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Gene Review

APOC3  -  apolipoprotein C-III

Homo sapiens

Synonyms: APOCIII, Apo-CIII, ApoC-III, Apolipoprotein C-III, Apolipoprotein C3, ...
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Disease relevance of APOC3

  • However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia [1].
  • METHODS: We evaluated the contribution of APOC3 -482C-->T, -455T-->C, and 3238C-->G; epsilon 2 and epsilon 4 alleles of APOE; and TNF -238G-->A to dyslipidemia and lipoatrophy by longitudinally modeling >2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years [1].
  • CONCLUSIONS: Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV [1].
  • Apolipoprotein C-III (apoC-III) is involved in triglycerides metabolism, and is therefore important for the pathogenesis of coronary heart diseases [2].
  • In a multiple regression analysis, high levels of APOC3 in Lp B and APOC3 Lp non-B were associated with the presence of clinical signs of lipodystrophy, even after adjustment for triglycerides and HDL-cholesterol levels [3].

Psychiatry related information on APOC3

  • The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population [4].
  • Factors influencing apoC-III concentration were age, BMI in adult men, alcohol consumption in adults, oral contraceptive intake in women, the post-pubescent status in boys [2].
  • In Hispanics, current PI antiretroviral therapy (ART) exposure was associated with a significantly smaller increase in TGs among patients with variant alleles at apoC-III-482, -455, and Intron 1, or at a composite apoC-III genotype, compared with patients with the wild-type genotypes [5].

High impact information on APOC3

  • These findings indicate that the polymorphism in the region between the apolipoprotein A-I and apolipoprotein C-III genes may be a useful marker for the risk of premature coronary artery disease and familial hypoalphalipoproteinemia [6].
  • We also show that the apo A-I and apo C-III genes are convergently transcribed and that a polymorphism previously reported to be associated with hypertriglyceridaemia may be due to a single base pair substitution in the 3'-noncoding region of apo C-III mRNA [7].
  • A mouse model displaying some of the features of FCHL was created by crossing mice carrying the human apolipoprotein C-III (APOC3) transgene with mice deficient in the LDL receptor [8].
  • Thus, overexpression of apolipoprotein CIII can be a primary cause of hypertriglyceridemia in vivo and may provide one possible etiology for this common disorder in humans [9].
  • Analysis of genomic DNA from the subjects revealed five polymorphic sites which defined two haplotypes in the intestinal enhancer region of the apoAI gene located upstream of the apolipoprotein CIII gene transcriptional start site (+ 1): (-641 C to A, -630 G to A, -625 T to deletion, -482 C to T, and -455 T to C) [10].

Chemical compound and disease context of APOC3


Biological context of APOC3

  • The genes coding for three proteins of the plasma lipid transport system--apolipoproteins A1 (APOA1), C3 (APOC3), and A4 (APOA4)--are closely linked and tandemly organized on the long arm of human chromosome 11 [15].
  • In contrast to APOA1 and APOC3 genes, which contain three introns, the APOA4 gene contains only two [15].
  • Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G) [16].
  • Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites [16].
  • In men, the APOC3 3206GG genotype was related to decreased diastolic blood pressure (DBP) and MAP levels (P < or = 0.01), and the APOC3 -482T allele with decreased PP levels (P < or = 0.05) [17].

Anatomical context of APOC3


Associations of APOC3 with chemical compounds

  • In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02) [23].
  • Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance [24].
  • From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipoproteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex [25].
  • RESULTS: Increases in triglycerides and non-high-density lipoprotein (HDL) cholesterol were associated with significantly higher levels of APOC3, in both Lp B (lipoproteins containing apolipoprotein B) and Lp non-B (lipoproteins free of apolipoprotein B), and a significant higher level of APOE Lp B [3].
  • In the present study, we estimated plasma APOA5 levels in patients with type 2 diabetes at baseline and during atorvastatin treatment, a lipid-lowering treatment that results in a reduction in plasma triglycerides and APOC3 [26].

Regulatory relationships of APOC3


Other interactions of APOC3

  • Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III [31].
  • The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T [16].
  • We found that (1) common variation at nucleotide -455 of the APOC3 promoter was associated with variation in plasma triglycerides (P = .006) and (2) common variation of APOE determining plasma isoforms of apo E was associated with variation in plasma apo B (P = .009) [32].
  • Allelic frequencies in 70 controls and 110 patients with diabetes from the Chennai Urban Population Study were 52.9% for FABP2 Thr54, 73.0% for APOC3 -482T, and 80.2% for APOC3 -455C [33].
  • In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors [34].

Analytical, diagnostic and therapeutic context of APOC3

  • The current analysis presents results from a subset of patients who had undergone additional tests to measure APOC3 and APOE in order to study their relationship with metabolic syndrome (n=157) and abnormal results in an oral glucose tolerance test (n=135) [3].
  • After treatment, APOC3 remained the major determinant of plasma triglyceride levels (59%), while the contributions of APOA5 and APOE were insignificant (2 and 3%) [26].
  • We conducted a cross-sectional study in a Spanish population (n = 1,029) to investigate associations between the LPL and APOC3 gene loci (LPL-HindIII, LPL-S447X, and APOC3-SstI) and plasma lipid levels and their interaction with APOE polymorphisms and smoking [35].
  • We conducted a study on the relationship between APOC3 SstI polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma TG levels in a group of 139 male healthy volunteers from Northern India. METHODS: DNA samples were analyzed by polymerase chain reaction (PCR) followed by SstI digestion [36].
  • ApoC-III levels in total plasma as quantitated by radioimmunoassay were stable regardless of the increase of plasma triglycerides [37].


  1. Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. Tarr, P.E., Taffé, P., Bleiber, G., Furrer, H., Rotger, M., Martinez, R., Hirschel, B., Battegay, M., Weber, R., Vernazza, P., Bernasconi, E., Darioli, R., Rickenbach, M., Ledergerber, B., Telenti, A. J. Infect. Dis. (2005) [Pubmed]
  2. Biological and genetic determinants of serum apoC-III concentration: reference limits from the Stanislas Cohort. Tilly, P., Sass, C., Vincent-Viry, M., Aguillon, D., Siest, G., Visvikis, S. J. Lipid Res. (2003) [Pubmed]
  3. Association of apolipoproteins C3 and E with metabolic changes in HIV-infected adults treated with a protease-inhibitor-containing antiretroviral therapy. Bard, J.M., Lassalle, R., Capeau, J., Bach-Ngohou, K., Nazih-Sanderson, F., Rémy, G., Reynes, J., Ecobichon, J.L., Savès, M., Raffi, F. Antivir. Ther. (Lond.) (2006) [Pubmed]
  4. The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population. Sun, Y., Shi, J., Zhang, S., Tang, M., Han, H., Guo, Y., Ma, C., Liu, X., Li, T. Neurosci. Lett. (2005) [Pubmed]
  5. Associations among Race/Ethnicity, ApoC-III Genotypes, and Lipids in HIV-1-Infected Individuals on Antiretroviral Therapy. Foulkes, A.S., Wohl, D.A., Frank, I., Puleo, E., Restine, S., Wolfe, M.L., Dube, M.P., Tebas, P., Reilly, M.P. PLoS Med. (2006) [Pubmed]
  6. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. Ordovas, J.M., Schaefer, E.J., Salem, D., Ward, R.H., Glueck, C.J., Vergani, C., Wilson, P.W., Karathanasis, S.K. N. Engl. J. Med. (1986) [Pubmed]
  7. Linkage of human apolipoproteins A-I and C-III genes. Karathanasis, S.K., McPherson, J., Zannis, V.I., Breslow, J.L. Nature (1983) [Pubmed]
  8. A mouse model with features of familial combined hyperlipidemia. Masucci-Magoulas, L., Goldberg, I.J., Bisgaier, C.L., Serajuddin, H., Francone, O.L., Breslow, J.L., Tall, A.R. Science (1997) [Pubmed]
  9. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Ito, Y., Azrolan, N., O'Connell, A., Walsh, A., Breslow, J.L. Science (1990) [Pubmed]
  10. Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene. Naganawa, S., Ginsberg, H.N., Glickman, R.M., Ginsburg, G.S. J. Clin. Invest. (1997) [Pubmed]
  11. Apolipoprotein C3 SstI polymorphism in the risk assessment of CAD. Chhabra, S., Narang, R., Lakshmy, R., Vasisht, S., Agarwal, D.P., Srivastava, L.M., Manchanda, S.C., Das, N. Mol. Cell. Biochem. (2004) [Pubmed]
  12. Serum apolipoprotein profile of patients with chronic renal failure. Attman, P.O., Alaupovic, P., Gustafson, A. Kidney Int. (1987) [Pubmed]
  13. Response to a urate-lowering diet according to polymorphisms in the apolipoprotein AI-CIII-AIV cluster. Cardona, F., Tinahones, F.J., Collantes, E., Garcia-Fuentes, E., Escudero, A., Soriguer, F. J. Rheumatol. (2005) [Pubmed]
  14. Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. Chan, D.C., Watts, G.F., Mori, T.A., Barrett, P.H., Beilin, L.J., Redgrave, T.G. Eur. J. Clin. Invest. (2002) [Pubmed]
  15. Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4). Karathanasis, S.K., Oettgen, P., Haddad, I.A., Antonarakis, S.E. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  16. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Talmud, P.J., Hawe, E., Martin, S., Olivier, M., Miller, G.J., Rubin, E.M., Pennacchio, L.A., Humphries, S.E. Hum. Mol. Genet. (2002) [Pubmed]
  17. Genetic influences on blood pressure within the Stanislas Cohort. Sass, C., Cheng, S., Siest, G., Visvikis, S. J. Hypertens. (2004) [Pubmed]
  18. Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects. Auwerx, J., Schoonjans, K., Fruchart, J.C., Staels, B. J. Atheroscler. Thromb. (1996) [Pubmed]
  19. Refined mapping of two regions of loss of heterozygosity on chromosome band 11q23 in lung cancer. Wang, S.S., Virmani, A., Gazdar, A.F., Minna, J.D., Evans, G.A. Genes Chromosomes Cancer (1999) [Pubmed]
  20. Detection of apolipoprotein C in human and rat enterocytes. Schonfeld, G., Grimme, N., Alpers, D. J. Cell Biol. (1980) [Pubmed]
  21. Characterization of an enhancer element in the human apolipoprotein C-III gene that regulates human apolipoprotein A-I gene expression in the intestinal epithelium. Bisaha, J.G., Simon, T.C., Gordon, J.I., Breslow, J.L. J. Biol. Chem. (1995) [Pubmed]
  22. Overview of fenofibrate. Packard, C.J. Eur. Heart J. (1998) [Pubmed]
  23. Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism. Sijbrands, E.J., Hoffer, M.J., Meinders, A.E., Havekes, L.M., Frants, R.R., Smelt, A.H., De Knijff, P. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
  24. Interaction of the common apolipoprotein C-III (APOC3 -482C > T) and hepatic lipase (LIPC -514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS-II). Jansen, H., Waterworth, D.M., Nicaud, V., Ehnholm, C., Talmud, P.J. Ann. Hum. Genet. (2001) [Pubmed]
  25. Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice. Jong, M.C., Havekes, L.M. International journal of tissue reactions. (2000) [Pubmed]
  26. Plasma apolipoprotein A5 and triglycerides in type 2 diabetes. Dallinga-Thie, G.M., van Tol, A., Hattori, H., van Vark-van der Zee, L.C., Jansen, H., Sijbrands, E.J. Diabetologia (2006) [Pubmed]
  27. Role of apolipoprotein CIII in triglyceride-rich lipoprotein metabolism. Fredenrich, A. Diabetes Metab. (1998) [Pubmed]
  28. An indirect negative autoregulatory mechanism involved in hepatocyte nuclear factor-1 gene expression. Kritis, A.A., Ktistaki, E., Barda, D., Zannis, V.I., Talianidis, I. Nucleic Acids Res. (1993) [Pubmed]
  29. Mitogen-activated protein kinase regulates transcription of the ApoCIII gene. Involvement of the orphan nuclear receptor HNF4. Reddy, S., Yang, W., Taylor, D.G., Shen, X., Oxender, D., Kust, G., Leff, T. J. Biol. Chem. (1999) [Pubmed]
  30. Apo CIII gene transcription is regulated by a cytokine inducible NF-kappa B element. Gruber, P.J., Torres-Rosado, A., Wolak, M.L., Leff, T. Nucleic Acids Res. (1994) [Pubmed]
  31. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. Wang, C.S., McConathy, W.J., Kloer, H.U., Alaupovic, P. J. Clin. Invest. (1985) [Pubmed]
  32. Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins. Hegele, R.A., Connelly, P.W., Hanley, A.J., Sun, F., Harris, S.B., Zinman, B. Arterioscler. Thromb. Vasc. Biol. (1997) [Pubmed]
  33. Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population. Guettier, J.M., Georgopoulos, A., Tsai, M.Y., Radha, V., Shanthirani, S., Deepa, R., Gross, M., Rao, G., Mohan, V. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  34. Genetic influences on lipid metabolism trait variability within the Stanislas Cohort. Pallaud, C., Gueguen, R., Sass, C., Grow, M., Cheng, S., Siest, G., Visvikis, S. J. Lipid Res. (2001) [Pubmed]
  35. Associations of LPL and APOC3 gene polymorphisms on plasma lipids in a Mediterranean population: interaction with tobacco smoking and the APOE locus. Corella, D., Guillén, M., Sáiz, C., Portolés, O., Sabater, A., Folch, J., Ordovas, J.M. J. Lipid Res. (2002) [Pubmed]
  36. Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians. Chhabra, S., Narang, R., Krishnan, L.R., Vasisht, S., Agarwal, D.P., Srivastava, L.M., Manchanda, S.C., Das, N. BMC Genet. (2002) [Pubmed]
  37. Postprandial exchange of apolipoprotein C-III between plasma lipoproteins. Barr, S.I., Kottke, B.A., Mao, S.J. Am. J. Clin. Nutr. (1981) [Pubmed]
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