BMC Medicine (Aug 2019)

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

  • Paul M. McKeigue,
  • Athina Spiliopoulou,
  • Stuart McGurnaghan,
  • Marco Colombo,
  • Luke Blackbourn,
  • Timothy J. McDonald,
  • Suna Onengut-Gomuscu,
  • Stephen S. Rich,
  • Colin N. A. Palmer,
  • John A. McKnight,
  • Mark W. J. Strachan,
  • Alan W. Patrick,
  • John Chalmers,
  • Robert S. Lindsay,
  • John R. Petrie,
  • Sandeep Thekkepat,
  • Andrew Collier,
  • Sandra MacRury,
  • Helen M. Colhoun

DOI
https://doi.org/10.1186/s12916-019-1392-8
Journal volume & issue
Vol. 17, no. 1
pp. 1 – 11

Abstract

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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.

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