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Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.

ABSTRACT: Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18?1 (hazard ratio [HR] per standard deviation [SD] increment?=?0.77, P-value<0.001), lysophosphatidylcholine 18?2 (HR?=?0.81, P-value<0.001), monoglyceride 18?2 (MG 18?2; HR?=?1.18, P-value?=?0.011) and sphingomyelin 28?1 (HR?=?0.85, P-value?=?0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18?2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18?2. MG 18?2 showed an enrichment (P-value?=?0.002) of significant associations with CHD-associated SNPs (P-value?=?1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio?=?1.05 per SD increment in MG 18?2, P-value?=?0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

SUBMITTER: Ganna A

PROVIDER: S-EPMC4263376 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.

Ganna Andrea A Salihovic Samira S Sundström Johan J Broeckling Corey D CD Hedman Asa K AK Magnusson Patrik K E PK Pedersen Nancy L NL Larsson Anders A Siegbahn Agneta A Zilmer Mihkel M Prenni Jessica J Arnlöv Johan J Lind Lars L Fall Tove T Ingelsson Erik E

PLoS genetics 20141211 12

Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascula ...[more]

PMID: 25502724

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Project description:Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

Dataset Information

Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.

Publications

Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.

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