Cystic fibrosis gene modifierSLC26A9modulates airway response to CFTR-directed therapeutics

Abstract

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.

Gene modifiers of cystic fibrosis lung disease: A systematic review

“…modified the magnitude of response to ivacaftor is an example of this. 91 This has subsequently been replicated in a further recent study. 103 Much more comprehensive validation is needed however before this discovery could be used in routine clinical practice.…”

“…The magnitude of response to these treatments may represent an important phenotype worthy of further studies, as already highlighted in the studies examining the response to ivacaftor. 91,103 Any significant findings should then be replicated in separate cohorts using similar endpoints. For future work examining DNA methylation and gene expression, it will be important that initial gene discovery is based on samples from biologically relevant tissue (BAL, nasal epithelial cells) with subsequent replication in more easily obtained samples such as blood.…”

“…Receptor 2 (ADRB2), which is involved in bronchoconstriction, would affect whether patients responded to inhaled bronchodilator, and found there was no significant relationship. In a more recent, and highly relevant study, Strug et al 91 examined the effect of gene modifier SLC26A9 (an alternate chloride channel identified via the GWAS meta-analysis) on the response to treatment with the CFTR modulator ivacaftor. They studied 24 Canadian patients with at least one gating mutation and measured FEV 1 before and after treatment with ivacaftor.…”

The evidential statistical paradigm in genetics

“…CF as a plausible value demarcating the associated region. Rs7512462 in intron 5 and rs4077468 have been demonstrated in previous P-value based studies as associated with CF pancreatic disease (Blackman et al, 2013;Miller et al, 2015) and therapeutic response (Strug et al, 2016).…”

“…These variants, and others with similar strength of evidence, are located in a cluster just 5′ or in intron 1 of SLC26A9 in a region where few variants favor OR = 1 as a plausible value demarcating the associated region. Rs7512462 in intron 5 and rs4077468 have been demonstrated in previous P‐ value based studies as associated with CF pancreatic disease (Blackman et al, ; Miller et al, ) and therapeutic response (Strug et al, ).…”