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-Gumuscu; 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:10.1186/s12916-019-1392-8

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-Gumuscu, 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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Article number	165
Journal	BMC Medicine
Volume	17
DOIs	https://doi.org/10.1186/s12916-019-1392-8
Publication status	Published - 23 Aug 2019

Keywords / Materials (for Non-textual outputs)

C-Peptide
Diabetes mellitus type 1
Age at diagnosis
Insulin secretion
Genetics
Cross-sectional studies

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10.1186/s12916-019-1392-8Licence: Creative Commons: Attribution (CC-BY)

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Final published version, 1.04 MBLicence: Creative Commons: Attribution (CC-BY)

Athina Spiliopoulou
- Deanery of Molecular, Genetic and Population Health Sciences - Chancellor's Fellow
- Usher Institute
- Centre for Population Health Sciences
Person: Academic: Research Active (Research Assistant)

Cite this

McKeigue, P. M., Spiliopoulou, A., McGurnaghan, S., Colombo, M., Blackbourn, L., McDonald, T. J., Onengut-Gumuscu, S., Rich, S. S., Palmer, C. N. A., McKnight, J. A., Strachan, M. W. J., Patrick, A. W., Chalmers, J., Lindsay, R. S., Petrie, J. R., Thekkepat, S., Collier, A., MacRury, S., & Colhoun, H. M. (2019). Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes. BMC Medicine, 17, Article 165. https://doi.org/10.1186/s12916-019-1392-8

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

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.",

keywords = "C-Peptide, Diabetes mellitus type 1, Age at diagnosis, Insulin secretion, Genetics, Cross-sectional studies",

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

year = "2019",

month = aug,

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doi = "10.1186/s12916-019-1392-8",

language = "English",

volume = "17",

journal = "BMC Medicine",

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}

McKeigue, PM , Spiliopoulou, A , McGurnaghan, S, Colombo, M, Blackbourn, L, McDonald, TJ, Onengut-Gumuscu, S, Rich, SS, Palmer, CNA, McKnight, JA, Strachan, MWJ, Patrick, AW, Chalmers, J, Lindsay, RS, Petrie, JR, Thekkepat, S, Collier, A, MacRury, S & Colhoun, HM 2019, 'Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes', BMC Medicine, vol. 17, 165. https://doi.org/10.1186/s12916-019-1392-8

TY - JOUR

T1 - Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

AU - McKeigue, Paul M.

AU - Spiliopoulou, Athina

AU - McGurnaghan, Stuart

AU - Colombo, Marco

AU - Blackbourn, Luke

AU - McDonald, Timothy J.

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S.

AU - Palmer, Colin N. A.

AU - McKnight, John A.

AU - Strachan, Mark W. J.

AU - Patrick, Alan W.

AU - Chalmers, John

AU - Lindsay, Robert S.

AU - Petrie, John R.

AU - Thekkepat, Sandeep

AU - Collier, Andrew

AU - MacRury, Sandra

AU - Colhoun, Helen M.

PY - 2019/8/23

Y1 - 2019/8/23

N2 - 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.

AB - 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.

KW - C-Peptide

KW - Diabetes mellitus type 1

KW - Age at diagnosis

KW - Insulin secretion

KW - Genetics

KW - Cross-sectional studies

U2 - 10.1186/s12916-019-1392-8

DO - 10.1186/s12916-019-1392-8

M3 - Article

SN - 1741-7015

VL - 17

JO - BMC Medicine

JF - BMC Medicine

M1 - 165

ER -

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

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Athina Spiliopoulou

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