Variants at the Interleukin 1 Gene Locus and Pericarditis

• Published in: JAMA Cardiology
• Main 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
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2024
• Subjects: Iceland
• Online Access: https://curis.ku.dk/portal/da/publications/variants-at-the-interleukin-1-gene-locus-and-pericarditis(801250e0-1d9c-4679-ac71-ae84b21b5cb7).html; https://doi.org/10.1001/jamacardio.2023.4820

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 ...