Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase-Independent Effects.
BACKGROUND
Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low-density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures.


RESULTS
A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low-density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low-density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL.


CONCLUSIONS
We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.). n.j.timpson@bris.ac.uk f.drenos@bristol.ac.uk.
Fotios
F
Drenos
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
George
G
Davey Smith
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Mika
M
Ala-Korpela
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Johannes
J
Kettunen
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Peter
P
Würtz
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Pasi
P
Soininen
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Antti J
AJ
Kangas
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Caroline
C
Dale
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Debbie A
DA
Lawlor
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Tom R
TR
Gaunt
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.).
Juan-Pablo
JP
Casas
From the MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol (F.D., G.D.S., M.A.-K., D.A.L., T.R.G., N.J.T.); Institute of Cardiovascular Science, University College London, London, United Kingdom (F.D., C.D., J.-P.C.); Computational Medicine, Faculty of Medicine, University of Oulu & Biocenter Oulu, Oulu (M.A.-K., J.K., P.W., P.S., A.J.K.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (M.A.-K., J.K., P.S.); Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (J.K.); and Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom (C.D., J.-P.C.). n.j.timpson@bris.ac.uk f.drenos@bristol.ac.uk.
Nicholas J
NJ
Timpson
D000293:Adolescent; D000328:Adult; D000368:Aged; D053305:Apolipoprotein C-III / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D015415:Biomarkers / Q000097:blood; D002648:Child; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000627:therapeutic use; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood; D006113:United Kingdom
D053305:Apolipoprotein C-III; D015415:Biomarkers; D000960:Hypolipidemic Agents; C000593612:ISIS 304801; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D009841:Oligonucleotides; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase
LPL; VLDL; association studies; genetics; lipids; metabolism; triglycerides