High heritability of metabolomic profiles in families burdened with premature cardiovascular disease.
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.
Shah
Svati H
SH
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. svati.shah@duke.edu
Hauser
Elizabeth R
ER
Bain
James R
JR
Muehlbauer
Michael J
MJ
Haynes
Carol
C
Stevens
Robert D
RD
Wenner
Brett R
BR
Dowdy
Z Elaine
ZE
Granger
Christopher B
CB
Ginsburg
Geoffrey S
GS
Newgard
Christopher B
CB
Kraus
William E
WE
D017668:Age of Onset; D000596:Amino Acids / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D005192:Family Health; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D025341:Principal Component Analysis
D000596:Amino Acids; D005227:Fatty Acids; C116917:acylcarnitine; D002331:Carnitine