ESPEYB19 10. Type 1 Diabetes Genetics (1 abstracts)
10.16. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
Robertson CC , Inshaw JRJ , Onengut-Gumuscu S , Chen WM , Santa Cruz DF , Yang H , Cutler AJ , Crouch DJM , Farber E , Bridges SL Jr , Edberg JC , Kimberly RP , Buckner JH , Deloukas P , Divers J , Dabelea D , Lawrence JM , Marcovina S , Shah AS , Greenbaum CJ , Atkinson MA , Gregersen PK , Oksenberg JR , Pociot F , Rewers MJ , Steck AK , Dunger DB; Type 1 Diabetes Genetics Consortium , Wicker LS , Concannon P , Todd JA & Rich SS
Nat Genet. 2021 Jul;53(7):962-971. https://pubmed.ncbi.nlm.nih.gov/34127860/
Brief Summary: The authors report the largest and most diverse genome-wide association study (GWAS) of type 1 diabetes (T1D) to date, including 61,427 participants from different ancestries. It identified 78 significant genomic regions associated with T1D, of which 36 were new. The integration of genetic evidence, functional genomic maps, and immune protein–protein interactions led to the characterization of 12 genes implicated in T1D that are already targets in clinical trials for autoimmune diseases.
In recent years, large GWASs have shed light on genetic contributors to T1D. However, most have included only people of European ancestry, whereas other ancestries have been underrepresented (1). The current GWAS study included a diverse population and provides additional remarkable information on the complex genetic landscape of T1D. The study also addressed the mechanisms underlying the genetic T1D associations, which up to now were largely unknown. They identified up to 78 genetic regions associated with T1D, with 36 being new, and some also associated with other autoimmune conditions. The study highlighted that these regions are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. The analysis of CD4+ T cells from 115 people (58 with T1D and 57 controls) identified five regions where T1D risk variants co-localize with chromatin accessibility quantitative trait loci. Of note, rs72928038 in BACH2 was identified as a candidate causal T1D variant. BACH2 haploinsufficiency has been associated with congenital autoimmunity and immunodeficiency, supporting its role in the immune system. Further analysis of the genetic data led to the identification of 12 genes, which have already been targeted in trials for other autoimmune disease and which could represent targets for future drugs to arrest or prevent T1D.
Overall, this large study sheds new light on the complex T1D genetic background and unveils several new potential drug targets.
Reference: 1. Redondo MJ, Gignoux CR, Dabelea D, Hagopian WA, Onengut-Gumuscu S, Oram RA, Rich SS. Type 1 diabetes in diverse ancestries and the use of genetic risk scores. Lancet Diabetes Endocrinol. 2022 Jun 16:S2213–8587(22)00159–0.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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