MacMillan, Hannah JKong, YahuiCalvo-Roitberg, EzequielAlonso, Laura CPai, Athma A2023-10-032023-10-032022-05-11MacMillan HJ, Kong Y, Calvo-Roitberg E, Alonso LC, Pai AA. High-throughput analysis of ANRIL circRNA isoforms in human pancreatic islets. Sci Rep. 2022 May 11;12(1):7745. doi: 10.1038/s41598-022-11668-w. PMID: 35546161; PMCID: PMC9095874.2045-232210.1038/s41598-022-11668-w35546161https://hdl.handle.net/20.500.14038/52599The antisense non-coding RNA in the INK locus (ANRIL) is a hotspot for genetic variants associated with cardiometabolic disease. We recently found increased ANRIL abundance in human pancreatic islets from donors with certain Type II Diabetes (T2D) risk-SNPs, including a T2D risk-SNP located within ANRIL exon 2 associated with beta cell proliferation. Recent studies have found that expression of circular species of ANRIL is linked to the regulation of cardiovascular phenotypes. Less is known about how the abundance of circular ANRIL may influence T2D phenotypes. Herein, we sequence circular RNA in pancreatic islets to characterize circular isoforms of ANRIL. We identify several consistently expressed circular ANRIL isoforms whose expression is correlated across dozens of individuals and characterize ANRIL splice sites that are commonly involved in back-splicing. We find that samples with the T2D risk allele in ANRIL exon 2 had higher ratios of circular to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL was associated with decreased beta cell proliferation. Our study points to a combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies of the molecular mechanisms by which ANRIL impacts cellular function in pancreatic islets.enOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons. org/ licenses/ by/4. 0/. © The Author(s) 2022Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/GeneticsNon-coding RNAsType 2 diabetesJournal ArticleScientific reports