Variants at the Interleukin 1 Gene Locus and Pericarditis
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Variants at the Interleukin 1 Gene Locus and Pericarditis. / 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.
In: JAMA Cardiology, Vol. 9, No. 2, 2024, p. 165-172.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Variants at the Interleukin 1 Gene Locus and Pericarditis
AU - Thorolfsdottir, Rosa B.
AU - Jonsdottir, Andrea B.
AU - Sveinbjornsson, Gardar
AU - Aegisdottir, Hildur M.
AU - Oddsson, Asmundur
AU - Stefansson, Olafur A.
AU - Halldorsson, Gisli H.
AU - Saevarsdottir, Saedis
AU - Thorleifsson, Gudmar
AU - Stefansdottir, Lilja
AU - Pedersen, Ole B.
AU - Sørensen, Erik
AU - Ghouse, Jonas
AU - Raja, Anna Axelsson
AU - Zheng, Chaoqun
AU - Silajdzija, Elvira
AU - Rand, Søren Albertsen
AU - Erikstrup, Christian
AU - Ullum, Henrik
AU - Mikkelsen, Christina
AU - Banasik, Karina
AU - Brunak, Søren
AU - Ivarsdottir, Erna V.
AU - Sigurdsson, Asgeir
AU - Beyter, Doruk
AU - Sturluson, Arni
AU - Einarsson, Hafsteinn
AU - Tragante, Vinicius
AU - Helgason, Hannes
AU - Lund, Sigrun H.
AU - Halldorsson, Bjarni V.
AU - Sigurpalsdottir, Brynja D.
AU - Olafsson, Isleifur
AU - Arnar, David O.
AU - Thorgeirsson, Gudmundur
AU - Knowlton, Kirk U.
AU - Nadauld, Lincoln D.
AU - Gretarsdottir, Solveig
AU - Helgadottir, Anna
AU - Ostrowski, Sisse R.
AU - Gudbjartssson, Daniel F.
AU - Jonsdottir, Ingileif
AU - Bundgaard, Henning
AU - Holm, Hilma
AU - Sulem, Patrick
AU - Stefansson, Kari
N1 - Publisher Copyright: © 2024 American Medical Association. All rights reserved.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1001/jamacardio.2023.4820
DO - 10.1001/jamacardio.2023.4820
M3 - Journal article
C2 - 38150231
AN - SCOPUS:85181501045
VL - 9
SP - 165
EP - 172
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 2
ER -
ID: 379797208