Genotypic Associations with C-Peptide Persistence in People with Type 1 Diabetes

Abstract

There is substantial variation in C-peptide levels in those with clinically diagnosed type 1 diabetes (T1DM). We examined the association of C-peptide levels with genotypic risk scores (GRS) for T1DM and T2DM in 5856 genotyped people diagnosed with T1DM and requiring insulin within 1 year of diagnosis (the SDRNT1BIO). Region-specific GRS and residual genome wide scores for T1DM and T2DM were computed based on publicly available summary GWAS data. Total genome wide scores were the sum of the residual and region specific scores. C-peptide was measured using a Roche ultrasensitive immunoassay on untimed serum. Overall 39% had detectable C-peptide (≥5 pmol/L) with prevalence being highest with older age of onset (p=6.9x10-05) and shorter duration (p=1.8x10-10). Heritability was 0.31 for age at onset and 0.26 for C-peptide adjusted for sex and age at onset. Lower T1DM genome-wide score and higher T2DM score were positively associated with C-peptide level, associations that were stronger with older age at onset (p=4.9x10- for T1DM score, p=0.009 for T2DM score interactions with age at onset). The T1DM and T2DM GRS were uncorrelated except at the HLA region. Most T1DM region specific scores were lower with increasing age at onset in particular at the HLA (p=3.2x10-34), INS (1.9x10-05) CTSH (9.1x10-06) and IKZF1 (p=0.0001) regions. Adjusted for age at onset, higher C-peptide level was also associated with lower T1DM GRS at the HLA (p=9.8x10-17) and INS (p=2.7x10-06) regions. Most T2DM region specific scores were higher with older age at onset and adjusted C-peptide except a T2DM associated HLA region score which was lower at higher age of onset (p=1.7x10-17) and higher C-peptide (p=1.1x10-09). These results show that in people diagnosed with T1DM, especially at older ages, the variation in persistence of C-peptide secretion in part reflects a continuous spectrum of genetic risk for T1DM and T2DM. The lack of correlation in T1DM and T2DM GRS is in keeping with this continuum rather than “misdiagnosis” of T1DM as T2DM. Disclosure P. McKeigue: Stock/Shareholder; Self; Bayer AG, Roche Pharma. A. Spiliopoulou: None. S. McGurnaghan: None. M. Colombo: None. T.J. McDonald: None. H. Colhoun: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Stock/Shareholder; Self; Bayer AG. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Other Relationship; Self; Eli Lilly and Company. Advisory Panel; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Advisory Panel; Self; Regeneron Pharmaceuticals, Inc.. Speaker's Bureau; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; Regeneron Pharmaceuticals, Inc.. Research Support; Self; Pfizer Inc., Roche Pharma. Stock/Shareholder; Self; Roche Pharma. Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi. Research Support; Self; Novo Nordisk Inc..