APOC1 T45S polymorphism is associated with reduced obesity indices and lower plasma concentrations of leptin and apolipoprotein C-I in aboriginal Canadians

Apolipoprotein (apo) C-I is a constituent of chylomicrons, very low density lipoprotein, and high density lipoprotein. The role of apo C-I in human metabolism is incompletely defined. We took advantage of a naturally occurring amino acid polymorphism that is present in aboriginal North Americans, namely apo C-I T45S. We assessed the hypothesis that metabolic traits, including obesity-related and lipoprotein-related traits, would differ between carriers and noncarriers of apo C-I T45S. A genotyping assay was developed for APOC1 T45S and genotypes were determined in a sample of 410 Canadian Oji-Cree subjects. The allele frequency of the apo C-I S45 allele was ∼8% in this sample. We observed the apo C-I S45 allele was significantly associated with 1) lower percent body fat (P < 0.05), 2) lower waist circumference (P = 0.058), 3) lower serum leptin levels (P < 0.05), and 4) lower plasma apo C-I levels (P < 0.0001), using a newly developed ELISA-based method. Taken together, these results suggest that at the whole human phenotype level, apo C-I is associated with the complex metabolic trait of obesity as well as with serum leptin levels. Apolipoprotein (apo) C-I is a constituent of chylomicrons, very low density lipoprotein, and high density lipoprotein. The role of apo C-I in human metabolism is incompletely defined. We took advantage of a naturally occurring amino acid polymorphism that is present in aboriginal North Americans, namely apo C-I T45S. We assessed the hypothesis that metabolic traits, including obesity-related and lipoprotein-related traits, would differ between carriers and noncarriers of apo C-I T45S. A genotyping assay was developed for APOC1 T45S and genotypes were determined in a sample of 410 Canadian Oji-Cree subjects. The allele frequency of the apo C-I S45 allele was ∼8% in this sample. We observed the apo C-I S45 allele was significantly associated with 1) lower percent body fat (P < 0.05), 2) lower waist circumference (P = 0.058), 3) lower serum leptin levels (P < 0.05), and 4) lower plasma apo C-I levels (P < 0.0001), using a newly developed ELISA-based method. Taken together, these results suggest that at the whole human phenotype level, apo C-I is associated with the complex metabolic trait of obesity as well as with serum leptin levels. Complex quantitative traits such as obesity are influenced by both genetic and environmental factors. Moreover, evaluation of the genetic contribution identifies gene products and their interactions in biological pathways, aiding in overall understanding of these complex traits. We have previously identified significant associations between genomic variants and complex traits in the Oji-Cree, an isolated Canadian First Nations population (1Pollex R.L. Hanley A.J. Zinman B. Harris S.B. Hegele R.A. Clinical and genetic associations with hypertriglyceridemic waist in a Canadian aboriginal population.Int. J. Obes. 2006; 30: 484-491Crossref PubMed Scopus (34) Google Scholar, 2Pollex R.L. Mamakeesick M. Zinman B. Harris S.B. Hegele R.A. Hanley A.J. Peroxisome proliferator-activated receptor gamma polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes.J. Diabetes Complications. 2007; 21: 166-171Crossref PubMed Scopus (31) Google Scholar). The Oji-Cree are an ideal population to study association of genetic factors with complex traits because their background genetic and environmental variation is relatively low. Apolipoprotein (apo) C-I is a protein constituent of chylomicrons, VLDL, and HDL (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar). Apo C-I is a member of the human apo C family, which also includes apo C-II and apo C-III. In contrast to other extensively investigated apolipoproteins such as apo E, B, and AI, and even apo C-II and C-III, the physiological role of apo C-I is less well established. In vitro, apo C-I has been suggested to be positively involved in HDL metabolism through activation of LCAT (4Soutar A.K. Garner C.W. Baker H.N. Sparrow J.T. Jackson R.L. Gotto A.M. Smith L.C. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase.Biochemistry. 1975; 14: 3057-3064Crossref PubMed Scopus (263) Google Scholar), inhibition of HL (5Conde-Knape K. Bensadoun A. Sobel J.H. Cohn J.S. Shachter N.S. Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase.J. Lipid Res. 2002; 43: 2136-2145Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 6Kinnunen P.K. Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Crossref PubMed Scopus (144) Google Scholar), and inhibition of cholesteryl ester (CE) transfer protein (CETP) activity (7Gautier T. Masson D. de Barros J.P. Athias A. Gambert P. Aunis D. Metz-Boutigue M.H. Lagrost L. Human apolipoprotein C–I accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity.J. Biol. Chem. 2000; 275: 37504-37509Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). Using in vivo models of apo C-I-deficient and apo C-I-over-expressing mice, apo C-I has also been suggested to have a positive relationship with LDL. Apo C-I has been observed to affect metabolism of apo B-containing lipoproteins by attenuating VLDL clearance by inhibiting LPL, directly (8Berbee J.F. van der Hoogt C.C. Sundararaman D. Havekes L.M. Rensen P.C. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.J. Lipid Res. 2005; 46: 297-306Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) or indirectly (9Westerterp M. Van Eck M. de Haan W. Offerman E.H. Van Berkel T.J. Havekes L.M. Rensen P.C. Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages.Atherosclerosis. 2007; 195: e9-e16Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar), and by inhibiting liver-specific LDL receptor (LDLR) (10Sehayek E. Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.J. Biol. Chem. 1991; 266: 18259-18267Abstract Full Text PDF PubMed Google Scholar) and LDLR-related protein (LRP) (11Weisgraber K.H. Mahley R.W. Kowal R.C. Herz J. Goldstein J.L. Brown M.S. Apolipoprotein C–I modulates the interaction of apolipoprotein E with beta-migrating very low density lipoproteins (beta-VLDL) and inhibits binding of beta-VLDL to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 22453-22459Abstract Full Text PDF PubMed Google Scholar), as well as the peripheral tissue-specific VLDL receptor (VLDLR) (12Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). Overall, apo C-I has been shown to increase the production of VLDL (13Westerterp M. de Haan W. Berbee J.F. Havekes L.M. Rensen P.C. Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL.J. Lipid Res. 2006; 47: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), triglyceride (TG) and cholesterol in mice (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar, 8Berbee J.F. van der Hoogt C.C. Sundararaman D. Havekes L.M. Rensen P.C. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.J. Lipid Res. 2005; 46: 297-306Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Human genetic studies have had limited success in better elucidating the physiological role of apo C-I. This is due in part to the paucity of naturally-occurring human variants in apo C-I compared with numerous common and rare variants affecting the protein sequences of apo E, B, A-I, A-II, A-IV, A-V, C-II, and C-III (14Lusis A.J. Fogelman A.M. Fonarow G.C. Genetic basis of atherosclerosis: part II: clinical implications.Circulation. 2004; 110: 2066-2071Crossref PubMed Scopus (70) Google Scholar). The human variants of these other apolipoproteins have often served to identify and specify key pathways and mechanisms for more intensive study (15Hegele R.A. Plasma lipoproteins: genetic influences and clinical implications.Nat. Rev. Genet. 2009; 10: 109-121Crossref PubMed Scopus (318) Google Scholar). Common noncoding DNA variants of APOC1 located in the promoter region were among the first to have been reported for genes affecting lipoprotein metabolism (16Frossard P.M. Coleman R.T. Malloy M.J. Kane J.P. Levy-Wilson B. Appleby V.A. Human apolipoprotein CI (apoC1) gene locus: DraI dimorphic site.Nucleic Acids Res. 1987; 15: 1884Crossref PubMed Scopus (10) Google Scholar, 17Frossard P.M. Lim D.W. Coleman R.T. Funke H. Assmann G. Malloy M.J. Kane J.P. Human apolipoprotein CI (ApoC1) gene locus: BglI dimorphic site.Nucleic Acids Res. 1987; 15: 1344Crossref PubMed Scopus (7) Google Scholar) with somewhat variable associations with plasma lipoproteins (18Smit M. van der Kooij-Meijs E. Woudt L.P. Havekes L.M. Frants R.R. Exact localization of the familial dysbetalipoproteinemia associated HpaI restriction site in the promoter region of the APOC1 gene.Biochem. Biophys. Res. Commun. 1988; 152: 1282-1288Crossref PubMed Scopus (26) Google Scholar, 19Hubacek J.A. Waterworth D.M. Poledne J. P.J. Genetic of plasma and in the PubMed Scopus Google Scholar, N.S. D. S. K. Cohn J.S. L. S. 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Google Scholar). apo C-I was at at a of by with well was for at with and and by with serum and apo C-I with and were to well and for at at were with and by the of apo C-I in and in and in was developed by of of and of The was at with of development was at using a this a of Oji-Cree were to in to for on was for are as or as for were were were for were in were for and differences in and between with and the S45 using the or the was at a < for The clinical and of the 410 Oji-Cree are shown in This of the Oji-Cree had even of and In to the traits their and their were also in clinical and traits of and = A-I, B, = body = = = = = = = body waist to of metabolic using the J. G. M. Human apolipoprotein by Clin. Chem. Clin. Google of of hypertriglyceridemic waist using from the J. G. M. Human apolipoprotein by Clin. Chem. Clin. Google = = = = in a body waist to of metabolic using the J. G. M. Human apolipoprotein by Clin. Chem. Clin. Google of of hypertriglyceridemic waist using from the J. G. 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In this sample of Oji-Cree, had the APOC1 had the and had the were S45 was as a allele for the of Overall, the APOC1 T45S in the Oji-Cree significantly from of the In the allele for and S45 carriers are in and allele in in their in percent in their in in a The clinical and and of the Oji-Cree to their APOC1 genotypes are shown in for or clinical trait was for and were significant differences (P in of the plasma In were significant differences in the of or in or The lower in waist circumference and in S45 compared with was to significant with = (P = using and = were significant differences (P < in percent body serum leptin and with lower levels of these traits in the APOC1 S45 In that the APOC1 S45 allele was associated with a significantly lower serum apo C-I (P < and traits of Oji-Cree to APOC1 T45S = = = body percent body = = waist = = = = = body waist to of hypertriglyceridemic of hypertriglyceridemic waist using from the of The of The on of In J. significant with are are for and The in the observed for the trait is significant or to = = = = in a body waist to of hypertriglyceridemic of hypertriglyceridemic waist using from the of The of The on of In J. significant with are are for and The in the observed for the trait is significant or to The of this study in Oji-Cree were significant associations between the APOC1 T45S polymorphism and in obesity serum and apo C-I levels. in the APOC1 S45 allele 1) lower waist including lower frequency of 2) lower percent body 3) lower serum leptin and 4) lower serum apo C-I using an ELISA-based quantitative method. the T45S in APOC1 among the Canadian First Nations is associated with in and lower serum apo C-I levels. Human apo C-II, and C-III, are protein of chylomicrons, VLDL, and is the of the apo C-II and C-III in lipoprotein less is the biological of apo C-I. The gene for human apo is part of a gene on The gene also includes and the gene (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar, D. Levy-Wilson B. of the human apolipoprotein C–I gene are to the apolipoprotein E Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). The APOC1 gene is in the with lower in the and D. Levy-Wilson B. of the human apolipoprotein C–I gene are to the apolipoprotein E Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). The gene from APOC1 has products in D. Levy-Wilson B. of the human apolipoprotein C–I gene are to the apolipoprotein E Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). 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Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar, E. Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.J. Biol. Chem. 1991; 266: 18259-18267Abstract Full Text PDF PubMed Google Scholar, K.H. Mahley R.W. Kowal R.C. Herz J. Goldstein J.L. Brown M.S. Apolipoprotein C–I modulates the interaction of apolipoprotein E with beta-migrating very low density lipoproteins (beta-VLDL) and inhibits binding of beta-VLDL to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 22453-22459Abstract Full Text PDF PubMed Google Scholar, R.C. Herz J. K.H. Mahley R.W. Brown M.S. Goldstein J.L. of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). such is the that apo C-I has by the activity of as well as a protein to cholesterol in HDL such that increases HDL levels and (4Soutar A.K. Garner C.W. Baker H.N. Sparrow J.T. Jackson R.L. Gotto A.M. Smith L.C. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase.Biochemistry. 1975; 14: 3057-3064Crossref PubMed Scopus (263) Google Scholar). the metabolic of apo have been by the of gene through human transgenic mice and mice Human a or have been to in lipoprotein such as inhibition of (8Berbee J.F. van der Hoogt C.C. Sundararaman D. Havekes L.M. Rensen P.C. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.J. Lipid Res. 2005; 46: 297-306Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, M. de Haan W. Berbee J.F. Havekes L.M. Rensen P.C. Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL.J. Lipid Res. 2006; 47: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), inhibition of apo clearance via (12Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar), and the binding of VLDL to the (12Jong M.C. Dahlmans V.E. van Gorp P.J. van Dijk K.W. Breuer M.L. Hofker M.H. Havekes L.M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.J. Clin. Invest. 1996; 98: 2259-2267Crossref PubMed Scopus (101) Google Scholar). have been associated with hyperlipidemia and development (9Westerterp M. Van Eck M. de Haan W. Offerman E.H. Van Berkel T.J. Havekes L.M. Rensen P.C. Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages.Atherosclerosis. 2007; 195: e9-e16Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). In to of plasma acid and M.C. M.J. Dahlmans V.E. Gorp P.J. M. Hofker M.H. Havekes L.M. and in transgenic mice human apolipoprotein Clin. Invest. PubMed Scopus Google Scholar), which an role for apo C-I in as well as transgenic mice hyperlipidemia N.S. T. G. J.L. H.N. 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Overall, in vitro, in and clinical that apo C-I inhibits the uptake of lipoproteins via hepatic and as a the of apo C-I on the lipoprotein their in the and their to LDL (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar). Apo C-I also to which in activity to production activity has a positive on LDL K.H. J.S. Apolipoprotein E is the physiological of on apolipoprotein 2005; PubMed Scopus Google Scholar). In apo C-I has a role in as observed in human transgenic mice M.C. M.J. Dahlmans V.E. Gorp P.J. M. Hofker M.H. Havekes L.M. and in transgenic mice human apolipoprotein Clin. Invest. PubMed Scopus Google Scholar). study that the S45 in the Canadian First Nations results in lower of apo C-I and which to lower percent body fat and waist a study has suggested the S45 to have and to the VLDL compared with the APOC1 M.S. J.T. C. A functional polymorphism of apolipoprotein C1 by J. 2006; PubMed Scopus Google of apo C-I was observed to be associated with fat in with der R.L. Berbee J.F. H. de A. J.A. Rensen P.C. J.T. Plasma apolipoprotein CI and levels are associated with plasma triglyceride levels and fat in with the metabolic 2009; PubMed Scopus Google Scholar). on the studies apo C-I to HDL as well as LDL production due to on and on lipoprotein clearance and LCAT A study of a be to as levels be by or lipoprotein studies are to the of the T45S polymorphism on the and of apo C-I in Canadian First Nations and other using and plasma of apolipoproteins in to the clinical of this In studies to the of this on the for obesity and Overall, such studies using isolated the physiological role of this relatively protein in complex metabolic In the of apo C-I is the human genetic suggest a role for the APOC1 S45 in obesity and as by the in body waist of as well as a serum leptin levels. Moreover, this is the first of a relationship of APOC1 genetic variation with the serum of apo C-I. We the of apolipoprotein cholesteryl ester transfer protein hypertriglyceridemic waist metabolic cholesterol triglyceride

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