HGNC Approved Gene Symbol: APOA4
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:116,820,700-116,823,304 (from NCBI)
Apolipoprotein A-IV is a component of chylomicrons and high-density lipoproteins. By isoelectric focusing, 2 isoforms, designated A-IV-1 and A-IV-2, can be identified. Menzel et al. (1982) demonstrated another variant form.
Anderson and Anderson (1977) and Tracy et al. (1982) described genetic polymorphism of an unidentified serum peptide with a molecular weight of about 45,000. Schamaun et al. (1984) immunologically identified this serum protein as apoA-IV.
Karathanasis et al. (1986) isolated and characterized the APOA4 gene.
Elshourbagy et al. (1986) determined the complete nucleotide sequence of the human APOA4 mRNA. The derived amino acid sequence showed that mature plasma APOA4 contained 376 residues. Throughout most of its length, human APOA4 was found to contain multiple tandem 22-residue repeated segments having amphipathic, alpha-helical potential.
Karathanasis et al. (1986) found that, in contrast to APOA1 (107680) and APOC3 (107720) genes, which contain 3 introns, the APOA4 gene contains only 2. An intron interrupting the 5-prime noncoding region of the APOA1 and APOC3 mRNAs is absent from the corresponding position of the APOA4 mRNA. However, similar to APOA1 and APOC3 genes, the introns of the APOA4 gene separate nucleotide sequences coding for the signal peptide and the amphipathic domains in APOA4. The similarities suggested that the 3 closely linked genes were derived from a common evolutionary ancestor, and that during evolution, the APOA4 gene lost one of its introns.
Elshourbagy et al. (1987) determined the complete nucleotide sequence of the APOA4 gene and reported that, contrary to the findings of Karathanasis et al. (1986), the gene contains 3 exons of 162, 127, and 1180 nucleotides separated by 2 introns of 357 and 777 nucleotides. They stated that the human APOA4 gene lacks an intron in the area encoding the 5-prime untranslated region of its mRNA, which distinguishes it from all the other human apolipoprotein genes whose sequences are known.
Duverger et al. (1996) expressed the human APOA4 gene in the livers of mice deficient in apoE (107741). They found that apoA-4 levels did not affect the levels of HDL cholesterol in these mice. However, transgenic mice had a significant reduction in the size of atherosclerotic lesions. Duverger et al. (1996) suggested that apoA-IV protects against atherosclerosis by a mechanism that does not involve an increase in HDL cholesterol concentration. They stated that their data support other evidence that suggests that apoA-IV may participate in reverse cholesterol transport (from tissues to the liver for elimination).
Cohen et al. (1997) produced transgenic mice with inserts of several copies of murine apoA-IV gene. They found 3-fold increases in plasma apoA-IV levels in mice fed a chow diet and 6-fold increases in those fed an atherogenic diet. Plasma triglycerides, total cholesterol, HDL cholesterol, and free fatty acids were increased, while unesterified cholesterol was decreased, in the atherogenic diet group. Transgenic mice exhibited 70% fewer aortic lesions than controls. HDL-sized lipoproteins from mice fed the atherogenic diet promoted greater cholesterol efflux from cholesterol-loaded human monocytes than controls, and plasma from these mice showed raised cholesterol esterification rates. Cohen et al. (1997) suggested that apoA-IV levels may influence metabolism of HDL and its effects on atherogenesis.
By Southern blot analyses of APOA4 gene-containing cosmids, Elshourbagy et al. (1986) determined that the APOA4, APOA1, and APOC3 genes reside within a 20-kilobase span of chromosome 11 DNA. The APOA4 gene is located about 14 kilobases downstream from the APOA1 gene in the same orientation, with the APOC3 gene located between them in the opposite orientation.
Karathanasis et al. (1986) found that a site in the second intron of APOA4 and a site 9 kb 3-prime to the gene were polymorphic in Mediterranean and other European populations.
Kamboh and Ferrell (1987) determined the frequency of polymorphism at the APOA4 locus by a simple and rapid 1-dimensional isoelectric-focusing technique followed by immunoblotting. In an Icelandic population, Menzel et al. (1990) found a higher frequency of the APOA4*2 allele (0.117 vs 0.077) than in Tyroleans (Menzel et al., 1988). In both populations the alleles at the APOA4 locus had significant effects on plasma high-density lipoprotein cholesterol and triglyceride levels. In the Icelandic population, the average effect of the APO4*2 allele was to raise cholesterol by 4.9 mg/dl and to lower triglyceride levels by 19.4 mg/dl. Menzel et al. (1990) estimated that the genetic variability at the APOA4 locus accounted for 3.1% of the total variability of HDL cholesterol and for 2.8% of the total variability of triglycerides in the Icelandic population. Genetically determined polymorphism of apoA-IV has been reported in dogs, horses, and baboons, in addition to humans. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In a Norwegian family with a mutant APOA1 gene and polymorphism of APOA4, Schamaun et al. (1984) found close linkage of the APOA1 and APOA4 loci; for the sexes combined, the peak lod score was 3.01 at a recombination fraction of 0.00. Rogne et al. (1986) raised the lod score to 6.32 by using 2 DNA polymorphisms of an APOA1 probe to study families informative for apoA-IV protein variants. Karathanasis (1985) showed that the APOA4 gene is located 12 kb 3-prime to the APOA1 gene.
Lohse et al. (1990) demonstrated that the genetic polymorphism of plasma apolipoprotein A-IV, detected by isoelectric focusing followed by immunoblotting, results from a single nucleotide change. Specifically, the difference between APOA4*1 and APOA4*2 is a G-to-T substitution leading to a conversion of glutamine-360 to histidine in the mature protein. The allelic change is predicted to cause the loss of 2 restriction enzyme sites in the formation of a new restriction site for a third enzyme. In Caucasian populations, the APOA4*1 and APOA4*2 alleles have a frequency of about 0.9 and 0.08, respectively; 3 rare alleles, APOA4*0 (107690.0002), APOA4*3 (107690.0003), and APOA4*4, have been described. In a study of various polymorphisms of APOA4, von Eckardstein et al. (1992) could not confirm the previously reported association of elevated HDL cholesterol concentrations with the his360 allele; from other associations, the authors concluded that the APOA4 gene locus has an important role in the metabolism of apolipoprotein B and, to a lesser extent, apolipoprotein A-I-containing lipoproteins.
Lohse et al. (1990) described the molecular basis of the rare variant APOA4*0: an insertion of 12 nucleotides in the carboxyl-terminal region, which is highly conserved among human, rat, and mouse A-IV apolipoproteins. This in-frame insertion of 4 amino acids, glu-gln-gln-gln, between residues 361 and 362 of the mature protein, produces the 1-charge unit, more acidic APOA4*0 isoprotein (pI = 4.92).
Lohse et al. (1990) identified a single G-to-A substitution that converted the glutamic acid (GAG) at position 230 of the mature apoA-IV protein to lysine (AAG). The change added 2 positive charge units to the apoA-IV-1 isoprotein (pI = 4.97) to give the more basic APOA4*3 isoprotein (pI, 5.08).
Kamboh et al. (1992) described the same in-frame insertion of 12 nucleotides (coding for the 4 amino acids glu-gln-gln-gln) near the carboxy-terminal region of the mature protein as Lohse et al. (1990) (see 107690.0002). This study also revealed a polymorphism (G to T, codon 316, third position) that did not result in an amino acid substitution. Kamboh et al. (1992) noted that finding the exact position of the 12 inserted bases was difficult because the sequences of 2 of the 5 repeat units in the APOA4*5 allele are identical. Possible sites of insertion are between codons 357 and 358, or between codons 361 and 362. Using data obtained from 308 subjects, they estimated the frequency of the APOA4*5 allele in African Americans to be 3.2%.
Anderson, L., Anderson, N. G. High resolution two-dimensional electrophoresis of human plasma proteins. Proc. Nat. Acad. Sci. 74: 5421-5425, 1977. [PubMed: 271964] [Full Text: https://doi.org/10.1073/pnas.74.12.5421]
Cohen, R. D., Castellani, L. W., Qiao, J.-H., Van Lenten, B. J., Lusis, A. J., Reue, K. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J. Clin. Invest. 99: 1906-1916, 1997. [PubMed: 9109435] [Full Text: https://doi.org/10.1172/JCI119358]
Duverger, N., Tremp, G., Caillaud, J.-M., Emmanuel, F., Castro, G., Fruchart, J.-C., Steinmetz, A., Denefle, P. Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. Science 273: 966-968, 1996. [PubMed: 8688083] [Full Text: https://doi.org/10.1126/science.273.5277.966]
Elshourbagy, N. A., Walker, D. W., Boguski, M. S., Gordon, J. I., Taylor, J. M. The nucleotide and derived amino acid sequence of human apolipoprotein A-IV mRNA and the close linkage of its gene to the genes of apolipoproteins A-I and C-III. J. Biol. Chem. 261: 1998-2002, 1986. [PubMed: 3080432]
Elshourbagy, N. A., Walker, D. W., Paik, Y.-K., Boguski, M. S., Freeman, M., Gordon, J. I., Taylor, J. M. Structure and expression of the human apolipoprotein A-IV gene. J. Biol. Chem. 262: 7973-7981, 1987. [PubMed: 3036793]
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Kamboh, M. I., Ferrell, R. E. Genetic studies of human apolipoproteins. I. Polymorphism of apolipoprotein A-IV. Am. J. Hum. Genet. 41: 119-127, 1987. [PubMed: 3618592]
Kamboh, M. I., Williams, E. R., Law, J. C., Aston, C. E., Bunker, C. H., Ferrell. R. E., Pollitzer, W. S. Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism. Genet. Epidemiol. 9: 379-388, 1992. [PubMed: 1487136] [Full Text: https://doi.org/10.1002/gepi.1370090602]
Karathanasis, S. K., Oettgen, P., Haddad, I. A., Antonarakis, S. E. Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4). Proc. Nat. Acad. Sci. 83: 8457-8461, 1986. [PubMed: 3095836] [Full Text: https://doi.org/10.1073/pnas.83.22.8457]
Karathanasis, S. K. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc. Nat. Acad. Sci. 82: 6374-6378, 1985. [PubMed: 3931073] [Full Text: https://doi.org/10.1073/pnas.82.19.6374]
Lohse, P., Kindt, M. R., Rader, D. J., Brewer, H. B., Jr. Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene. J. Biol. Chem. 265: 10061-10064, 1990. [PubMed: 2351649]
Lohse, P., Kindt, M. R., Rader, D. J., Brewer, H. B., Jr. Human plasma apolipoproteins A-IV-0 and A-IV-3: molecular basis for two rare variants of apolipoprotein A-IV-1. J. Biol. Chem. 265: 12734-12739, 1990. [PubMed: 1973689]
Menzel, H.-J., Boerwinkle, E., Schrangl-Will, S., Utermann, G. Human apolipoprotein A-IV polymorphism: frequency and effect on lipid and lipoprotein levels. Hum. Genet. 79: 368-372, 1988. [PubMed: 3410462] [Full Text: https://doi.org/10.1007/BF00282179]
Menzel, H.-J., Kovary, P. M., Assmann, G. Apolipoprotein A-IV polymorphism in man. Hum. Genet. 62: 349-352, 1982. [PubMed: 7166311] [Full Text: https://doi.org/10.1007/BF00304554]
Menzel, H.-J., Sigurdsson, G., Boerwinkle, E., Schrangl-Will, S., Dieplinger, H., Utermann, G. Frequency and effect of human apolipoprotein A-IV polymorphism on lipid and lipoprotein levels in an Icelandic population. Hum. Genet. 84: 344-346, 1990. [PubMed: 2307455] [Full Text: https://doi.org/10.1007/BF00196231]
Rogne, S., Myklebost, O., Olaisen, B., Gedde-Dahl, T., Jr., Prydz, H. Confirmation of the close linkage between the loci for human apolipoproteins AI and AIV by the use of a cloned cDNA probe and two restriction site polymorphisms. Hum. Genet. 72: 68-71, 1986. [PubMed: 3002953] [Full Text: https://doi.org/10.1007/BF00278820]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Schamaun, O., Olaisen, B., Mevag, B., Gedde-Dahl, T., Jr., Ehnholm, C., Teisberg, P. The two apolipoprotein loci apoA-I and apoA-IV are closely linked in man. Hum. Genet. 68: 181-184, 1984. [PubMed: 6500569] [Full Text: https://doi.org/10.1007/BF00279311]
Tracy, R. P., Currie, R. M., Young, D. S. Two-dimensional gel electrophoresis of serum specimens from a normal population. Clin. Chem. 28: 890-899, 1982. [PubMed: 6176364]
von Eckardstein, A., Funke, H., Schulte, M., Erren, M., Schulte, H., Assmann, G. Nonsynonymous polymorphic sites in the apolipoprotein (apo) A-IV gene are associated with changes in the concentration of apo B- and apo A-I-containing lipoproteins in a normal population. Am. J. Hum. Genet. 50: 1115-1128, 1992. [PubMed: 1349197]