Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

McKeigue, P. M. et al. (2019) Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes. BMC Medicine, 17(1), 165. (doi: 10.1186/s12916-019-1392-8) (PMID:31438962) (PMCID:PMC6706940)

Abstract

Background: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. Methods: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Results: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Conclusions: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.

• Item Type: Articles
• Additional Information: The establishment of the SDRN Type 1 Bioresource was supported by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates [ETM/47] by Diabetes UK [10/0004010] and by in-kind contributions from the Scottish Diabetes Research Network to facilitate recruitment. The genotyping was supported by the Juvenile Diabetes Research Fund [17-2013-7].
• Keywords: Age at diagnosis, C-peptide, cross-sectional studies, diabetes mellitus type 1, genetics, insulin secretion.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lindsay, Dr Robert and Petrie, Professor John
• Authors: McKeigue, P. M., Spiliopoulou, A., McGurnaghan, S., Colombo, M., Blackbourn, L., McDonald, T. J., Onengut-Gomuscu, S., Rich, S. S., A Palmer, C. N., McKnight, J. A., J Strachan, M. W., Patrick, A. W., Chalmers, J., Lindsay, R. S., Petrie, J. R., Thekkepat, S., Collier, A., MacRury, S., and Colhoun, H. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: BMC Medicine
• Publisher: BioMed Central
• ISSN: 1741-7015
• ISSN (Online): 1741-7015
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in BMC Medicine 17(1):165
• Publisher Policy: Reproduced under a Creative Commons License