Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

An apolipoprotein CIII marker associated with hypertriglyceridemia in Caucasians also confers increased risk in a west Japanese population

  • 47 Accesses

  • 25 Citations


Polymorphisms and haplotypes at the adjacent apolipoprotein (apo) AI and CIII gene loci were investigated in 61 Japanese patients with triglycerides greater than 350 mg/dl and in 66 unrelated normolipidemic subjects. The polymorphic sites were the SstI site in the apoCIII 3′ untranslated region, whose presence has previously been shown to be associated with hypertriglyceridemia (HTG) in Caucasians, and the MspI site in the third intron of the apoAI gene. The frequencies of the SstI minor allele (S2) were 0.48 in HTG patients and 0.25 in normolipidemic subjects (P < 0.00015). The frequencies of the MspI minor allele (M2) were 0.61 in HTG patients and 0.33 in normolipidemic subjects (P < 0.00001). The two polymorphic sites were in strong linkage disequilibrium, and maximum likelihood analysis supported the existence of three of the four possible haplotypes: S1-M1, S1-M2, and S2-M2. Since all S2 alleles were estimated to be present on M2-bearing chromosomes, the HTG-associated S2-M2 haplotype conferred the same approximate relative risk as the S2 allele alone when compared with the other two haplotypes (odds ratio 2.8). This study demonstrates that the S2 allele is a marker for HTG among west Japanese subjects as well as among Caucasians. The results suggest that S2-M2 chromosomes carry HTG susceptibility sequences that predate the separation of the Asian and Caucasian races.

This is a preview of subscription content, log in to check access.


  1. Aalto-Setälä K, Bisgaier CL, Ho A, Kieft KA, Traber MG, Kayden HJ, Ramakrishnan R, Walsh A, Essenburg AD, Breslow JL (1994) Intestinal expression of human apolipoprotein A-IV in transgenic mice fails to influence dietary lipid absorption or feeding behavior. J Clin Invest 93: 1776–1786

  2. Austin MA (1991) Plasma triglyceride and coronary heart disease. Arterioscler Thromb 11: 2–14

  3. Babirak SP, Iverius P-H, Fujimoto WY, Brunzel JD (1989) Detection and characterization of the heterozygote state for lipoprotein lipase deficiency. Arteriosclerosis 9: 326–334

  4. Brans GAP, Karathanasis SK, Breslow JL (1984) Human apolipoprotein AI-CIII gene complex is located on chromosome 11. Arteriosclerosis 4: 97–102

  5. Brunzell JD (1989) Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scrivner CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, vol 1, 6th edn. McGraw-Hill, New York, pp 1165–1180

  6. Cheung P, Kao F-T, Law ML, Jones C, Puck TT, Chan L (1984) Localization of the structural gene for human apolipoprotein AI on the long arm of chromosome 11. Proc Natl Acad Sci USA 81:508–511

  7. Cox NJ, Bell GI, Xiang K (1988) Linkage disequilibrium in the human insulin/insulin-like growth factor II region of human chromosome 11. Am J Hum Genet 43: 495–501

  8. Dammerman M, Sandkuijl LA, Halaas JL, Chung W, Breslow JL (1993) An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3′ untranslated region polymorphisms. Proc Natl Acad Sci USA 90: 4562–4566

  9. Ferns GAA, Galton DJ (1986) Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis. Hum Genet 73: 245–249

  10. Fielding CJ, Shore VG, Fielding PE (1972) A protein cofactor of lecithin:cholesterol acyltransferase. Biochem Biophys Res Commun 46: 1493–1498

  11. Havel RJ, Kane JP (1989) Introduction: structure and metabolism of plasma lipoproteins. In: Scrivner CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, vol 1, 6th edn. McGraw-Hill, New York, pp 1129–1138

  12. Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL (1990) Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science 249: 790–793

  13. Karathanasis SK, McPherson J, Zannis VI, Breslow JL (1983) Linkage of human apolipoproteins AI and CIII genes. Nature 304: 371–373

  14. Law SW, Gray G, Brewer HB Jr, Sakaguchi AY, Naylor SL (1984) Human apolipoprotein A-I and C-III genes reside in the p11-q13 region of chromosome 11. Biochem Biophys Res Commun 118: 934–942

  15. MacLean CJ, Morton NE (1985) Estimation of myriad haplotype frequencies. Genet Epidemiol 2: 263–272

  16. Miller GJ, Miller NE (1975) Plasma-high-density-lipoprotein concentration and development of ischaemic heart disease. Lancet I: 16–19

  17. Ordovas JM, Civeira F, Genest J Jr, Craig S, Robbins AH, Meade T, Pocovi M, Frossard PM, Masharani U, Wilson PWF, Salem DN, Ward RH, Schaefer EJ (1991) Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus: relationships with lipids, apolipoproteins, and premature coronary artery disease. Atherosclerosis 87: 75–86

  18. Paul H, Galton D, Stocks J (1987) DNA polymorphic patterns and haplotype arrangements of the apo-AI, apo-CIII, apo-AIV gene cluster in different ethnic groups. Hum Genet 75: 264–268

  19. Rees A, Stocks J, Sharpe CR, Vella MA, Shoulders CC, Katz J, Jowett NI, Baralle FE, Galton DJ (1985) Deoxyribonucleic acid polymorphism in the apolipoprotein A-I-C-III gene cluster: association with hypertriglyceridemia. J Clin Invest 76: 1090–1095

  20. Rees A, Stocks J, Paul H, Ohuchi Y, Galton D (1986) Haplotypes identified by DNA polymorphisms at the apolipoprotein A-I and C-III loci and hypertriglyceridaemia: a study in a Japanese population. Hum Genet 72: 168–171

  21. Schonfeld G, George PK, Miller J, Reilly P, Witztum J (1979) Apolipoprotein C-II and C-III levels in hyperlipoproteinemia. Metabolism 28: 1001–1010

  22. Seilhamer JJ, Protter AA, Frossard P, Levy-Wilson B (1984) Isolation and DNA sequence of full-length cDNA and of the entire gene for human apolipoprotein AI: discovery of a new genetic polymorphism in the apo AI gene. DNA 3: 309–317

  23. Stocks J, Paul H, Galton D (1987) Haplotypes identified by DNA restriclion-fragment-length polymorphisms in the A-I C-III AIV gene region and hypertriglyceridemia. Am J Hum Genet 41: 106–118

  24. Takada Y, Sasaki J, Seki M, Ogata S, Teranishi Y, Arakawa K (1991) Characterization of a new human apolipoprotein A-I Yame by direct sequencing of polymerase chain reaction-amplified DNA. J Lipid Res 32: 1275–1280

  25. Tas S (1989) Slrong association of a single nucleolide subslilulion in the 3′-untranslated region of the apolipoprotein-CIII gene with common hypertriglyceridemia in Arabs. Clin Chem 35: 256–259

  26. Wang C-S, McConathy WJ, Kloer HU, Alaupovic P (1985) Modulation of lipoprotein lipase activity by apolipoproteins. J Clin Invest 75: 384–390

  27. Wilson DE, Emi M, Iverius P-H, Hata A, Wu LL, Hillas E, Williams RR, Lalouel J-M (1990) Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation. J Clin Invest 86: 735–750

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zeng, Q., Dammerman, M., Takada, Y. et al. An apolipoprotein CIII marker associated with hypertriglyceridemia in Caucasians also confers increased risk in a west Japanese population. Hum Genet 95, 371–375 (1995). https://doi.org/10.1007/BF00208957

Download citation


  • Triglyceride
  • Linkage Disequilibrium
  • Minor Allele
  • Japanese Population
  • Polymorphic Site