CF Patients’ Response to Kalydeco Impaired by Single Variants in SLC26A9 Gene, Study Reports
Single nucleotide polimorphisms (or variants), known as SNPs — the most common type of genetic variation — in the SLC26A9 gene are linked to poorer lung responses to Kalydeco in cystic fibrosis (CF) patients, a French study reports.
The study, “SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis” was published in the journal Frontiers in Pharmacology.
In 2012, the U.S. Food and Drug Administration approved Kalydeco (ivacaftor), developed and marketed by Vertex Pharmaceuticals, to treat CF patients 6 and older who had a single type of mutation, called G551D, affecting the CFTR gene (the gene defective in CF).
The CFTR gene encodes a protein channel, also called CFTR, with a “gate” that can open and close to control the movement of charged salts (such as chloride) in and out of cells. The G551D is called a “gating” mutation, meaning that it leads to the production of a faulty CFTR protein and the gate can be stuck closed.
However, there is variability among CF patients’ lung responses to Kalydeco, and previous reports have suggested that a potential cause are SNPs in the SLC26A9 gene (short for Solute Carrier Family 26 Member 9).
“In CF patients carrying at least one CFTR-G551D mutation, the single nucleotide polymorphism (SNP) rs7512462, in the SLC26A9 gene, was shown to explain 28% of the response variability to ivacaftor,” researchers wrote.
Now, researchers examined a large, independent French cohort of CF patients to evaluate whether SLC26A9 variants contribute to the variability of response to treatment, and whether they influence the lung response to Kalydeco.
There were 4,840 CF patients enrolled in the French CF Modifier Gene Study. Only patients 6 or older with severe CFTR mutations were considered. Of these, 2,143 patients were homozygous for F508del mutation — the most common genetic mutation in CF. (“Homozygous” means that these patients have both copies of the CFTR gene with this mutation — one from the father and one from the mother.)
There were 119 who carried at least one gating mutation for which Kalydeco has been approved in Europe. Of these, 81 had been prescribed Kalydeco.
Ultimately, 30 patients older than 6 with a lung function assessment of 40% to 90% in the three months before the start of treatment qualified to be analyzed. Lung function was measured as percent-predicted forced expiratory volume measured in 1 second (FEV1pp), the volume of air that can be forced out in one second after taking a deep breath.
The team measured patients’ response to Kalydeco by changes in FEV1pp from the beginning of the study (baseline), between days 15 and 75 (early response), and after a year (long-term response).
Researchers also performed genome analysis on all patients to identify whether SLC26A9 variants were involved in the lung’s response variability.
Results showed that in untreated patients, SLC26A9 variants showed no association with lung function variability for any of the CFTR mutations.
In patients carrying at least one G551D mutation, the response to Kalydeco changed with the SLC26A9 rs7512462 variant, with patients showing significantly less improvement in lung function.
Patients who previously had been treated with Kalydeco and carried one G551D mutation showed an improvement in lung function of 14.39% after 15–75 days and 15.06% over a year. Those with the SLC26A9 rs7512462 variant and the same CFTR mutation, however, showed poorer lung function, with a decline in FEV1pp of −7.7% over 15–75 days, and −7.8% over a year of treatment.
Other SLC26A9 SNPs also contributed to an impaired response to Kalydeco, namely rs4077468 and rs4077469.
“We confirmed that rs7512462 was associated with variability in ivacaftor lung response, with a significant reduction in lung function improvement,” the researchers said.
However, “the exact mechanism explaining how SLC26A9 variants affect the ivacaftor responses that we observed in our patients is unknown (…) and requires future investigation,” they said.
Overall, the findings support the detrimental effects of single variants in the SLC26A9 gene, and potentially other genes, that can affect CF patients’ response to therapies.
Moreover, the findings highlight how integrating pharmacogenomics — a field that includes a person’s genome analysis to assess his or her likely response to a treatment — as a personalized medicine approach can help improve CF patients’ care.