APOA5

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Apolipoprotein A-V
Identifiers
Symbols APOA5 ; APOAV; RAP3
External IDs OMIM606368 MGI1913363 HomoloGene14197 GeneCards: APOA5 Gene
Orthologs
Species Human Mouse
Entrez 116519 66113
Ensembl ENSG00000110243 ENSMUSG00000032079
UniProt Q6Q788 Q8C7G5
RefSeq (mRNA) NM_001166598 NM_080434
RefSeq (protein) NP_001160070 NP_536682
Location (UCSC) Chr 11:
116.79 – 116.79 Mb
Chr 9:
46.27 – 46.27 Mb
PubMed search [1] [2]

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene.[1][2][3]

The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors.[4]

This gene uses alternate polyadenylation sites and is located proximal to the apolipoprotein gene cluster on chromosome 11q23.[3]

Discovery[edit]

The gene for apolipoprotein A5 (APOA5, gene ID 116519, OMIM accession number – 606368) was originally found by comparative sequencing of human and mice DNA as a last member of the gene cluster of apolipoproteins APOA1/APOC3/APOA4/APOA5, located on human chromosome 11 at position 11q23.[1] The creation of two mice models (APOA5 transgenic and APOA5 knock-out) confirmed the important role of this gene in plasma triglyceride determination. The transgenic mice had lower and the knock-out mice higher levels of plasma triglycerides, while plasma cholesterol levels remained unchanged in both animal models. Interestingly, a Dutch group simultaneously described an identical gene as apolipoprotein which it is associated with the early phase of liver regeneration, but failed to recognise its important role in the determination of plasma triglyceride levels.[2]

Gene and protein[edit]

The gene for apolipoprotein A5 is small, spans approximately 3 kbp, is constituted in a similar way to other apolipoprotein genes (with apolipoprotein B as an exception), is composed of 4 exons and 3 introns and codes for the 366 amino acid protein (with the 23 amino acid signal peptide and the 343 amino acid of mature APOA5).

Tissue distribution[edit]

In humans, APOA5 is expressed almost exclusively in the liver tissue;[1] some minor expressions have also been detected in the small intestine.[5] Nothing is known about the existence of the potential alternative splicing variants of this gene. In comparison with other apolipoproteins, plasma concentration of APOA5 is very low (less than 1 μg/mL).[6] This suggests that it has more catalytic than structural functions, since there is less than one APOA5 molecule per one lipoprotein particle. APOA5 is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.

Function[edit]

There are many possible explanations as to how APOA5 influences plasma triglyceride levels.[7] The first suggested mechanism supposes that APOA5 functions as an activator of lipoprotein lipase (which is a key enzyme in triglyceride catabolism) and, through this process, enhances the metabolism of TG-rich particles. The second is the possible effect of APOA5 on the secretion of VLDL particles, since APOA5 reduces hepatic production by inhibiting VLDL-particle production and assembly by binding to cellular membranes and lipids.[8] Finally, the third possibility relates to the acceleration of the hepatic uptake of lipoprotein remnants and it has been shown that APOA5 binds to different members of the low-density lipoprotein receptor family.[9]

Gene variability[edit]

Within the APOA5 gene, a couple of important SNPs with a widely confirmed effect on plasma TG levels as well as rare mutations have been described. In Caucasians, the common variants are inherited mostly in three haplotypes, which are characterised by two SNPs, namely rs662799 (T-1131˃C; in almost complete LD with A-3˃G, where the minor allele is associated with about 50% lower gene expression) and rs3135506 (Ser19˃Trp; C56˃G; alters the signal peptide and influences APOA5 secretion into plasma). There are also a further three common variants (A-3˃G, IVS+476 G˃A and T1259˃C) which are not necessary for haplotype characterisation. Population frequencies of common APOA5 alleles exhibit large interethnic differences. For example, there are about 15% of carriers of the -1131C allele among Caucasians, but the frequency could reach even between 40% and 50% among Asians. In contrast, the Trp19 allele is very rare in the Asian population (less than 1% of carriers) but is common in Caucasians (about 15% of carriers). Vice versa, important SNP (rs2075291, G553T, Gly185˃Cys) with a population frequency of about 5% has been detected among Asians, but it is extremely rare among Caucasians. Sporadic publications refer to some other common polymorphisms, e.g. Val153˃Met (rs3135507, G457A) and also suggest significant sex-dependent associations[10] with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the “common mutations/rare SNPs”, one of the most characterised on a population level is the Ala315˃Val[11] exchange. Originally detected in patients with extreme TG levels over 10 mmo/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes preliminary stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only.[12]

Clinical significance[edit]

As a risk factor[edit]

Even though plasma concentration of APOA5 is very low, some studies have focused on the analysis of the potential association of this biochemical parameter with cardiovascular disease (CVD). This relationship remains controversial, as higher plasma levels of APOA5 in individuals with CVD disease have been found in some, but not in all studies.[13][14]

Plasma lipids and cardiovascular disease[edit]

The major effect of the apolipoprotein A5 gene (and its variants) is on plasma triglyceride levels. Minor alleles (C1131 and Trp19) are primarily associated with the elevation of plasma triglyceride levels. The most extensive information available has been drawn from Caucasian populations, particularly in relation to the rs662799 SNP. Here, one minor allele is associated with an approximate 0,25 mmol/L increase of plasma TG levels.[15] A similar effect is associated with the Trp19 allele, even though it has not been confirmed by a huge number of studies. Original studies have further described that the strongest effect of APOA5 polymorphisms on plasma TG levels is observed among Hispanics, with only minor effects detected among Africans. Among Asians, the effect on plasma TG levels is similar that found among Caucasians. Generally, studies have suggested significant interethnic differences and in some cases sex-dependent associations as well.[10][16][17]

Sporadic publications have also mentioned a weak but nonetheless significant effect of APOA5 variants on plasma HDL-cholesterol and non-HDL cholesterol levels.

Myocardial infarction[edit]

A large meta-analysis of 101 studies[15] confirmed a risk associated with the presence of the minor APOA5 allele -1131C and coronary heart disease. The odds ratio was 1.18 for every C allele. There are far fewer studies on the second common APOA5 polymorphism, Ser19>Trp, even though available studies have detected that its effect on plasma triglycerides is similar to C-1131>T. Nevertheless, the minor Trp allele is also associated with increased risk of CVD, and it seems that especially homozygotes and carriers of more minor alleles (both -1131C and 19Trp) are at higher risk of CVD.[18]

BMI, metabolic syndrome[edit]

Obesity and metabolic syndrome are both closely related to plasma triglyceride levels. Therefore, the focus on an association between APOA5 and BMI or metabolic syndrome is understandable. Available studies show that minor APOA5 alleles could be associated with an enhanced risk of obesity or metabolic syndrome development. However, genome wide studies have failed to prove that APOA5 is a gene associated with BMI values and/or obesity, so the effect could be far from clinically significant or at least significantly context-dependent.

Nutri-, acti- and pharmacogenetic associations[edit]

Several studies have focused on changes of anthropometrical (body weight, BMI, WHR,…) or biochemical parameters (mostly plasma lipid levels) as a result of the interactions between common APOA5 variants and dietary habits (polyunsaturated fatty acid intake, n-3 and n-6 fatty acid intake, total fat and total energy intake, alcohol intake), dietary (lowering the energy intake) and/or physical activity interventions or dyslipidaemic (using statins or fenofibrate) treatment. Due to the high heterogeneity of the examined populations, differences in protocol and/or interventions used, the studies are difficult to directly compare and draw definitive conclusions.[19][20][21][22][23][24] However, with caution, it could be concluded that carriers of the minor C-1131, Trp19, or T553 alleles are in some cases less prone to the positive effects of environmental and/or pharmacological interventions. Some papers suggest the importance of the interactions between APOA5 and other genes, especially with common APOE (OMIM acc. No. 107741) three allelic (E2, E3, and E4) polymorphism, in the modulation of plasma lipids. In these cases, the interaction between minor alleles of both genes seems to be of importance. In the general population, APOE4 seems to have the potential to diminish the effect of minor APOA5 rs662799 and rs3135506 alleles, especially in females. Interaction between APOE and APOA5 Ser19˃Trp has been suggested to play some role in the development of type III hyperlipidaemia.[25] Further studies, in which interaction with APOA5 has been described, have included, for example, variants within FTO, lipoprotein lipase, USF-1 and FEN-1. They have also focused not only on plasma lipids, but on BMI values or hypertension as well.

Other roles[edit]

Some other possible roles of APOA5 variants have been discussed, but generally these reports comprise only one or two papers – and first original papers with positive findings are usually not confirmed in second publications. These papers focus on the possible effect of different APOA5 variants on maternal height, longer foetal birth length, putative associations with plasma levels of C-reactive protein, LDL particle size and haemostatic markers. Despite the very low plasma concentration, variants within apolipoprotein A5 are potent determinants of plasma triglyceride levels. Minor alleles of three SNPs (rs662799, rs3135506, rs3135507) are associated with the higher risk of cardiovascular disease.

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

See also[edit]

References[edit]

  1. ^ a b c Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM (Oct 2001). "An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing". Science 294 (5540): 169–73. doi:10.1126/science.1064852. PMID 11588264. 
  2. ^ a b van der Vliet HN, Sammels MG, Leegwater AC, Levels JH, Reitsma PH, Boers W, Chamuleau RA (Nov 2001). "Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration". The Journal of Biological Chemistry 276 (48): 44512–20. doi:10.1074/jbc.M106888200. PMID 11577099. 
  3. ^ a b "Entrez Gene: APOA5 apolipoprotein A-V". 
  4. ^ Nilsson SK, Christensen S, Raarup MK, Ryan RO, Nielsen MS, Olivecrona G (Sep 2008). "Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families". The Journal of Biological Chemistry 283 (38): 25920–7. doi:10.1074/jbc.M802721200. PMC 2533778. PMID 18603531. 
  5. ^ Guardiola M, Alvaro A, Vallvé JC, Rosales R, Solà R, Girona J, Serra N, Duran P, Esteve E, Masana L, Ribalta J (Sep 2012). "APOA5 gene expression in the human intestinal tissue and its response to in vitro exposure to fatty acid and fibrate". Nutrition, Metabolism, and Cardiovascular Diseases 22 (9): 756–62. doi:10.1016/j.numecd.2010.12.003. PMID 21489765. 
  6. ^ O'Brien PJ, Alborn WE, Sloan JH, Ulmer M, Boodhoo A, Knierman MD, Schultze AE, Konrad RJ (Feb 2005). "The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins". Clinical Chemistry 51 (2): 351–9. doi:10.1373/clinchem.2004.040824. PMID 15528295. 
  7. ^ Nilsson SK, Heeren J, Olivecrona G, Merkel M (Nov 2011). "Apolipoprotein A-V; a potent triglyceride reducer". Atherosclerosis 219 (1): 15–21. doi:10.1016/j.atherosclerosis.2011.07.019. PMID 21831376. 
  8. ^ Beckstead JA, Oda MN, Martin DD, Forte TM, Bielicki JK, Berger T, Luty R, Kay CM, Ryan RO (Aug 2003). "Structure-function studies of human apolipoprotein A-V: a regulator of plasma lipid homeostasis". Biochemistry 42 (31): 9416–23. doi:10.1021/bi034509t. PMID 12899628. 
  9. ^ Nilsson SK, Lookene A, Beckstead JA, Gliemann J, Ryan RO, Olivecrona G (Mar 2007). "Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family". Biochemistry 46 (12): 3896–904. doi:10.1021/bi7000533. PMID 17326667. 
  10. ^ a b Hubacek JA, Skodová Z, Adámková V, Lánská V, Poledne R (Dec 2005). "Sex-specific effect of APOAV variant (Val153>Met) on plasma levels of high-density lipoprotein cholesterol". Metabolism 54 (12): 1632–5. doi:10.1016/j.metabol.2005.06.012. PMID 16311097. 
  11. ^ Hubacek JA, Wang WW, Skodová Z, Adámková V, Vráblík M, Horínek A, Stulc T, Ceska R, Talmud PJ. "APOA5 Ala315>Val, identified in patients with severe hypertriglyceridemia, is a common mutation with no major effects on plasma lipid levels". Clinical Chemistry and Laboratory Medicine 46 (6): 773–7. doi:10.1515/CCLM.2008.160. PMID 18601597. 
  12. ^ Melegh BI, Duga B, Sümegi K, Kisfali P, Maász A, Komlósi K, Hadzsiev K, Komoly S, Kosztolányi G, Melegh B. "Mutations of the apolipoprotein A5 gene with inherited hypertriglyceridaemia: review of the current literature". Current Medicinal Chemistry 19 (36): 6163–70. PMID 23150946. 
  13. ^ Yang Y, Walijee SM, Jin J, Zhao SP, Peng DQ. "Serum apolipoprotein A-V in patients with coronary artery disease and its association with triglyceride". Journal of Clinical Lipidology 6 (5): 462–8. doi:10.1016/j.jacl.2012.02.004. PMID 23009782. 
  14. ^ Manpuya MW, Guo J, Zhao Y (Mar 2001). "The relationship between plasma apolipoprotein A-IV levels and coronary heart disease". Chinese Medical Journal 114 (3): 275–9. PMID 11780313. 
  15. ^ a b Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ, Saleheen D, Lawlor D, Reilly MP, Hingorani AD, Talmud PJ, Danesh J (May 2010). "Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies". Lancet 375 (9726): 1634–9. doi:10.1016/S0140-6736(10)60545-4. PMID 20452521. 
  16. ^ Pennacchio LA, Olivier M, Hubacek JA, Krauss RM, Rubin EM, Cohen JC (Nov 2002). "Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels". Human Molecular Genetics 11 (24): 3031–8. PMID 12417524. 
  17. ^ Lai CQ, Tai ES, Tan CE, Cutter J, Chew SK, Zhu YP, Adiconis X, Ordovas JM (Dec 2003). "The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore". Journal of Lipid Research 44 (12): 2365–73. doi:10.1194/jlr.M300251-JLR200. PMID 12951359. 
  18. ^ Hubacek JA, Skodová Z, Adámková V, Lánská V, Poledne R (Feb 2004). "The influence of APOAV polymorphisms (T-1131>C and S19>W) on plasma triglyceride levels and risk of myocardial infarction". Clinical Genetics 65 (2): 126–30. PMID 14984471. 
  19. ^ Lai CQ, Corella D, Demissie S, Cupples LA, Adiconis X, Zhu Y, Parnell LD, Tucker KL, Ordovas JM (May 2006). "Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study". Circulation 113 (17): 2062–70. doi:10.1161/CIRCULATIONAHA.105.577296. PMID 16636175. 
  20. ^ Liu Y, Ordovas JM, Gao G, Province M, Straka RJ, Tsai MY, Lai CQ, Zhang K, Borecki I, Hixson JE, Allison DB, Arnett DK (Feb 2009). "Pharmacogenetic association of the APOA1/C3/A4/A5 gene cluster and lipid responses to fenofibrate: the genetics of lipid-lowering drugs and diet network study". Pharmacogenetics and Genomics 19 (2): 161–9. doi:10.1097/FPC.0b013e32831e030e. PMID 19057464. 
  21. ^ Hubacek JA, Adamkova V, Prusikova M, Snejdrlova M, Hirschfeldova K, Lanska V, Ceska R, Vrablik M (Jun 2009). "Impact of apolipoprotein A5 variants on statin treatment efficacy". Pharmacogenomics 10 (6): 945–50. doi:10.2217/pgs.09.17. PMID 19530961. 
  22. ^ Sánchez-Moreno C, Ordovás JM, Smith CE, Baraza JC, Lee YC, Garaulet M (Mar 2011). "APOA5 gene variation interacts with dietary fat intake to modulate obesity and circulating triglycerides in a Mediterranean population". The Journal of Nutrition 141 (3): 380–5. doi:10.3945/jn.110.130344. PMID 21209257. 
  23. ^ Hishida A, Morita E, Naito M, Okada R, Wakai K, Matsuo K, Nakamura K, Takashima N, Suzuki S, Takezaki T, Mikami H, Ohnaka K, Watanabe Y, Uemura H, Kubo M, Tanaka H, Hamajima N. "Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese - a cross-sectional data from the J-MICC Study". Endocrine Journal 59 (7): 589–99. PMID 22517333. 
  24. ^ Hubacek JA, Peasey A, Kubinova R, Pikhart H, Bobak M (Mar 2014). "The association between APOA5 haplotypes and plasma lipids is not modified by energy or fat intake: the Czech HAPIEE study". Nutrition, Metabolism, and Cardiovascular Diseases 24 (3): 243–7. doi:10.1016/j.numecd.2013.08.008. PMID 24462044. 
  25. ^ Schaefer JR, Sattler AM, Hackler B, Kurt B, Hackler R, Maisch B, Soufi M (Nov 2004). "Hyperlipidemia in patients with apolipoprotein E 2/2 phenotype: apolipoprotein A5 S19W mutation as a cofactor". Clinical Chemistry 50 (11): 2214. doi:10.1373/clinchem.2004.037689. PMID 15502102. 

Further reading[edit]

  • Garelnabi M, Lor K, Jin J, Chai F, Santanam N (Jan 2013). "The paradox of ApoA5 modulation of triglycerides: evidence from clinical and basic research". Clinical Biochemistry 46 (1-2): 12–9. doi:10.1016/j.clinbiochem.2012.09.007. PMID 23000317. 
  • Hubacek JA. "Apolipoprotein A5 and triglyceridemia. Focus on the effects of the common variants". Clinical Chemistry and Laboratory Medicine 43 (9): 897–902. doi:10.1515/CCLM.2005.153. PMID 16176166. 
  • Hubácek JA, Adámková V, Vrablík M, Kadlecová M, Zicha J, Kunes J, Pitha J, Suchánek P, Poledne R. "Apolipoprotein A5 in health and disease". Physiological Research / Academia Scientiarum Bohemoslovaca. 58 Suppl 2: S101–9. PMID 20131928. 
  • Sharma V, Forte TM, Ryan RO (Apr 2013). "Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol". Current Opinion in Lipidology 24 (2): 153–9. doi:10.1097/MOL.0b013e32835c8c1a. PMID 23241513. 
  • Tai ES, Ordovas JM (Aug 2008). "Clinical significance of apolipoprotein A5". Current Opinion in Lipidology 19 (4): 349–54. doi:10.1097/MOL.0b013e328304b681. PMID 18607181. 
  • Pennacchio LA, Rubin EM (Apr 2003). "Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice". Arteriosclerosis, Thrombosis, and Vascular Biology 23 (4): 529–34. doi:10.1161/01.ATV.0000054194.78240.45. PMID 12615678. 
  • Jakel H, Nowak M, Helleboid-Chapman A, Fruchart-Najib J, Fruchart JC (2006). "Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins?". Annals of Medicine 38 (1): 2–10. doi:10.1080/07853890500407488. PMID 16448983. 
  • Calandra S, Priore Oliva C, Tarugi P, Bertolini S (Apr 2006). "APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency". Current Opinion in Lipidology 17 (2): 122–7. doi:10.1097/01.mol.0000217892.00618.54. PMID 16531747. 
  • Wong K, Ryan RO (Jun 2007). "Characterization of apolipoprotein A-V structure and mode of plasma triacylglycerol regulation". Current Opinion in Lipidology 18 (3): 319–24. doi:10.1097/MOL.0b013e328133856c. PMID 17495607. 
  • Nabika T, Nasreen S, Kobayashi S, Masuda J (Dec 2002). "The genetic effect of the apoprotein AV gene on the serum triglyceride level in Japanese". Atherosclerosis 165 (2): 201–4. doi:10.1016/S0021-9150(02)00252-6. PMID 12417270. 
  • Pennacchio LA, Olivier M, Hubacek JA, Krauss RM, Rubin EM, Cohen JC (Nov 2002). "Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels". Human Molecular Genetics 11 (24): 3031–8. doi:10.1093/hmg/11.24.3031. PMID 12417524. 
  • Talmud PJ, Hawe E, Martin S, Olivier M, Miller GJ, Rubin EM, Pennacchio LA, Humphries SE (Nov 2002). "Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides". Human Molecular Genetics 11 (24): 3039–46. doi:10.1093/hmg/11.24.3039. PMID 12417525. 
  • Vu-Dac N, Gervois P, Jakel H, Nowak M, Bauge E, Dehondt H, Staels B, Pennacchio LA, Rubin EM, Fruchart-Najib J, Fruchart JC (May 2003). "Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators". The Journal of Biological Chemistry 278 (20): 17982–5. doi:10.1074/jbc.M212191200. PMID 12637506. 
  • Prieur X, Coste H, Rodriguez JC (Jul 2003). "The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element". The Journal of Biological Chemistry 278 (28): 25468–80. doi:10.1074/jbc.M301302200. PMID 12709436. 
  • Weinberg RB, Cook VR, Beckstead JA, Martin DD, Gallagher JW, Shelness GS, Ryan RO (Sep 2003). "Structure and interfacial properties of human apolipoprotein A-V". The Journal of Biological Chemistry 278 (36): 34438–44. doi:10.1074/jbc.M303784200. PMID 12810715. 
  • Horínek A, Vráblík M, Ceska R, Adámková V, Poledne R, Hubacek JA (Apr 2003). "T-1131-->C polymorphism within the apolipoprotein AV gene in hypertriglyceridemic individuals". Atherosclerosis 167 (2): 369–70. doi:10.1016/S0021-9150(03)00022-4. PMID 12818421. 
  • Kao JT, Wen HC, Chien KL, Hsu HC, Lin SW (Oct 2003). "A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia". Human Molecular Genetics 12 (19): 2533–9. doi:10.1093/hmg/ddg255. PMID 12915450. 
  • Vrablík M, Horínek A, Ceska R, Adámková V, Poledne R, Hubacek JA (Aug 2003). "Ser19-->Trp polymorphism within the apolipoprotein AV gene in hypertriglyceridaemic people". Journal of Medical Genetics 40 (8): e105. doi:10.1136/jmg.40.8.e105. PMC 1735562. PMID 12920097. 
  • Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (Oct 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.