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Metabolomic Study Identifies Four Biomarkers Linked to Coronary Heart Disease

NEW YORK (GenomeWeb) — Through a non-targeted metabolomics study, Swedish researchers and their colleagues uncovered four novel biomarkers for coronary heart disease.

As they reported in PLOS Genetics today, researchers led by Uppsala University's Erik Ingelsson studied the metabolomes of more than 3,600 individuals to find four metabolites associated with disease risk: monoglyceride, sphingomyelin, and two types of lysophosphatidylcholine.

Further, one metabolite — monoglyceride 18:2 — was associated with SNPs that had previously been linked to coronary heart disease, suggesting that it could have a causal role in disease development.

"These biomarkers moderately improved risk reclassification beyond traditional risk factors, when commonly used risk categories were considered," Ingelsson and his colleagues wrote in their paper.

Using metabolomic profiling, the researchers searched for metabolites linked with coronary heart disease incidents in 1,028 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM). Of those participants, 131 had coronary heart disease incidents during a median 10 years of follow up. From this, the researchers identified 32 metabolites linked to disease.

By drawing on 1,670 people from the TwinGene study, the researchers were able to replicate five of the metabolites, though a meta-analysis combining the ULSAM and TwinGene studies could only replicate three of the original 32 metabolites — monoglyceride 18:2, sphingomyelin 28:1, and lysophosphatidylcholine 18:2.

As lysophosphatidylcholine 18:2 had the strongest association with heart disease in the ULSAM cohort and in the older participants of the TwinGene cohort, the researchers expanded their scope to examine whether additional lysophosphatidylcholine species could be linked to disease. From this, they found that lysophosphatidylcholine 18:1 was also inversely correlated to disease, as was lysophosphatidylcholine 18:2.

Adding these four metabolites into a model of risk factors included in the Framingham Heart study risk score, the researchers saw a moderate improvement in the Net Reclassification Index for events and non-events.

Ingelsson and his colleagues also explored whether these biomarkers might point to biological mechanisms underlying coronary heart disease.

In particular, they examined how these metabolites were associated with other cardiovascular disease risk factors and markers of oxidative stress, inflammation, and subclinical heart disease in the ULSAM, Twin Gene, and the Prospective Investigation of the Vasculature in Uppsala Seniors cohorts.

The two lysophosphatidylcholines species, they reported, are associated with higher levels of HDL cholesterol, lower levels of LDL cholesterol, and lower BMI. Sphingomyelin 28:1 exhibited similar associations.

The monoglyceride, however, was positively correlated with trigelycerides and BMI. Most circulating monoglycerides, the researchers noted, are released when lipoprotein lipases and hepatic lipases hydrolyze triglycerides into non-esterified fatty acids and monoglycerides. In the intestine, they added, monoglycerides are used to synthesize diglycerides and triglycerides that are then transported to the liver.

When the researchers added monoglyceride 18:2 to the model of cardiovascular risk factors, it alone better predicted coronary heart disease than triglycerides.

Ingelsson and his colleagues also performed a series of genome-wide association studies to uncover SNPs linked to these four metabolites. From this, they found a number of SNPs, such as ones near A4GALT and FADS2 linked to lysophosphatidylcholines 18:1 and lysophosphatidylcholines 18:2, respectively.

Monoglyceride 18:2, though, was linked to a number of known coronary heart disease-linked SNPs, including ones near PCSK9, HHIPL1, PLG, ApoE/ApoC1, and COL4A1/COL4A2.

As the researchers noted, their cohorts included middle-aged to elderly people of Northern European decent and may not be generalizable to other ethnicities or age groups.

Still, they said that metabolites they identified appear to be risk factors of coronary heart disease, and that monoglyceride 18:2 may have a causal effect on disease.

"[W]e found one metabolite to be strongly associated with single nucleotide polymorphisms previously reported for association with CHD, and consistent with a potential causal role in CHD development, as suggested by Mendelian randomization analysis," Ingelsson and his colleagues said.