{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:45:47Z","timestamp":1759970747193,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for Northern Ireland"},{"name":"Northern Ireland Public Health Agency (HSC R&amp;D)"},{"name":"Ulster University"},{"name":"Department for the Economy, Northern Ireland"},{"name":"Exeter NIHR Clinical Research Facility"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: The variants rs10517086 and rs1534422 are predictive of type 1 diabetes mellitus (T1DM) development and poor residual \u03b2 cell function within the first year of diagnosis. However, the mechanism by which risk is conferred is unknown. We explored the impact of both variants on \u03b2 cell function in vitro and assessed their relationship with C-peptide in people with T1DM and type 2 diabetes mellitus (T2DM). Methods: Using CRISPR\/Cas9, the variants were introduced into a \u03b2 cell line (BRIN-BD11) and a T cell line (Jurkat cells) from which the conditioned media was applied to otherwise healthy \u03b2 cells to model the inflammatory environment associated with these variants. Results: Both variants significantly reduced glucose-stimulated insulin secretion, increased production of pro-inflammatory cytokines and reduced expression of several \u03b2 cell markers and transcription factors (KCNJ11, KCNQ1, SCL2A2, GCK, NKX6.1, Pdx1 NGN3). However, HNF1A was significantly upregulated in the presence of both variants. We subsequently silenced HNF1A in variant expressing BRIN-BD11 cells using siRNA and found that gene expression profiles were normalised. Induction of each variant significantly increased expression of the lncRNAs they encode, which was normalised upon HNF1A silencing. Analysis of the DARE (Diabetes Alliance for Research in England) study revealed an association of rs10517086_A genotype with C-peptide in 153 individuals with T1DM, but not in 417 people with T2DM. Conclusions: These data suggest that rs1534422 and rs10517086 exert multiple insults on the \u03b2 cell through excessive upregulation of HNF1A and induction of pro-inflammatory cytokines, and highlight their utility as prognostic markers of \u03b2 cell function.<\/jats:p>","DOI":"10.3390\/genes16020172","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T09:06:38Z","timestamp":1738141598000},"page":"172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Type 1 Diabetes Risk Variants Reduce Beta Cell Function"],"prefix":"10.3390","volume":"16","author":[{"given":"Wiktoria","family":"Ratajczak","sequence":"first","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital Campus, Glenshane Road, Derry BT48 7JL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angus G.","family":"Jones","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter EX1 2LU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah D.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catriona","family":"Kelly","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital Campus, Glenshane Road, Derry BT48 7JL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Burrack, A.L., Martinov, T., and Fife, B.T. 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