Multiomic integration analysis identifies atherogenic metabolites mediating between novel immune genes and cardiovascular risk
Carreras-Torres, Robert (Hospital Universitari de Bellvitge)
Galván-Femenía, Iván (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Farré Ramon, Xavier (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Cortés, Beatriz (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Díez-Obrero, Virginia (Hospital Universitari de Bellvitge)
Carreras Nolla, Anna (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Moratalla-Navarro, Ferran (Hospital Universitari de Bellvitge)
Iraola-Guzmán, Susana (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Blay, Natalia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Obón-Santacana, Mireia (Hospital Universitari de Bellvitge)
Moreno Aguado, Víctor (Hospital Universitari de Bellvitge)
de Cid, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Universitat Autònoma de Barcelona

Date:	2024
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.
Grants:	Instituto de Salud Carlos III PI18/01512
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cardiovascular risk ; Genome-wide association analysis ; Immune tissue expression ; Mendelian randomization ; Metabolite levels ; Transcriptome-wide association analysis
Published in:	Genome medicine, Vol. 16 Núm. 1 (december 2024) , p. 122, ISSN 1756-994X

DOI: 10.1186/s13073-024-01397-2
PMID: 39449064

22 p, 3.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles