Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Endocrinology Genetics

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

  • Text
  • PDF
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

×

Figure 4

Regulatory annotations 5′ and within SLC26A9 from the UCSC Genome Browser.

Options: View larger image (or click on image) Download as PowerPoint
Regulatory annotations 5′ and within SLC26A9 from the UCSC Genome Browse...
The key CFRD-risk variants (8) 5′ and within SLC26A9 are annotated at the top. The blue region highlights the 1.172 kb region 5′ of SLC26A9. The yellow region highlights the 1.173 kb region that together with the blue region denotes the 2.3 kb region 5′ of SLC26A9. The green highlight denotes the 2.5 kb region, which encompasses the rest of the 5′ 4.8 kb region upstream of SLC26A9. The ORegAnno track displays TF-binding sites. The bottom track displays the Vertebrate Multiz Alignment & Conservation.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts