Affordable Access

deepdyve-link
Publisher Website

Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

Authors
  • Aksit, Melis A1
  • Pace, Rhonda G2
  • Vecchio-Pagán, Briana3
  • Ling, Hua4
  • Rommens, Johanna M5
  • Boelle, Pierre-Yves6
  • Guillot, Loic7
  • Raraigh, Karen S1
  • Pugh, Elizabeth4
  • Zhang, Peng4
  • Strug, Lisa J5
  • Drumm, Mitch L8
  • Knowles, Michael R2
  • Cutting, Garry R1
  • Corvol, Harriet7
  • Blackman, Scott M1, 9
  • 1 McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 2 Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 3 Applied Physics Laboratory, Johns Hopkins University, Laurel, Maryland.
  • 4 Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland.
  • 5 The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. , (Canada)
  • 6 Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, iPLESP, AP-HP, Hôpital Saint-Antoine, Paris, France. , (France)
  • 7 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Paris, France. , (France)
  • 8 Case Western Reserve University, Cleveland, Ohio.
  • 9 Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Type
Published Article
Journal
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Publication Date
May 01, 2020
Volume
105
Issue
5
Identifiers
DOI: 10.1210/clinem/dgz102
PMID: 31697830
Source
Medline
Language
English
License
Unknown

Abstract

Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants. To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes. A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD. Genome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate < 0.1) and the genome-wide significant variants was associated with CFRD in a replication population. CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: [email protected]

Report this publication

Statistics

Seen <100 times