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High heritability of metabolomic profiles in families burdened with premature cardiovascular disease.

Shah SH, Hauser ER, Bain JR, Muehlbauer MJ, Haynes C, Stevens RD, Wenner BR, Dowdy ZE, Granger CB, Ginsburg GS, Newgard CB, Kraus WE - Mol. Syst. Biol. (2009)

Bottom Line: We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h(2)=0.33-0.80, P=0.005-1.9 x 10(-16)), free fatty acids (arachidonic, palmitic, linoleic; h(2)=0.48-0.59, P=0.002-0.00005) and acylcarnitines (h(2)=0.23-0.79, P=0.05-0.0000002).Principal components analysis was used to identify metabolite clusters.These results have implications for understanding CAD pathophysiology and genetics.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. svati.shah@duke.edu

ABSTRACT
Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantitative mass spectrometry-based metabolic profiling in 117 individuals within eight multiplex families from the GENECARD study of premature CAD. Heritabilities were calculated using variance components. We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h(2)=0.33-0.80, P=0.005-1.9 x 10(-16)), free fatty acids (arachidonic, palmitic, linoleic; h(2)=0.48-0.59, P=0.002-0.00005) and acylcarnitines (h(2)=0.23-0.79, P=0.05-0.0000002). Principal components analysis was used to identify metabolite clusters. Reflecting individual metabolites, several components were heritable, including components comprised of ketones, beta-hydroxybutyrate and C2-acylcarnitine (h(2)=0.61); short- and medium-chain acylcarnitines (h(2)=0.39); amino acids (h(2)=0.44); long-chain acylcarnitines (h(2)=0.39) and branched-chain amino acids (h(2)=0.27). We report a novel finding of high heritabilities of metabolites in premature CAD, establishing a possible genetic basis for these profiles. These results have implications for understanding CAD pathophysiology and genetics.

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Related in: MedlinePlus

Heritabilities of conventional metabolites. Heritabilities of the conventional metabolites are displayed in graphical form. The Y-axis is the negative log10 of the P-value for the heritability estimate (X-axis). Error bars around heritability point estimates are in light gray.
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f1: Heritabilities of conventional metabolites. Heritabilities of the conventional metabolites are displayed in graphical form. The Y-axis is the negative log10 of the P-value for the heritability estimate (X-axis). Error bars around heritability point estimates are in light gray.

Mentions: Consistent with prior reports (Beekman et al, 2002), we found high heritabilities for conventional risk factors such as lipids and body mass index (BMI) (Figure 1). Total ketones (h2=0.75, P=3.8 × 10−8) had the highest heritability among the metabolites analyzed by non-mass spectrometry-based methods, with similarly high heritability of the individual ketone β-hydroxybutyrate (HBUT; h2=0.51, P=0.004). Among analytes measured by mass spectrometry, several amino acids had high heritability (Figure 2; Supplementary information). Arginine (ARG) had the highest score (h2=0.80, P=1.9 × 10−16), with strong heritabilities also for glutamine/glutamate (GLX; h2=0.73, P=0.00006), alanine (ALA; h2=0.55, P=0.00002), proline (PRO; h2=0.52, P=0.00004), ornithine (ORN; h2=0.48, P=0.000005), phenylalanine (PHE; h2=0.46, P=0.0001) and the branched-chain amino acids leucine/isoleucine (LEU/ILE; h2=0.39, P=0.00005) and valine (VAL; h2=0.44, P=0.00006). Of the free fatty acids (Figure 2), FA-C20:4 (arachidonic acid, a key component in inflammatory pathways) was the most heritable (h2=0.59, P=0.00005), as well as FA-C18:2 (linoleic acid, precursor to arachidonic acid, h2=0.48, P=0.002). Many acylcarnitines also had high heritabilities (Figure 3; Supplementary information), the highest being the C18 acylcarnitines (C18, C18:1, and C18:2; h2=0.39–0.82, P=0.0000007–0.004); C14:1 (h2=0.79, P=0.0000002); C5:1 (h2=0.67, P=0.000003); the C10s (C10-OH:C8-DC, C10 and C10:1; h2=0.35–0.57, P=0.00003–0.02); C16 (h2=0.57, P=0.0002); C4:Ci4 (h2=0.56, P=0.00003); short chain dicarboxylacylcarnitines (C5-DC, C6-DC; h2=0.45–0.51, P=0.003–0.004) and C2 acylcarnitine (h2=0.50, P=0.00008). Interestingly, estimates for the genetic component of the variability of each metabolite often exceeded the proportion of variance explained by clinical covariates (Supplementary information).


High heritability of metabolomic profiles in families burdened with premature cardiovascular disease.

Shah SH, Hauser ER, Bain JR, Muehlbauer MJ, Haynes C, Stevens RD, Wenner BR, Dowdy ZE, Granger CB, Ginsburg GS, Newgard CB, Kraus WE - Mol. Syst. Biol. (2009)

Heritabilities of conventional metabolites. Heritabilities of the conventional metabolites are displayed in graphical form. The Y-axis is the negative log10 of the P-value for the heritability estimate (X-axis). Error bars around heritability point estimates are in light gray.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683717&req=5

f1: Heritabilities of conventional metabolites. Heritabilities of the conventional metabolites are displayed in graphical form. The Y-axis is the negative log10 of the P-value for the heritability estimate (X-axis). Error bars around heritability point estimates are in light gray.
Mentions: Consistent with prior reports (Beekman et al, 2002), we found high heritabilities for conventional risk factors such as lipids and body mass index (BMI) (Figure 1). Total ketones (h2=0.75, P=3.8 × 10−8) had the highest heritability among the metabolites analyzed by non-mass spectrometry-based methods, with similarly high heritability of the individual ketone β-hydroxybutyrate (HBUT; h2=0.51, P=0.004). Among analytes measured by mass spectrometry, several amino acids had high heritability (Figure 2; Supplementary information). Arginine (ARG) had the highest score (h2=0.80, P=1.9 × 10−16), with strong heritabilities also for glutamine/glutamate (GLX; h2=0.73, P=0.00006), alanine (ALA; h2=0.55, P=0.00002), proline (PRO; h2=0.52, P=0.00004), ornithine (ORN; h2=0.48, P=0.000005), phenylalanine (PHE; h2=0.46, P=0.0001) and the branched-chain amino acids leucine/isoleucine (LEU/ILE; h2=0.39, P=0.00005) and valine (VAL; h2=0.44, P=0.00006). Of the free fatty acids (Figure 2), FA-C20:4 (arachidonic acid, a key component in inflammatory pathways) was the most heritable (h2=0.59, P=0.00005), as well as FA-C18:2 (linoleic acid, precursor to arachidonic acid, h2=0.48, P=0.002). Many acylcarnitines also had high heritabilities (Figure 3; Supplementary information), the highest being the C18 acylcarnitines (C18, C18:1, and C18:2; h2=0.39–0.82, P=0.0000007–0.004); C14:1 (h2=0.79, P=0.0000002); C5:1 (h2=0.67, P=0.000003); the C10s (C10-OH:C8-DC, C10 and C10:1; h2=0.35–0.57, P=0.00003–0.02); C16 (h2=0.57, P=0.0002); C4:Ci4 (h2=0.56, P=0.00003); short chain dicarboxylacylcarnitines (C5-DC, C6-DC; h2=0.45–0.51, P=0.003–0.004) and C2 acylcarnitine (h2=0.50, P=0.00008). Interestingly, estimates for the genetic component of the variability of each metabolite often exceeded the proportion of variance explained by clinical covariates (Supplementary information).

Bottom Line: We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h(2)=0.33-0.80, P=0.005-1.9 x 10(-16)), free fatty acids (arachidonic, palmitic, linoleic; h(2)=0.48-0.59, P=0.002-0.00005) and acylcarnitines (h(2)=0.23-0.79, P=0.05-0.0000002).Principal components analysis was used to identify metabolite clusters.These results have implications for understanding CAD pathophysiology and genetics.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. svati.shah@duke.edu

ABSTRACT
Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantitative mass spectrometry-based metabolic profiling in 117 individuals within eight multiplex families from the GENECARD study of premature CAD. Heritabilities were calculated using variance components. We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h(2)=0.33-0.80, P=0.005-1.9 x 10(-16)), free fatty acids (arachidonic, palmitic, linoleic; h(2)=0.48-0.59, P=0.002-0.00005) and acylcarnitines (h(2)=0.23-0.79, P=0.05-0.0000002). Principal components analysis was used to identify metabolite clusters. Reflecting individual metabolites, several components were heritable, including components comprised of ketones, beta-hydroxybutyrate and C2-acylcarnitine (h(2)=0.61); short- and medium-chain acylcarnitines (h(2)=0.39); amino acids (h(2)=0.44); long-chain acylcarnitines (h(2)=0.39) and branched-chain amino acids (h(2)=0.27). We report a novel finding of high heritabilities of metabolites in premature CAD, establishing a possible genetic basis for these profiles. These results have implications for understanding CAD pathophysiology and genetics.

Show MeSH
Related in: MedlinePlus