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

ImportanceRecurrent 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.ObjectiveTo use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis.Design, Setting, and ParticipantsThis 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.ExposureGenotype.Main Outcomes and MeasuresPericarditis.ResultsIn 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 RelevanceThis 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.