Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) diagnosed below the age of 7 years between the PTPRK and thymocyte-selection-associated (THEMIS) genes. As the thymus plays a central role in shaping the T cell repertoire, we aimed to identify the most likely causal genetic factors behind this association using thymocyte genomic data. In four thymocyte populations, we identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele of rs138300818, associated with protection from diabetes, created thymocyte motifs for multiple histone modifications and thymocyte types. In a parallel approach to identifying variants that alter transcription factor binding motifs, the same variant disrupted a predicted motif for Rfx7, which is abundantly expressed in the thymus. Chromatin state and RNA sequencing data suggested strong transcription overlapping rs138300818 in fetal thymus, while expression quantitative trait locus and chromatin conformation data associate the insertion with lower THEMIS expression. Extending the analysis to other T1D loci further highlighted rs66733041 affecting the GATA3 transcription factor binding in the AFF3 locus. Taken together, our results support a role for thymic THEMIS gene expression and the rs138300818 variant in promoting the development of early-onset T1D.Peer reviewe

The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes

The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the β-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.L.Pasquali was supported by grants from the Spanish Ministry of Economy and Competitiveness (nos. BFU2014-58150-R and SAF2017-86242-R), Marató TV3 (no. 201624.10) and a young investigator award from the Spanish Society of Diabetes (Ayuda SED a Proyectos de Investigación, no. 2017-SED). L.Pasquali is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (no. RYC-2013-12864). The Pasquali lab is further supported by Instituto de Salud Carlos III (no. PIE16/00011). M.R. is supported by an FI Agència de Gestió d’Ajuts Universitaris i de Recerca PhD fellowship (no. 2019FI_B100203). J.J. was supported by a Marie Skłodowska-Curie Actions fellowship grant from the Horizons 2020 European Union (EU) Programme (project no. 660449). M.I.A. was supported by a FRIA fellowship from the Fonds de la Recherche Scientifique (FNRS) (no. 26410496). Human islets were provided through the European Consortium for Islet Transplantation distribution program for basic research supported by JDRF (no. 31-2008-416). D.L.E. was supported by the Walloon Region through the FRFS-WELBIO Fund for Strategic Fundamental research (no. CR-2015A-06s and CR-2019C-04) and by grants from the Fonds National de la Recherche Scientifique (no. T003613F), the Horizon 2020 Programme (project T2Dsystems, no. GA667191), Brussels Capital Region Innoviris (project DiaType, no. 2017-PFS-24), Dutch Diabetes Research Fundation (project Innovate2CureType1, DDRF; no. 2018.10.002) and the Innovative Medicines Initiative 2 Joint Undertaking (project INNODIA, no. 115797). This Innovative Medicines Initiative 2 Joint Undertaking receives support from the EU’s Horizon 2020 Research and Innovation Programme and European Federation of Pharmaceutical Industries and Associations, JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (project INNODIA, no. 115797). T.O.M. and D.L.E. were supported by a grant from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases-Human Islet Research Network Consortium (no. 1UC4DK104166-01). Part of the work was performed at the Environmental Molecular Sciences Laboratory, a US Department of Energy national scientific user facility located at Pacific Northwest National Laboratory. Battelle operates the Pacific Northwest National Laboratory for the Department of Energy (contract no. DE-AC05-76RLO01830)

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D