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Comment
. 2024 Feb 1;9(2):165-172.
doi: 10.1001/jamacardio.2023.4820.

Variants at the Interleukin 1 Gene Locus and Pericarditis

Rosa B Thorolfsdottir  1 , Andrea B Jonsdottir  1 , Gardar Sveinbjornsson  1 , Hildur M Aegisdottir  1 , Asmundur Oddsson  1 , Olafur A Stefansson  1 , Gisli H Halldorsson  1   2 , Saedis Saevarsdottir  1   3   4 , Gudmar Thorleifsson  1 , Lilja Stefansdottir  1 , Ole B Pedersen  5   6 , Erik Sørensen  7 , Jonas Ghouse  8   9 , Anna Axelsson Raja  8 , Chaoqun Zheng  8 , Elvira Silajdzija  8 , Søren Albertsen Rand  8   9 , Christian Erikstrup  10   11 , Henrik Ullum  12 , Christina Mikkelsen  7   13 , Karina Banasik  14   15 , Søren Brunak  15 , Erna V Ivarsdottir  1 , Asgeir Sigurdsson  1 , Doruk Beyter  1 , Arni Sturluson  1 , Hafsteinn Einarsson  1   2 , Vinicius Tragante  1 , Hannes Helgason  1   2 , Sigrun H Lund  1 , Bjarni V Halldorsson  1   16 , Brynja D Sigurpalsdottir  1   16 , Isleifur Olafsson  17 , David O Arnar  1   3   4 , Gudmundur Thorgeirsson  1 , Kirk U Knowlton  18   19 , Lincoln D Nadauld  20   21 , Solveig Gretarsdottir  1 , Anna Helgadottir  1 , Sisse R Ostrowski  6   7 , Daniel F Gudbjartssson  1   2 , Ingileif Jonsdottir  1   3   22 , Henning Bundgaard  6   8 , Hilma Holm  1 , Patrick Sulem  1 , Kari Stefansson  1   3 ; Danish Blood Donor Study Genomic Consortium
Collaborators, Affiliations
Comment

Variants at the Interleukin 1 Gene Locus and Pericarditis

Rosa B Thorolfsdottir et al. JAMA Cardiol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Thorolfsdottir, A. Jonsdottir, Sveinbjornsson, Aegisdottir, Oddsson, O. Stefansson, G. Halldorsson, Saevarsdottir, Thorleifsson, Stefansdottir, Ivarsdottir, Sigurdsson, Beyter, Sturluson, Einarsson, Tragante, Helgason, Lund, B. Halldorsson, Sigurpalsdottir, Arnar, Thorgeirsson, Gretarsdottir, Helgadottir, Gudbjartssson, I. Jonsdottir, Holm, Sulem, and K. Stefansson are employed at deCODE genetics, Amgen. Dr Brunak reported grants from Novo Nordisk during the conduct of the study and personal fees from Intomics (board of directors) and Proscion (board of directors) outside the submitted work. Dr Knowlton reported grants from Amgen Heredigene during the conduct of the study. Dr Nadauld reported stock options with Culmination Bio. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Results of a Meta-Analysis of Genome-Wide Association Studies of Pericarditis
A total of 4894 individuals were included in studies from Iceland (deCODE genetics), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study), the UK (UK Biobank), the US (Intermountain), and Finland (FinnGen). The –log10(P value) is plotted against the position of each single-nucleotide variant on each chromosome. The horizontal lines represent the most stringent (P < 4.74 × 10−10, solid line) and least stringent (P < 1.57 × 10−7, dotted line) thresholds for genome-wide significance applied in this study (eMethods in Supplement 2). Orange and blue differentiate data points belonging to each chromosome.
Figure 2.
Figure 2.. Association With Pericarditis on Chromosome 2q14
The plot depicts association P values in a meta-analysis of genome-wide association studies of data from Iceland, Denmark, the UK, the US, and Finland. The y-axis shows the −log10(P value) and the x-axis shows the genomic position (hg38). Variants are colored according to correlation (r2) with the lead variant, rs12992780 in Iceland. The 2 sentinel pericarditis variants (rs12992780 and rs7575402) were not correlated (r2 ≤ 0.06) in Iceland, Denmark, the UK, or the US. The horizontal lines represent the most stringent (P < 4.74 × 10−10, solid line) and least stringent (P < 1.57 × 10−7, dotted line) thresholds for genome-wide significance applied in this study (eMethods in Supplement 2). NA indicates not applicable (variant is not found in Iceland).
See this image and copyright information in PMC

Comment on

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