Alternative titles; symbols
HGNC Approved Gene Symbol: APOA5
SNOMEDCT: 34349009;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38) : 11:116,789,367-116,792,420 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | {Hypertriglyceridemia, susceptibility to} | 145750 | Autosomal dominant | 3 |
| Hyperchylomicronemia, late-onset | 144650 | Autosomal dominant | 3 |
Apolipoprotein A-V (APOA5) is thought to be an important determinant of plasma triglyceride levels.
Pennacchio et al. (2001) identified the APOA5 gene by comparative genomic analysis of human and mouse DNA. The APOA5 gene consists of 4 exons and encodes a 366-amino acid protein with 71% identity to mouse Apoa5 and 27% identity to human APOA4 (107690). Protein structure analyses predicted several amphipathic helical domains and an N-terminal signal peptide, characteristic features of lipid-binding apolipoproteins, in both human and mouse APOA5. Northern blot analysis identified transcripts of 1.3 and 1.9 kb, predominantly in liver tissue.
Martin et al. (2003) studied the influence of APOA5 variants on fasting lipids and on response to an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT). They concluded that APOA5 has a role in determining plasma triglyceride levels in an age-independent manner.
Pennacchio et al. (2001) identified 3 single-nucleotide polymorphisms (SNPs) separated by 3 kb within APOA5 that were in significant linkage disequilibrium. A fourth SNP was located approximately 11 kb upstream of the gene. These markers were scored in about 500 random unrelated normolipidemic Caucasian individuals who had been phenotyped for numerous lipid parameters before and after consumption of high- and low-fat diets. Pennacchio et al. (2001) found significant associations between both plasma triglyceride levels and very low density lipoprotein (VLDL) mass and the 3 neighboring SNPs within APOA5, but not with the distant upstream SNP. Specifically, the minor allele of each SNP was associated with higher triglyceride levels independent of diet. This study found no significant association of triglyceride levels with an APOC3 polymorphism associated with hypertriglyceridemia (see 107720). In a second study, Pennacchio et al. (2001) examined the allele frequencies for SNP3 in an unrelated group of Caucasians stratified according to plasma triglyceride levels. The 2 groups represented 161 individuals with triglyceride levels in the top 10th percentile and 298 individuals from the bottom 10th percentile. A significant overrepresentation of the heterozygous genotype was found in individuals with high compared with low plasma triglyceride levels (21.7% vs 6.7%, respectively). When the cohort was stratified based on gender, an even more pronounced overrepresentation of the heterozygous genotype was found in males with high compared with low plasma triglyceride levels (29.9% vs 4.2%, respectively).
Endo et al. (2002) demonstrated an association between the promoter region polymorphism of the APOA5 gene (SNP3 of Pennacchio et al. (2001)) and serum triglyceride level in Japanese school children.
Pennacchio et al. (2001) demonstrated that the APOA5 gene is located proximal to the APOA1 (107680), APOC3 (107720), and APOA4 gene cluster on chromosome 11q23.
The APOA5*2 haplotype, which consists of 3 SNPs (see 606368.0004), is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations (Pennacchio et al., 2001). Pennacchio et al. (2002) described an APOA5 haplotype, APOA5*3, defined by the rare 56C-G transversion, which results in a ser19-to-trp substitution (S19W; 606368.0002). In 3 independent samples of 264 or more individuals, the APOA5*3 haplotype was associated with high plasma triglyceride levels. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25 to 50% of African Americans, Hispanics, and Caucasians.
Talmud et al. (2002) used association studies to examine the relative influence of human APOA5 variants on plasma lipids compared to the impact of variation in APOC3 and APOA4, which lie in the same cluster. Among 2,808 healthy middle-aged men, those homozygous for the S19W and -1131T-C SNPs in APOA5 had 52% and 40% higher triglycerides (p less than 0.003) compared to common allele homozygotes, respectively, effects that were independent and additive. Men homozygous for the APOA4 thr347-to-ser (T347S) SNP had 23% lower triglycerides compared to common allele homozygotes (p less than 0.002). Haplotype analysis was performed to identify triglyceride-raising alleles. The major triglyceride-raising alleles were defined by trp19 in APOA5 and -482T in APOC3. Talmud et al. (2002) suggested that the triglyceride-lowering effect of ser347 in APOA4 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. They concluded that variation in APOA5 is associated with differences in triglycerides in healthy men, independent of those previously reported for APOC3, whereas association between APOA4 and triglycerides reflects linkage disequilibrium with these sites.
Kao et al. (2003) found a variant in the APOA5 coding region (606368.0001) that was associated with hypertriglyceridemia (145750) in Chinese subjects.
Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. To determine whether each gene independently influences human triglyceride concentrations, Olivier et al. (2004) examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. They identified 5 common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein genes in the cluster by a region of significantly increased recombination. One previously identified triglyceride risk haplotype of APOA5, APOA5*3, showed no association with 3 APOC3 SNPs previously associated with triglyceride concentrations. These results highlighted the complex genetic relationship between APOA5 and APOC3 and supported the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans.
While type I hyperlipidemia is associated with lipoprotein lipase deficiency (238600) or deficiency of apolipoprotein C-II (608083), the etiology of type V hyperlipoproteinemia (144650) was largely unknown. Marcais et al. (2005) explored APOA5 as a new candidate gene for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 (606368.0003) was found in both the proband and his affected son and was absent in 200 controls. This mutation was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested that Q139X is a founder mutation. Family studies showed that 5 of 9 carriers of the Q139X had hyperchylomicronemia, 1 individual being a homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes, e.g., S19W (606368.0002). Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of APOA5 truncated and wildtype proteins to lipoproteins, whereas in normal plasma, APOA5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Marcais et al. (2005) concluded that their observations strongly supported in humans a role for APOA5 in regulation of lipolysis and in familial hyperchylomicronemia.
Most patients with type III hyperlipidemia are homozygous for the epsilon-2 allele of the APOE gene. However, only about 10% of APOE2 homozygotes develop type III hyperlipidemia, and it has been proposed that additional genetic factors are required for the development of the condition. Evans et al. (2005) determined the frequency of 2 polymorphisms in the APOA5 gene, -1131T-C and S19W, in 72 hyperlipidemic patients with APOE2/2 genotype attending a lipid clinic. The frequency of both polymorphisms were significantly higher in APOE2/2 patients than in the normal population. Fifty-three percent of APOE2/2 patients were carriers of 1 of the polymorphisms, compared to 19.7% of controls. Thus, genetic variation in the APOA5 gene is an important cofactor in the development of type III HLP.
Do et al. (2015) sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR (606945) and APOA5. Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by Goldstein et al. (1973) using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol (see 143890), whereas APOA5 mutation carriers had higher plasma triglycerides (see 145750). Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; 609708) and apolipoprotein C-III (APOC3; 107720). Do et al. (2015) concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk.
Pennacchio et al. (2001) developed transgenic mice overexpressing human APOA5 in the liver. These transgenic mice had levels of plasma triglycerides that were about one-third of those of control littermates. These results were confirmed in a second independent founder line. Pennacchio et al. (2001) also generated Apoa5 knockout mice. These mice were born at the expected mendelian rate and appeared normal. Apoa5 -/- mice had about 4 times as much plasma triglyceride as their wildtype littermates. The levels of very low density lipoprotein (VLDL) particles were increased in the homozygous knockout mice and decreased in the transgenic mice compared with controls. VLDL levels in a heterozygous knockout mouse were intermediate between homozygous knockout and control mice.
To determine whether baboons, like humans, have particular haplotypes associated with lipid phenotypes, Wang et al. (2004) genotyped 634 well characterized baboons using 16 haplotype tagging SNPs within the apolipoprotein gene cluster on chromosome 11q23, for which the human orthologs have well established roles in influencing plasma HDL cholesterol and triglyceride concentrations. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 (107720) variants with HDL cholesterol and triglyceride concentrations, respectively. The authors concluded that independent variation in orthologous genomic intervals associates with similar quantitative lipid traits in both species, supporting the possibility of identifying human quantitative trait loci genes in a highly controlled nonhuman primate model.
Kao et al. (2003) screened the coding region of the APOA5 gene in 290 Chinese hypertriglyceridemic (HYTG1; 145750) and 303 normal Chinese individuals and found a novel variant, G553T in exon 4, associated with hypertriglyceridemia. The variant results in substitution of cysteine for glycine-185. The minor allele frequencies were 0.042 and 0.27 (P less than 0.001) for control and hypertriglyceridemic patients, respectively. The serum triglyceride level was significantly different among the genotypic groups (G/G 92.5 +/- 37.8 mg/dl, G/T 106.6 +/- 34.8 mg/dl, T/T 183.0 mg/dl, P = 0.014) in control subjects. Multiple logistic regression revealed that individuals carrying the minor allele had age, gender, and BMI (body mass index)-adjusted odds ratio of 11.73 (95% confidence interval of 6.617-20.793; P less than 0.0001) for developing hypertriglyceridemia in comparison to individuals without that allele.
Pennacchio et al. (2002) identified an APOA5 haplotype, APOA5*3, defined by a 56C-G transversion, resulting in a ser19-to-trp (S19W) substitution. The APOA5*3 haplotype was associated with high plasma triglyceride levels (HYTG1; 145750) in 3 independent samples: 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, 419 Caucasian men and women who were studied while consuming their self-selected diets as well as after high-carbohydrate and high-fat diets, and 2,660 randomly selected individuals of various ethnicities. The APOA5*3 haplotype was found in 7% of African Americans, 6% of Caucasians, and 15% of Hispanics.
In a cohort of 2,808 healthy middle-aged men, Talmud et al. (2002) reported an association between homozygosity for S19W and elevated triglyceride levels (p = 0.003).
Marcais et al. (2005) found a truncating heterozygous mutation, gln139-to-stop (Q139X), in the APOA5 gene in a proband and his affected son with late-onset hyperchylomicronemia (144650). The index case was a 63-year-old white male with severe unmanageable hypertriglyceridemia. His first episode was discovered when he was age 38. His lipid profile was initially normalized by dietary restriction, but he relapsed in his forties and fifties, despite optimal dietary adherence. Severe hypertriglyceridemia became permanent when he reached 60, fluctuating between 15 and 40 mM/l triglycerides with transiently higher concentrations of over 60 mM/l. He never suffered from acute pancreatitis and showed no evidence of coronary heart disease (negative maximal treadmill test); however, his carotid intima media thickness was increased, and he had atheromatous plaques both in the carotid and the aorta. The proband's 34-year-old son of normal weight was found to be severely hypertriglyceridemic at age 29, although at age 24 his fasting plasma triglyceride levels had been normal. With dietary advice and intensive exercise training, he was able to normalize his plasma triglyceride concentrations at first but in the 4 years before report had become permanently hypertriglyceridemic. Marcais et al. (2005) described a second unrelated family with the same mutation in the APO5 gene and with severe hypertriglyceridemia. In this family the dyslipidemia was closely associated with abdominal obesity and mild type II diabetes (125853).
In another patient with hyperchylomicronemia, Marcais et al. (2005) found homozygosity for the Q139X mutation. In this patient, hyperchylomicronemia was discovered at age 34 upon the occurrence of acute pancreatitis. During a 20-year follow-up for permanent unmanageable hypertriglyceridemia, he suffered 3 additional episodes of acute pancreatitis. At age 49, he presented with a silent myocardial infarction. At age 60, he died from a cause unrelated to his dyslipidemia.
The APOA5*2 haplotype includes the rare C allele of the SNP c.*158C-T (rs2266788, also referred to as c.1891T-C, c.1259T-C, or SNP1), located in the 3-prime untranslated region (UTR), in strong linkage disequilibrium with 3 other SNPs (g.4430C-T, rs662799, also referred to g.-1131T-C or SNP3; c.-3A-G, rs651821; and c.162-43A-G, rs2072560, also referred to as IVS3+476G-A or SNP2). The APOA5*2 haplotype was associated with a 20 to 30% elevation in plasma triglyceride levels (HYTG1; 145750) in 500 unrelated Caucasian men and women, and was more than 3 times as common in individuals who had plasma triglyceride concentrations greater than the 90th percentile than in those with plasma triglyceride concentrations below the 10th percentile for age and sex (Pennacchio et al., 2001; summary by Pennacchio et al., 2002). Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. Caussy et al. (2014) hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3-prime UTR. Bioinformatic studies identified the creation of a potential miRNA binding site for liver-expressed MIR485 (615385)-5p in the mutant APOA5 3-prime UTR with the c.*158C allele. In HEK293T cells cotransfected with an APOA5 3-prime UTR luciferase reporter vector and a MIR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in Huh-7 cells endogenously expressing MIR485-5p, Caussy et al. (2014) observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a MIR485-5p inhibitor. Caussy et al. (2014) suggested that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by MIR485-5p. Caussy et al. (2014) cited a frequency of APOA5*2 of approximately 7% in populations of European descent.
Caussy, C., Charriere, S., Marcais, C., Di Filippo, M., Sassolas, A., Delay, M., Euthine, V., Jalabert, A., Lefai, E., Rome, S., Moulin, P. An APOA5 3-prime UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site. Am. J. Hum. Genet. 94: 129-134, 2014. [PubMed: 24387992] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.001]
Do, R., Stitziel, N. O., Won, H.-H., Berg Jorgensen, A., Duga, S., Merlini, P. A., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., and 82 others. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518: 102-106, 2015. [PubMed: 25487149] [Full Text: https://doi.org/10.1038/nature13917]
Endo, K., Yanagi, H., Araki, J., Hirano, C., Yamakawa-Kobayashi, K., Tomura, S. Association found between the promoter region polymorphism in the apolipoprotein A-V gene and the serum triglyceride level in Japanese schoolchildren. Hum. Genet. 111: 570-572, 2002. [PubMed: 12436249] [Full Text: https://doi.org/10.1007/s00439-002-0825-0]
Evans, D., Seedorf, U., Beil, F. U. Polymorphisms in the apolipoprotein A5 (APOA5) gene and type III hyperlipidemia. Clin. Genet. 68: 369-372, 2005. [PubMed: 16143024] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00510.x]
Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J. Clin. Invest. 52: 1544-1568, 1973. [PubMed: 4718953] [Full Text: https://doi.org/10.1172/JCI107332]
Kao, J.-T., Wen, H.-C., Chien, K.-L., Hsu, H.-C., Lin, S.-W. A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. Hum. Molec. Genet. 12: 2533-2539, 2003. [PubMed: 12915450] [Full Text: https://doi.org/10.1093/hmg/ddg255]
Marcais, C., Verges, B., Charriere, S., Pruneta, V., Merlin, M., Billon, S., Perrot, L., Drai, J., Sassolas, A., Pennacchio, L. A., Fruchart-Najib, J., Fruchart, J.-C., Durlach, V., Moulin, P. Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J. Clin. Invest. 115: 2862-2869, 2005. [PubMed: 16200213] [Full Text: https://doi.org/10.1172/JCI24471]
Martin, S., Nicaud, V., Humphries, S. E., Talmud, P. J. Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges. Biochim. Biophys. Acta 1637: 217-225, 2003. [PubMed: 12697303] [Full Text: https://doi.org/10.1016/s0925-4439(03)00033-4]
Olivier, M., Wang, X., Cole, R., Gau, B., Kim, J., Rubin, E. M., Pennacchio, L. A. Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11. Genomics 83: 912-923, 2004. [PubMed: 15081120] [Full Text: https://doi.org/10.1016/j.ygeno.2003.11.016]
Pennacchio, L. A., Olivier, M., Hubacek, J. A., Cohen, J. C., Cox, D. R., Fruchart, J.-C., Krauss, R. M., Rubin, E. M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 294: 169-173, 2001. [PubMed: 11588264] [Full Text: https://doi.org/10.1126/science.1064852]
Pennacchio, L. A., Olivier, M., Hubacek, J. A., Krauss, R. M., Rubin, E. M., Cohen, J. C. Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. Hum. Molec. Genet. 11: 3031-3038, 2002. [PubMed: 12417524] [Full Text: https://doi.org/10.1093/hmg/11.24.3031]
Talmud, P. J., Hawe, E., Martin, S., Olivier, M., Miller, G. J., Rubin, E. M., Pennacchio, L. A., Humphries, S. E. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum. Molec. Genet. 11: 3039-3046, 2002. [PubMed: 12417525] [Full Text: https://doi.org/10.1093/hmg/11.24.3039]
Wang, Q., Liu, X., O'Connell, J., Peng, Z., Krauss, R. M., Rainwater, D. L., VandeBerg, J. L., Rubin, E. M., Cheng, J.-F., Pennachio, L. A. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons. Hum. Molec. Genet. 13: 1049-1056, 2004. [PubMed: 15044382] [Full Text: https://doi.org/10.1093/hmg/ddh121]