{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T12:19:12Z","timestamp":1762604352298,"version":"3.41.2"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006458","name":"Children's Hospital of Philadelphia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Type 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study (GWAS) treating the age of first diagnosis as a quantitative trait.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed GWAS with a discovery cohort of 4,014 cases and a replication cohort of 493 independent cases. Genome-wide significant SNPs were mapped to a causal variant by Bayesian conditional analysis and gel shift assay. The causal protein-coding gene was identified and characterized by RNA interference treatment of primary human pan-CD4+ T cells with RNA-seq of the transcriptome. The candidate gene was evaluated functionally in primary cells by CD69 staining and proliferation assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our GWAS replicated the known association of the age of diagnosis with the human leukocyte antigen complex (HLA-DQB1). The second signal identified was in an intron of the NELL1 gene on chromosome 11 and fine-mapped to variant rs10833518 (P &amp;lt; 1.54 \u00d7 10<jats:sup>\u22129<\/jats:sup>). Homozygosity for the risk allele leads to average age of onset one year earlier. Knock-down of HIV TAT-interacting protein 2 (HTATIP2), but not other genes in the locus, resulted in alterations to gene expression in signal transduction pathways including MAP kinases and PI3-kinase. Higher levels of HTATIP2 expression are associated with increased viability, proliferation, and activation of T cells in the presence of signals from antigen and cytokine receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study implicates HTATIP2 as a new type 1 diabetes gene acting via T cell regulation. Larger population sample sizes are expected to reveal additional loci.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1101488","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T15:15:17Z","timestamp":1675264517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator"],"prefix":"10.3389","volume":"14","author":[{"given":"Christopher 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