Dataset Information

SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis.

ABSTRACT: Ivacaftor is a drug used to treat cystic fibrosis (CF) patients carrying specific gating CFTR mutations. Interpatient variability in the lung response has been shown to be partly explained by rs7512462 in the Solute Carrier Family 26 Member 9 (SLC26A9) gene. In an independent and larger cohort, we aimed to evaluate whether SLC26A9 variants contribute to the variability of the lung phenotype and if they influence the lung response to ivacaftor. We genotyped the French CF Gene Modifier Study cohort (n = 4,840) to investigate whether SLC26A9 variants were involved in the lung phenotype heterogeneity. Their influence in the response to ivacaftor was tested in the 30 treated patients who met the inclusion criteria: older than 6 years of age, percent-predicted forced expiratory volume measured in 1 s (FEV1pp) in the 3 months before treatment initiation ranging between 40 and 90%. Response to treatment was determined by the change in FEV1pp from baseline, averaged in 15-75 days, and the 1st-year post-treatment. We observed that SLC26A9 variants were not associated with lung function variability in untreated patients and that gain of lung function in patients treated with ivacaftor was similar to clinical trials. We confirmed that rs7512462 was associated with variability in ivacaftor-lung response, with a significant reduction in lung function improvement for patients with the C allele. Other SLC26A9 SNPs also contributed to the ivacaftor-response. Interindividual variability in lung response to ivacaftor is associated with SLC26A9 variants in French CF patients. Pharmacogenomics and personalized medicine will soon be part of CF patient care.

SUBMITTER: Corvol H

PROVIDER: S-EPMC6095007 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis.

Corvol Harriet H Mésinèle Julie J Douksieh Isman-Hassan IH Strug Lisa J LJ Boëlle Pierre-Yves PY Guillot Loïc L

Frontiers in pharmacology 20180726

Ivacaftor is a drug used to treat cystic fibrosis (CF) patients carrying specific gating CFTR mutations. Interpatient variability in the lung response has been shown to be partly explained by rs7512462 in the Solute Carrier Family 26 Member 9 (SLC26A9) gene. In an independent and larger cohort, we aimed to evaluate whether SLC26A9 variants contribute to the variability of the lung phenotype and if they influence the lung response to ivacaftor. We genotyped the French CF Gene ...[more]

PMID: 30140228

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Project description:BackgroundCystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period.ResultsThe number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%).ConclusionsCFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234 .).

Dataset Information

SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis.

Publications

<i>SLC26A9</i> Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis.

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