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 2

Two common haplotypes that associate with age at onset of CFRD.

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Two common haplotypes that associate with age at onset of CFRD. (A) Top:...
(A) Top: SLC26A9 variant haplotypes with MAF greater than 15% and MHF greater than 20%. Location of variants relative to SLC26A9 and luciferase constructs are shown above haplotypes (note: SLC26A9 is on [–] DNA strand, not drawn to scale). Cross indicates TGGGGCCTCGGGTATCTCA. Haplotype frequencies, P values, and β values are shown to the left of the respective haplotypes. rsIDs are shown for the CFRD-associated variants (8). Variants highlighted in blue indicate alleles composing the most common ancestral haplotype. Variants highlighted in red indicate alleles that differ from those in the common haplotype. Bottom: LD plot of variants with MAF greater than 15% created with Haploview. Black boxes indicate an r2 value of 1 or complete LD, while white boxes indicate an r2 of 0 or linkage equilibrium. Proposed LD blocks are outlined (triangles), defined by a recombination event between introns 5 and 8. (B) Cumulative incidence plot of proportion with CFRD relative to age among individuals with LR or HR haplotypes. LR/LR homozygotes (n = 46) versus HR/HR homozygotes (n = 36) are plotted (log-rank P = 6.5 × 10–3).