Abstract P365: A Variant Impacting Beta-Oxidation of Medium-Chain Fatty Acids is Associated With Response to Triglyceride Challenge and Lipoprotein Subfractions
Introduction: Genomic analysis of metabolomic profiles has revealed large effect genetic loci that may play a role in cardiovascular disease and metabolic syndrome. The ACADM gene is one such locus. Previous reports indicate that a common variant upstream of ACADM (rs211718) is robustly associated with serum levels of medium-chain acylcarnitines consistent with the gene product’s role in beta oxidation of medium-chain fatty acids. With this in mind, we tested the hypothesis that rs211718 would be associated with triglyceride excursion during a high-fat feeding challenge and with fasting lipoprotein subfractions in ~650 individuals from the Heredity and Phenotype Intervention (HAPI) Heart Study.
Methods: Participants in the high-fat challenge were given a whipping cream milk shake that was standardized to consist of 782 calories/m2 body surface and contain a calorie break down of 77.6% from fat, 19.2% from carbohydrate and 3.1% from protein. Blood was drawn before intervention and at 1, 2, 3, 4 and 6 hours to assess triglyceride response. Lipoprotein cholesterol subfractions including high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), very low density lipoprotein (VLDL-C), intermediate density lipoprotein (IDL-C) and their subclasses were measured by Vertical Auto Profile (VAP) technology (Atherotech, Birmingham, AL) on fasting samples. The rs211718 variant was genotyped as part of the Illumina exome gene chip. Analyses were conducted using linear mixed models that accounted for age, sex and relatedness of the study subjects.
Results: Both higher fasting triglyceride levels (p=2.3x10-4) and heightened 6-hour triglyceride response (p=9.0x10-4), as measured by the incremental area under the triglyceride excursion curve, were observed. We also observed higher fasting total VLDL-C (p=2.8x10-5), VLDL3-C (p=3.3x10-5), IDL-C (p=1.8x10-2) and remnant lipoprotein (ie VLDL3-C+IDL-C; p=7.3x10-5) but no difference in HDL-C or LDL-C.
Conclusion: Mutations in ACADM are responsible for the recessive disorder medium-chain acyl-CoA dehydrogenase deficiency (MCADD), which is marked by hypoglycemia and damaging build up of partially metabolized fatty acids in tissues and managed by avoidance of fasting. Common variants in the ACADM locus may fall on the same clinical spectrum as MCADD but with more subtle clinical manifestations. While further work to characterize additional cardiovascular phenotypes and determine the impact of this ACADM variant on various fasting and fed states is needed, we conclude that common variants associated with metabolite profiling may have relevant clinical and translational implications.
Author Disclosures: L.M. Yerges-Armstrong: B. Research Grant; Significant; NIH K01 HL116770. B.D. Mitchell: B. Research Grant; Significant; NIH R01 HL121007 . T.I. Pollin: B. Research Grant; Significant; NIH R01 HL104193. C.M. Damcott: None. A.R. Shuldiner: A. Employment; Significant; Regeneron Pharmaceuticals, Inc.. J.R. O'Connell: None.
- © 2015 by American Heart Association, Inc.