Year: 2024
Type: article
Study design: Observational Study
Abstract: 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 meta–genome-wide association studies (GWAS) of C-peptide and AAD in T1D and to identify the HLA allele/haplotypes associated with C-peptide and AAD. A total of 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, HLA-DRB1*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 the HLA region, rs115673528 on chromosome 5 (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 pro-cathepsin H reduced AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci were generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of T1D. Article Highlights Identified genetic loci for C-peptide and type 1 diabetes (T1D) age at diagnosis (AAD) explain only a small proportion of their variation. We aimed to identify additional genetic loci associated with C-peptide and AAD. Some HLA allele/haplotypes associated with T1D also contributed to variability of C-peptide and AAD, whereas outside the HLA region, T1D loci were mostly not associated with C-peptide or AAD. Genetic variation within CTSH can affect AAD. There is still residual heritability of C-peptide and AAD outside of HLA that could benefit from larger meta–genome-wide association studies.
Source: Diabetes
DOI: 10.2337/db24-0340
Institutions: Hospital for Sick Children, Institute of Genetics and Cancer, University of Edinburgh, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Wisconsin–Madison, Colorado School of Public Health, University of Colorado Anschutz, University of Pittsburgh
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Bayer, Wellcome Trust, Government of the United Kingdom, British Heart Foundation, Scottish Funding Council, Diabetes UK, Academy of Medical Sciences, European Commission, Novo Nordisk, National Institutes of Health, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Canadian Institutes of Health Research, Medical Research Council, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: UCHSC Diabetes and Endocrinology Research Center, Complications and Comorbidities of Type 1 Diabetes, G2437620908, General Clinical Research Center, Epidemiology of Diabetes Complications (EDC) Phase II: Renewal, Coronary Artery Calcification in Type 1 Diabetes, Quantitative Traits in Health and Disease, A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes, Scottish Diabetes Research Network Type 1 diabetes bioresource, Determinants of Accelerated CVD in Type 1 Diabetes, A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes, Colorado Clinical and Transational Sciences Institute, G839044655, G8395618216, G9000287722, University of Colorado Anschutz Medical Campus DRC, G902029169
OpenAlex ID: W4404470739