Variants at the Interleukin 1 Gene Locus and Pericarditis.
Variants at the Interleukin 1 Gene Locus and Pericarditis.
复制标题
白细胞介素 1 基因座的变异与心包炎。
DOI：
10.1001/jamacardio.2023.4820
复制
发表时间：
2023
期刊：
影响因子：
24
通讯作者：
Kári Stefánsson
中科院分区：
文献类型：
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作者：
Rosa B. Thorolfsdottir;Andrea B Jonsdottir;Gardar Sveinbjornsson;Hildur M Aegisdottir;A. Oddsson;Olafur A. Stefansson;G. Halldorsson;S. Saevarsdottir;G. Thorleifsson;L. Stefánsdóttir;O. B. Pedersen;E. Sørensen;J. Ghouse;A. Raja;Chaoqun Zheng;Elvira Silajdzija;S. A. Rand;C. Erikstrup;H. Ullum;Christina Mikkelsen;K. Banasik;S. Brunak;Erna V. Ivarsdottir;A. Sigurdsson;Doruk Beyter;Árni Sturluson;Hafsteinn Einarsson;V. Tragante;H. Helgason;S. Lund;B. Halldórsson;Brynja D. Sigurpálsdóttir;I. Olafsson;D. Arnar;G. Thorgeirsson;Kirk U Knowlton;Lincoln D Nadauld;S. Gretarsdottir;A. Helgadóttir;S. Ostrowski;Daniel F Gudbjartssson;I. Jónsdóttir;H. Bundgaard;H. Hólm;P. Sulem;Kári Stefánsson
重要性
复发性心包炎是一种治疗挑战，通常是一种使人衰弱的疾病。抑制白细胞介素1细胞因子的药物是一种有前途的新的治疗选择，但它们的使用是基于稀缺的生物学证据和适度规模的临床试验，先天性和适应性免疫过程的病理生理学的贡献是不完全理解的。
目的
利用人类基因组学、转录组学和蛋白质组学来阐明心包炎的发病机制。
设计、设置和参与者
这是对5个国家心包炎全基因组关联研究的荟萃分析。研究了心包炎相关变异与心包炎亚型（包括复发性心包炎）和继发表型之间的关系。为了探索机制，评估了与信使RNA表达（cis-eQTL）、血浆蛋白水平（pQTL）和DNA的CpG甲基化（ASM-QTL）的关联。包括来自冰岛（deCODE遗传学，1983-2020）、丹麦（哥本哈根医院生物库/丹麦献血者研究，1977-2022）、英国（英国生物库，1953-2021）、美国（Intermountain，1996-2022）和芬兰（FinnGen，1970-2022）的数据。数据分析时间为2022年9月至2023年8月。
暴露
基因型。
主要成果和措施
心包炎。
结果
在对4894例心包炎患者（诊断时平均[SD]年龄51.4 [17.9]岁，2734例[67.6%]男性，不包括FinnGen队列）进行的全基因组关联研究中，确定了与染色体2 q14上白细胞介素1基因座的2个独立常见基因间变异相关。前导变体为rs 12992780（T）（效应等位基因频率[EAF]，31%-40%;比值比[OR]，0.83; 95% CI，0.79-0.87; P = 6.67 × 10-16），IL 1B下游和次要变异rs7575402（A或T）（EAF，45%-55%;校正OR，0.89; 95% CI，0.85-0.93;校正P = 9.6 × 10-8）。前导变体rs 12992780复发性心包炎的优势比较小，（0.76）比急性型（0.86）（异质性P = 0.03），rs7575402与已知调节白细胞介素1产生的4种转录因子的CpG甲基化重叠结合位点相关：PU.1（由SPI 1编码）、STAT 1、STAT 3和CCAAT/增强子结合蛋白β（由CEBPB编码）。
结论和相关性
本研究发现心包炎与白细胞介素1基因位点的2个独立序列变异之间存在关联。这一发现有可能有助于开发更有针对性和个性化的治疗心包炎的白细胞介素1阻断药物。
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.
人类血细胞性状变异的等位基因景观及其与常见复杂疾病的联系
DOI：
10.17863/cam.7108
发表时间：
2016
期刊：
--
影响因子：
--
作者：
Astle W
通讯作者：
Astle W