Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis
Anh-Thu N. Lam, … , Scott M. Blackman, Garry R. Cutting
Anh-Thu N. Lam, … , Scott M. Blackman, Garry R. Cutting
Published October 3, 2019
Citation Information: J Clin Invest. 2020;130(1):272-286. https://doi.org/10.1172/JCI129833.
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Research Article Endocrinology Genetics

Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis

Abstract

Diabetes is a common complication of cystic fibrosis (CF) that affects approximately 20% of adolescents and 40%–50% of adults with CF. The age at onset of CF-related diabetes (CFRD) (marked by clinical diagnosis and treatment initiation) is an important measure of the disease process. DNA variants associated with age at onset of CFRD reside in and near SLC26A9. Deep sequencing of the SLC26A9 gene in 762 individuals with CF revealed that 2 common DNA haplotypes formed by the risk variants account for the association with diabetes. Single-cell RNA sequencing (scRNA-Seq) indicated that SLC26A9 is predominantly expressed in pancreatic ductal cells and frequently coexpressed with CF transmembrane conductance regulator (CFTR) along with transcription factors that have binding sites 5′ of SLC26A9. These findings were replicated upon reanalysis of scRNA-Seq data from 4 independent studies. DNA fragments derived from the 5′ region of SLC26A9-bearing variants from the low-risk haplotype generated 12%–20% higher levels of expression in PANC-1 and CFPAC-1 cells compared with the high- risk haplotype. Taken together, our findings indicate that an increase in SLC26A9 expression in ductal cells of the pancreas delays the age at onset of diabetes, suggesting a CFTR-agnostic treatment for a major complication of CF.

Authors

Anh-Thu N. Lam, Melis A. Aksit, Briana Vecchio-Pagan, Celeste A. Shelton, Derek L. Osorio, Arianna F. Anzmann, Loyal A. Goff, David C. Whitcomb, Scott M. Blackman, Garry R. Cutting

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Figure 5

Coexpression of SLC26A9 and CFTR in pancreatic cells.

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Coexpression of SLC26A9 and CFTR in pancreatic cells. Results were obtai...
Results were obtained from scRNA-Seq. (A) t-SNE plot of scRNA-Seq data. Each data point represents a cell, colored by its cell type. (B) t-SNE plot of scRNA-Seq of the pancreas, with cells expressing CFTR and/or SLC26A9 with a log-normalized expression of 0.50 or more appearing in color. (C) Venn diagram representing the number of cells that express CFTR, SLC26A9, or both and the percentage of cell types in which these genes are expressed. The number of cells per compartment is shown in parentheses. (D and E) Venn diagrams showing the number of cells expressing CFTR, SLC26A9, or both and the percentage of cell types in which these genes are expressed based upon a reanalysis of 2 publicly available scRNA-Seq data sets (44, 47).