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

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-Gomuscu, 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.

N1 - Funding: 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]. The funding bodies had no role in the design, conduct or reporting of this study.

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 - Age at diagnosis

KW - C-Peptide

KW - Cross-sectional studies

KW - Diabetes mellitus type 1

KW - Genetics

KW - Insulin secretion

UR - https://www.scopus.com/pages/publications/85071325129

U2 - 10.1186/s12916-019-1392-8

DO - 10.1186/s12916-019-1392-8

M3 - Article

C2 - 31438962

SN - 1741-7015

VL - 17

SP - 1

EP - 11

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 165

ER -