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

Ganna A, Salihovic S, Sundström J, Broeckling CD, Hedman AK, Magnusson PK, Pedersen NL, Larsson A, Siegbahn A, Zilmer M, Prenni J, Arnlöv J, Lind L, Fall T, Ingelsson E - PLoS Genet. (2014)

Bottom Line: MG 18∶2 was associated with CHD independently of triglycerides.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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.

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Association between four metabolites and cardiovascular traits and genotypes.Panel A: Association with main cardiovascular risk factors in three population-based studies. Panel B: Minus log10(P-value) for association with markers of inflammation, oxidative stress and subclinical CVD in PIVUS. Sex-adjusted analysis (upper panel) and adjusted by sex, systolic blood pressure, body mass index, current smoker, antihypertensive treatment, LDL-C, HDL-C, log-triglycerides and diabetes at baseline (lower panel). * indicates the alpha threshold after multiple-testing correction. Panel C: Minus log10(P-value) for association with 51 SNPs previously reported for association with CHD (44 SNPs) or selected from candidate pathways (7 SNPs).
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pgen-1004801-g002: Association between four metabolites and cardiovascular traits and genotypes.Panel A: Association with main cardiovascular risk factors in three population-based studies. Panel B: Minus log10(P-value) for association with markers of inflammation, oxidative stress and subclinical CVD in PIVUS. Sex-adjusted analysis (upper panel) and adjusted by sex, systolic blood pressure, body mass index, current smoker, antihypertensive treatment, LDL-C, HDL-C, log-triglycerides and diabetes at baseline (lower panel). * indicates the alpha threshold after multiple-testing correction. Panel C: Minus log10(P-value) for association with 51 SNPs previously reported for association with CHD (44 SNPs) or selected from candidate pathways (7 SNPs).

Mentions: We explored the associations of our four novel metabolites and main cardiovascular risk factors (Fig. 2, Panel A), as well as with markers of oxidative stress, inflammation and subclinical CVD (Fig. 2, Panel B). The two LysoPC species showed a similar pattern of association; higher LysoPC levels were associated with higher high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and lower body mass index (BMI). Similar associations were also observed for SM 28∶1. Monoglyceride 18∶2 was positively associated with triglycerides and BMI levels in all the three studies, while the association with HDL-C levels was in the inverse direction. The correlation between MG 18∶2 and triglycerides (measured in serum using standard methods) was strong (r2 range: 0.25–0.53). In TwinGene, when triglycerides and MG 18∶2 were included in the same model adjusting for only age and sex, both showed an independent significant positive association with incident CHD (S6 Table, panel A). Further, when they were separately added to models with all main cardiovascular risk factors except triglycerides, MG 18∶2 showed a larger increase in the likelihood ratio (204.6 vs. 197.6) and C-statistic (0.755 vs. 0.753) compared with triglycerides (S6 Table, panel B).


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

Ganna A, Salihovic S, Sundström J, Broeckling CD, Hedman AK, Magnusson PK, Pedersen NL, Larsson A, Siegbahn A, Zilmer M, Prenni J, Arnlöv J, Lind L, Fall T, Ingelsson E - PLoS Genet. (2014)

Association between four metabolites and cardiovascular traits and genotypes.Panel A: Association with main cardiovascular risk factors in three population-based studies. Panel B: Minus log10(P-value) for association with markers of inflammation, oxidative stress and subclinical CVD in PIVUS. Sex-adjusted analysis (upper panel) and adjusted by sex, systolic blood pressure, body mass index, current smoker, antihypertensive treatment, LDL-C, HDL-C, log-triglycerides and diabetes at baseline (lower panel). * indicates the alpha threshold after multiple-testing correction. Panel C: Minus log10(P-value) for association with 51 SNPs previously reported for association with CHD (44 SNPs) or selected from candidate pathways (7 SNPs).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263376&req=5

pgen-1004801-g002: Association between four metabolites and cardiovascular traits and genotypes.Panel A: Association with main cardiovascular risk factors in three population-based studies. Panel B: Minus log10(P-value) for association with markers of inflammation, oxidative stress and subclinical CVD in PIVUS. Sex-adjusted analysis (upper panel) and adjusted by sex, systolic blood pressure, body mass index, current smoker, antihypertensive treatment, LDL-C, HDL-C, log-triglycerides and diabetes at baseline (lower panel). * indicates the alpha threshold after multiple-testing correction. Panel C: Minus log10(P-value) for association with 51 SNPs previously reported for association with CHD (44 SNPs) or selected from candidate pathways (7 SNPs).
Mentions: We explored the associations of our four novel metabolites and main cardiovascular risk factors (Fig. 2, Panel A), as well as with markers of oxidative stress, inflammation and subclinical CVD (Fig. 2, Panel B). The two LysoPC species showed a similar pattern of association; higher LysoPC levels were associated with higher high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and lower body mass index (BMI). Similar associations were also observed for SM 28∶1. Monoglyceride 18∶2 was positively associated with triglycerides and BMI levels in all the three studies, while the association with HDL-C levels was in the inverse direction. The correlation between MG 18∶2 and triglycerides (measured in serum using standard methods) was strong (r2 range: 0.25–0.53). In TwinGene, when triglycerides and MG 18∶2 were included in the same model adjusting for only age and sex, both showed an independent significant positive association with incident CHD (S6 Table, panel A). Further, when they were separately added to models with all main cardiovascular risk factors except triglycerides, MG 18∶2 showed a larger increase in the likelihood ratio (204.6 vs. 197.6) and C-statistic (0.755 vs. 0.753) compared with triglycerides (S6 Table, panel B).

Bottom Line: MG 18∶2 was associated with CHD independently of triglycerides.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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.

Show MeSH
Related in: MedlinePlus