Variants at the Interleukin 1 Gene Locus and Pericarditis
Authors: Rosa B. Thorolfsdottir, Andrea B. Jonsdottir, Gardar Sveinbjornsson, Hildur M. Aegisdottir, Asmundur Oddsson, Olafur A. Stefansson, Gisli H. Halldorsson, Saedis Saevarsdottir, Gudmar Thorleifsson, Lilja Stefansdottir, Ole B. Pedersen, Erik Sørensen, Jonas Ghouse, Anna Axelsson Raja, Chaoqun Zheng, Elvira Silajdzija, Søren Albertsen Rand, Christian Erikstrup, Henrik Ullum, Christina Mikkelsen, Karina Banasik, Søren Brunak, Erna V. Ivarsdottir, Asgeir Sigurdsson, Doruk Beyter, Arni Sturluson, Hafsteinn Einarsson, Vinicius Tragante, Hannes Helgason, Sigrun H. Lund, Bjarni V. Halldorsson, Brynja D. Sigurpalsdottir, Isleifur Olafsson, David O. Arnar, Gudmundur Thorgeirsson, Kirk U. Knowlton, Lincoln D. Nadauld, Solveig Gretarsdottir, Anna Helgadottir, Sisse R. Ostrowski, Daniel F. Gudbjartssson, Ingileif Jonsdottir, Henning Bundgaard, Hilma Holm, Patrick Sulem, Kari Stefansson, Karina Banasik, Jakob Bay, Jens K. Boldsen, Thorsten Brodersen, Søren Brunak, Kristoffer Burgdorf, Mona A. Chalmer, Maria Didriksen, Khoa M. Dinh, Joseph Dowsett, Christian Erikstrup, Bjarke Feenstra, Frank Geller, Daniel Gudbjartsson, Thomas F. Hansen, Lotte Hindhede, Henrik Hjalgrim, Rikke L. Jacobsen, Gregor Jemec, Bitten A. Jensen, Katrine Kaspersen, Bertram D. Kjerulff, Lisette Kogelman, Margit A. H. Larsen, Ioannis Louloudis, Agnete Lundgaard, Susan Mikkelsen, Christina Mikkelsen, Ioanna Nissen, Mette Nyegaard, Sisse R. Ostrowski, Ole B. Pedersen, Alexander P. Henriksen, Palle D. Rohde, Klaus Rostgaard, Michael Schwinn, Kari Stefansson, Hreinn Stefánsson, Erik Sørensen, Unnur Thorsteinsdóttir, Lise W. Thørner, Mie Topholm Bruun, Henrik Ullum, Thomas Werge, David Westergaard
Journal: JAMA Cardiology (2023)

Importance Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression ( cis -eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure Genotype. Main Outcomes and Measures Pericarditis. Results In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10 −16 ), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10 −8 ). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) ( P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1 ), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB ). Conclusions and Relevance This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1–blocking drugs.