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
AU - Danish Blood Donor Study Genomic Consortium
A2 - Banasik, Karina
A2 - Bay, Jakob
A2 - Boldsen, Jens K.
A2 - Brodersen, Thorsten
A2 - Brunak, Søren
A2 - Burgdorf, Kristoffer
A2 - Chalmer, Mona A.
A2 - Didriksen, Maria
A2 - Dinh, Khoa M.
A2 - Dowsett, Joseph
A2 - Erikstrup, Christian
A2 - Feenstra, Bjarke
A2 - Geller, Frank
A2 - Gudbjartsson, Daniel
A2 - Hansen, Thomas F.
A2 - Hindhede, Lotte
A2 - Hjalgrim, Henrik
A2 - Jacobsen, Rikke L.
A2 - Jemec, Gregor
A2 - Jensen, Bitten A.
A2 - Kaspersen, Katrine
A2 - Kjerulff, Bertram D.
A2 - Kogelman, Lisette
A2 - Larsen, Margit A. H.
A2 - Louloudis, Ioannis
A2 - Lundgaard, Agnete
A2 - Mikkelsen, Susan
A2 - Mikkelsen, Christina
A2 - Nissen, Ioanna
A2 - Nyegaard, Mette
A2 - Ostrowski, Sisse R.
A2 - Pedersen, Ole Birger
A2 - Henriksen, Alexander P.
A2 - Rohde, Palle D.
A2 - Rostgaard, Klaus
A2 - Schwinn, Michael
A2 - Stefansson, Kari
A2 - Stefánsson, Hreinn
A2 - Sørensen, Erik
A2 - Thorsteinsdóttir, Unnur
A2 - Thørner, Lise W.
A2 - Topholm Bruun, Mie
A2 - Ullum, Henrik
A2 - Werge, Thomas
A2 - Westergaard, David
PY - 2024/2/1
Y1 - 2024/2/1
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.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.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.
UR - http://www.scopus.com/inward/record.url?scp=85181501045&partnerID=8YFLogxK
U2 - 10.1001/jamacardio.2023.4820
DO - 10.1001/jamacardio.2023.4820
M3 - Comment/debate
C2 - 38150231
SN - 2380-6583
VL - 9
SP - 165
EP - 172
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 2
ER -