Coronary artery disease, genetic risk and the metabolome in young individuals

Wellcome Open Research

article

Thomas Battram¹  Luke Hoskins¹  David A. Hughes¹  Johannes Kettunen¹  Susan M. Ring¹  George Davey Smith¹  Nicholas J. Timpson¹ 

[1] MRC Integrative Epidemiology Unit, University of Bristol;Population Health Sciences, Bristol Medical School, University of Bristol;Center for Life Course Health Research, Faculty of Medicine, University of Oulu;Biocenter Oulu, University of Oulu

关键词: Coronary artery disease;    metabolomics;    genetics;    childhood and adolescence;    ALSPAC;   

DOI  :  10.12688/wellcomeopenres.14788.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease.Methods: 148 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,907 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined.Results: The CAD-GRS associated with 118 of 148 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147PCSK9, rs12149545HERPUD1-CETP, rs17091891LPL, rs515135APOB, rs602633CELSR2-PSRC1, rs651821APOA5, rs7412APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299SERPINA1 and rs2519093ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. Along with further research, this knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise.

【 授权许可】

CC BY