{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:14:01Z","timestamp":1778649241350,"version":"3.51.4"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Graves' disease (GD) is a classical autoimmune disorder caused by interactions between genetic susceptibility and immune dysregulation. However, the transcriptomic mechanisms underlying disease relapse and remission, particularly those involving alternative splicing (AS), remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed an integrative RNA-seq analysis of peripheral blood samples from 33 GD patients in remission, 31 GD patients in relapse, and 30 normal controls (NC). Gene expression, transcript usage, alternative splicing events (ASEs), RNA-binding protein (RBP) regulation, and splicing quantitative trait loci (sQTLs) were systematically analyzed to characterize transcriptomic alterations associated with different disease states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with NC, relapse-associated differentially expressed genes (DEGs) were mainly enriched in antimicrobial humoral immunity and suppression of TNF signaling, whereas remission-associated DEGs were associated with metabolic homeostasis and apoptosis regulation. Notably, 74 DEGs were consistently upregulated in both disease states. Transcriptomic analysis identified 234,595 transcripts, including 17.1% novel isoforms, and detected 352 and 387 differentially expressed transcripts (DETs) in relapse and remission, respectively. Transcript-level alterations frequently occurred independently of gene-level expression changes, indicating extensive isoform-specific regulation, as exemplified by isoform switching of\n                      <jats:italic>HELZ2<\/jats:italic>\n                      . In addition, 858 relapse-associated and 670 remission-associated aberrant ASEs (AASEs) were identified. RBP-AASE regulatory network analysis suggested that key RBPs, including\n                      <jats:italic>APOBEC3C<\/jats:italic>\n                      , may contribute to stage-specific splicing remodeling. sQTL analysis further identified 4,507 significant SNP-ASE associations, with affected genes enriched in immune-related pathways, including Th1\/Th2\/Th17 cell differentiation and TNF signaling. Among these, 12 splicing-related genes also exhibited aberrant AS patterns, while\n                      <jats:italic>DDX5<\/jats:italic>\n                      and\n                      <jats:italic>PKM<\/jats:italic>\n                      showed sustained upregulation in both relapse and remission phases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that GD relapse and remission are closely associated with genetically and RBP-mediated alternative splicing regulation. Our study provides new insights into the molecular mechanisms underlying immune imbalance in GD and highlights potential transcriptomic biomarkers associated with disease relapse.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1791850","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:41:43Z","timestamp":1778647303000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated RNA-seq and sQTL analysis reveal immune and splicing regulatory features underlying relapse and remission after treatment of Graves\u2019 disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Yang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The Third Affiliated Hospital of Soochow University","place":["Changzhou, Jiangsu, 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