Genetics of C-peptide and Age at Diagnosis in Type 1 Diabetes.

Autor: Roshandel D; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada., Spiliopoulou A; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., McGurnaghan SJ; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Iakovliev A; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK., Lipschutz D; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK., Hayward C; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Bull SB; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada., Klein BEK; School of Medicine and Public Health, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, US., Lee KE; School of Medicine and Public Health, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, US., Kinney GL; Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, USA., Rewers M; Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA., Costacou T; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Miller RG; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., McKeigue PM; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK., Paterson AD; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada., Colhoun HM; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Jazyk: angličtina
Zdroj: Diabetes [Diabetes] 2024 Nov 18. Date of Electronic Publication: 2024 Nov 18.
DOI: 10.2337/db24-0340
Abstrakt: Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. HLA-DQB1*06:02 which is strongly protective against T1D was associated with higher C-peptide. HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 which increase T1D risk were independently associated with younger AAD. HLA-DR3-DR4 haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (GABRG2) was associated with C-peptide, and an indel, rs111970692, on Chr15 within CTSH, a known T1D locus, was associated with AAD. Genetically predicted CTSH expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of type 1 diabetes.
(© 2024 by the American Diabetes Association.)
Databáze: MEDLINE
Externí odkaz: