Multiomic integration analysis identifies atherogenic metabolites mediating between novel immune genes and cardiovascular risk.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY Genome Medicine Pub Date : 2024-10-24 DOI:10.1186/s13073-024-01397-2
Robert Carreras-Torres, Iván Galván-Femenía, Xavier Farré, Beatriz Cortés, Virginia Díez-Obrero, Anna Carreras, Ferran Moratalla-Navarro, Susana Iraola-Guzmán, Natalia Blay, Mireia Obón-Santacana, Víctor Moreno, Rafael de Cid
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Abstract

Background: Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions.

Methods: In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk.

Results: A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk.

Conclusions: These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels.

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多组学整合分析确定了介于新型免疫基因和心血管风险之间的致动脉粥样硬化代谢物。
背景:了解基因与代谢物的关联对心血管风险评估具有转化意义。对功能性遗传变异的研究可加深我们对疾病发病机制的了解,并促进有针对性干预措施的开发和优化:在这项研究中,对 GCAT| Genomes for Life 队列中的 4974 名欧洲血统的个体进行了共 187 种血浆代谢物水平分析。基因分析结果与其他数据集进行了荟萃分析,从而得出了多达约 4 万名欧洲人的基因分析结果。荟萃分析结果与来自 58 种组织和细胞类型的参考基因表达面板进行整合,以确定与代谢物水平相关的预测基因表达。这种方法还适用于三项独立的大型欧洲研究(N = 700,000)中的心血管结果,以确定与心血管风险额外相关的预测基因表达。最后,还进行了基因中介分析,以推断基因表达、代谢物水平和心血管风险之间的因果中介关系:结果:共有 44 个基因位点与 124 种代谢物相关。主导基因变异包括 11 个非同义变异。53个精细映射基因的预测表达与108种代谢物水平相关;其中6个基因的预测表达也与心血管结果相关,凸显了调控基因HCG27的新作用。此外,我们发现致动脉粥样硬化代谢物水平介导了基因表达与心血管风险之间的关联。其中一些基因在免疫组织中显示出更强的关联性,进一步证明了免疫细胞在增加心血管风险中的作用:这些发现提出了新的基因靶点,它们可能成为药物开发的潜在候选靶点,通过调节血液中致动脉粥样硬化代谢物的水平来降低心血管事件的风险。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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