario, Canada.
April
A
Price
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
Peter C
PC
Zuberbuhler
Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris, France|AP-HP, Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et al Recherche Medicale (INSERM) U938, Paris, France
Harriet
H
Corvol
Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
Felix
F
Ratjen
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada|Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada
Lei
L
Sun
Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada, Departments of Biochemestry and Physiology
Christine E
CE
Bear
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Johanna M
JM
Rommens
D000627:Aminophenols / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D002170:Canada; D002478:Cells, Cultured; D065101:Chloride Channel Agonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists; D005260:Female; D005602:France; D060045:Genes, Modifier; D056726:Genetic Association Studies; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008957:Models, Genetic; D062072:Patient Acuity; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D015363:Quinolones / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000076988:Sulfate Transporters
D000627:Aminophenols; D017920:Antiporters; C505032:CFTR protein, human; D065101:Chloride Channel Agonists; D015363:Quinolones; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor