Variants at the Interleukin 1 Gene Locus and Pericarditis

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

doi:10.1001/jamacardio.2023.4820

Variants at the Interleukin 1 Gene Locus and Pericarditis

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 MikkelsenKarina 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

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

7 Citations (Scopus)

Abstract

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.

Original language	English
Journal	JAMA Cardiology
Volume	9
Issue number	2
Pages (from-to)	165-172
Number of pages	8
ISSN	2380-6583
DOIs	https://doi.org/10.1001/jamacardio.2023.4820
Publication status	Published - 2024

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© 2024 American Medical Association. All rights reserved.

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Thorolfsdottir, R. B., Jonsdottir, A. B., Sveinbjornsson, G., Aegisdottir, H. M., Oddsson, A., Stefansson, O. A., Halldorsson, G. H., Saevarsdottir, S., Thorleifsson, G., Stefansdottir, L., Pedersen, O. B., Sørensen, E., Ghouse, J., Raja, A. A., Zheng, C., Silajdzija, E., Rand, S. A., Erikstrup, C., Ullum, H., ... Stefansson, K. (2024). Variants at the Interleukin 1 Gene Locus and Pericarditis. JAMA Cardiology, 9(2), 165-172. https://doi.org/10.1001/jamacardio.2023.4820

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

Thorolfsdottir, RB, Jonsdottir, AB, Sveinbjornsson, G, Aegisdottir, HM, Oddsson, A, Stefansson, OA, Halldorsson, GH, Saevarsdottir, S, Thorleifsson, G, Stefansdottir, L, Pedersen, OB, Sørensen, E, Ghouse, J, Raja, AA, Zheng, C, Silajdzija, E, Rand, SA, Erikstrup, C, Ullum, H, Mikkelsen, C , Banasik, K , Brunak, S, Ivarsdottir, EV, Sigurdsson, A, Beyter, D, Sturluson, A, Einarsson, H, Tragante, V, Helgason, H, Lund, SH, Halldorsson, BV, Sigurpalsdottir, BD, Olafsson, I, Arnar, DO, Thorgeirsson, G, Knowlton, KU, Nadauld, LD, Gretarsdottir, S, Helgadottir, A, Ostrowski, SR, Gudbjartssson, DF, Jonsdottir, I, Bundgaard, H, Holm, H, Sulem, P & Stefansson, K 2024, 'Variants at the Interleukin 1 Gene Locus and Pericarditis', JAMA Cardiology, vol. 9, no. 2, pp. 165-172. https://doi.org/10.1001/jamacardio.2023.4820

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. / Variants at the Interleukin 1 Gene Locus and Pericarditis. In: JAMA Cardiology. 2024 ; Vol. 9, No. 2. pp. 165-172.

@article{801250e01d9c4679ac71ae84b21b5cb7,

title = "Variants at the Interleukin 1 Gene Locus and Pericarditis",

abstract = "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. ",

author = "Thorolfsdottir, {Rosa B.} and Jonsdottir, {Andrea B.} and Gardar Sveinbjornsson and Aegisdottir, {Hildur M.} and Asmundur Oddsson and Stefansson, {Olafur A.} and Halldorsson, {Gisli H.} and Saedis Saevarsdottir and Gudmar Thorleifsson and Lilja Stefansdottir and Pedersen, {Ole B.} and Erik S{\o}rensen and Jonas Ghouse and Raja, {Anna Axelsson} and Chaoqun Zheng and Elvira Silajdzija and Rand, {S{\o}ren Albertsen} and Christian Erikstrup and Henrik Ullum and Christina Mikkelsen and Karina Banasik and S{\o}ren Brunak and Ivarsdottir, {Erna V.} and Asgeir Sigurdsson and Doruk Beyter and Arni Sturluson and Hafsteinn Einarsson and Vinicius Tragante and Hannes Helgason and Lund, {Sigrun H.} and Halldorsson, {Bjarni V.} and Sigurpalsdottir, {Brynja D.} and Isleifur Olafsson and Arnar, {David O.} and Gudmundur Thorgeirsson and Knowlton, {Kirk U.} and Nadauld, {Lincoln D.} and Solveig Gretarsdottir and Anna Helgadottir and Ostrowski, {Sisse R.} and Gudbjartssson, {Daniel F.} and Ingileif Jonsdottir and Henning Bundgaard and Hilma Holm and Patrick Sulem and Kari Stefansson",

year = "2024",

doi = "10.1001/jamacardio.2023.4820",

language = "English",

volume = "9",

pages = "165--172",

journal = "JAMA Cardiology",

issn = "2380-6583",

publisher = "American Medical Association",

number = "2",

}

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

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 -