Exp Clin Endocrinol Diabetes 2002; 110(7): 319-324
DOI: 10.1055/s-2002-34997
Article

© Johann Ambrosius Barth

Analyses of Serum Lipoprotein(a) And the Relation to Phenotypes And Genotypes of Apolipoprotein(a) in Type 2 Diabetic Patients With Retinopathy

M. Suehiro1, 2 , K. Ohkubo1 , H. Kato2 , Y. Kido3 , K. Anzai1 , K. Oshima2 , J. Ono1
  • 1 Department of Laboratory Medicine, Fukuoka University School of Medicine
  • 2 Department of Ophthalmology, Fukuoka University School of Medicine
  • 3 Hakujuji Hospital, Fukuoka, Japan
Weitere Informationen

Publikationsverlauf

received 13 September 01 first decision 5 December 01

accepted 20 April 02

Publikationsdatum:
24. Oktober 2002 (online)

Summary

To elucidate the association of lipoprotein(a) (Lp(a)) with diabetic retinopathy (DR), we studied the serum Lp(a) concentrations (n = 412), apolipoprotein(a) (apo(a)) phenotypes expressed by the number of kringle 4 (K4) repeats (n = 150), apo(a) gene genotypes (n = 161) of type 2 diabetes with or without DR. The 5′-untranslated region of apo(a) gene was classified into seven haplotypes (A to G) and 18 genotypes by PCR-RFLP at three distinct sites. The serum Lp(a) concentrations were significantly higher in diabetic patients than in normal controls. Furthermore, the patients with DR, especially proliferative retinopathy showed higher serum Lp(a) concentrations than those without DR. Although a negative correlation was found between the serum Lp(a) concentrations and the number of K4 repeats in total diabetic patients, no difference was seen in the distribution of the number of K4 repeats between those with and without DR. In the same apo(a) phenotypes, the patients with DR had higher Lp(a) concentrations than those without DR. Among the genotypes, type CC showed significantly higher serum Lp(a) concentrations than the other genotypes. However, there was no difference in the ratios of the type CC between the patients with and without DR. In conclusion, other factors than phenotypes and genotypes in the 5′-untranslated region of apo(a) may be responsible for the elevation of serum Lp(a) in diabetic patients with retinopathy.

References

  • 1 Berg K. A new serum type system in man; The Lp(a) system.  Acta Pathol Microbiol Scand. 1963;  59 369-382
  • 2 Boffelli D, Zajchowski D A, Yang Z, Lawn R M. Estrogen modulation of apolipoprotein(a) expression. Identification of a regulatory element.  J Biol Chem. 1999;  274 15569-15574
  • 3 Bopp S, Kochl S, Acquati F, Magnaghi P, Petho-Schramm A, Kraft H-G, Utermann G, Muller H-J, Taramelli R. Ten alleic apolipopratein[a] 5′ fragments exihibit comparable promoter activites in HepG2 cells.  J Lipid Res. 1995;  36 1721-1728
  • 4 Chakrabarti S, Cukiernik M, Hileeto D, Evans T, Chen S. Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy.  Diabetes Metab Res Rev. 2000;  16 393-407
  • 5 Chiarelli F, Santilli F, Mohn A. Role of growth factors in the development of diabetic complications.  Horm Res. 2000;  53 53-67
  • 6 Davis M D, Myers F L, Bresnick G H, de Venecia G. Natural evolution. In: L'Esperance FA Jr (ed) Current diagnosis and management of chorioretinal diseases. CV Mosby, St Louis 1977: 179-184
  • 7 Gaw A, Hobbs H H. Molecular genetics of lipoprotein(a): new pieces to the puzzle.  Curr Opin Lipidol. 1994;  5 149-155
  • 8 Grainger D J, Kirschenlor H L, Metcalfe J C, Weissberg P L, Wade D P, Lawn R M. Proliferation of human smooth muscle cells promoted by lipoprotein(a).  Science. 1993;  260 1655-1658
  • 9 Grainger D J, Kemp P R, Liu A C, Lawn R M, Metcalfe J C. Activation of transforming growth factor-β is inhibited in transgenic apolipoprotein(a) mice.  Nature. 1994;  370 460-462
  • 10 Hiraga T, Shimokawa K, Murase T, Yokoyama M. Reduction of serum lipoprotein(a) by estrogen in men with prostatic cancer.  Endocrin J. 1993;  40 507-513
  • 11 Hirata K, Saku K, Jimi S, Kikuchi S, Hamaguchi H, Arakawa K. Serum lipoprotein(a) concentrations and apolipoprotein(a) phenotypes in the families of NIDDM patient.  Diabetologia. 1995;  38 1434-1442
  • 12 Ichinose A, Kuriyama M. Detection of polymorphisms in the 5′-flanking region of the gene for apolipoprotein(a).  Biochem Biophys Res Commun. 1995;  209 372-378
  • 13 Kikuchi S, Nakagawa A, Kobayashi K, Li L, Yanagi H, Arinami T, Kozu Y, Miyazaki R, Tsuchiya S, Hamaguchi H. High degree of genetic polymorphism in apolipoprotein(a) associated with plasma lipoprotein(a) levels in Japanese and Chinese populations.  Hum Genet. 1993;  92 537-544
  • 14 Kagawa A, Azuma H, Akaike M, Kanagawa Y, Matsumoto T. Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription.  J Biol Chem. 1999;  274 34111-34115
  • 15 Lobentanz E-M, Krasznai K, Gruber A, Brunner C, Muller H-J, Sattler J, Kraft H-G, Utermann G, Dieplinger H. Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.  Biochemistry. 1998;  37 5417-5425
  • 16 Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein.  Atherosclerosis. 1989;  78 145-150
  • 17 McLean J W, Tomlinson J E, Wnn-Jing Kuang. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.  Nature. 1987;  330 132-137
  • 18 Miles L A, Fless G M, Levin E G, Scanu A M, Plow E F. A potential basis for the thrombotic risks associated with lipoprotein(a).  Nature. 1989;  339 301-303
  • 19 Miles L A, Fless G M, Scanu A M, Baynham P, Sebald M T, Skocir P, Curtiss L K, Levin E G, Hoover-Plow J L, Plow E F. Interaction of Lp(a) with plasminogen binding sites on cells.  Tromb Haemost. 1995;  73 458-465
  • 20 Mooser V, Mancini F P, Bopp S, Petho-Schramm A, Guerra R, Boerwinkle E, Muller H-J, Hobbs H H. Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma.  Human Molecular Genetics. 1995;  4 173-181
  • 21 Neele D M, de Wit E C, Princen H M. Inhibition of apolipoprotein(a) synthesis in cynomolgus monkey hepatocytes by retinoids via involvement of the retinoic acid receptor.  Biochem Pharmacol. 1999;  58 263-271
  • 22 Noma A, Abe A, Maeda S, Seishima M, Makino K, Yano Y, Shomokawa K. Lp(a): an acute-phase reactant?.  Chem Phys Lipids. 67-68 411-417 1994; 
  • 23 Perombelon Y FN, Soutar A K, Knight B L. Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles.  J Clin Invest. 1994;  93 1481-1492
  • 24 Pickup J C, Crook M A. Is Type II diabetes mellitus a disease of the innate immune system?.  Diabetologia. 1998;  41 1241-1248
  • 25 Rader D J, Clain W, Zech L A, Usher D, Brewer H B. Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein(a) isoform is determined by the rate of lipoprotein(a) production.  J Clin Invest. 1993;  91 443-447
  • 26 Rader D J, Cain W, Ikewaki K, Talley G, Zech L A, Usher D, Brewer H B. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.  J Clin Invest. 1994;  93 2758-2763
  • 27 Suzuki K, Kuriyama M, Saito T, Ichinose A. Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5′-flanking region.  J Clin Invest. 1997;  99 1361-1366
  • 28 Utermann G. The mysteries of lipoprotein(a).  Science. 1989;  246 904-910
  • 29 Wade D P, Clarke J G, Lindahl G E, Liu A C, Zysow B R, Meer K, Schwartz K, Lawn R M. 5′ control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family.  Proc Natl Acad Sci USA. 1993;  90 1369-1373
  • 30 White A L, Guerra B, Lanford R E. Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulm.  J Biol Chem. 1997;  272 5048-5055
  • 31 Zysow B R, Lindahl G E, Wade D P, Knight B L, Lawn R M. C/T polymorphism in the 5′ untranslated of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation.  Arterioscler Thromb Vac Biol. 1995;  15 58-64

M.D. Kumiko Ohkubo

Department of Laboratory Medicine

Fukuoka University School of Medicine

7-45-1, Nanakuma

Jonan-ku, Fukuoka, 814-0180

Japan

Telefon: + 81-92-801-1011

Fax: + 81-92-873-1050

eMail: kokubo@cis.fukuoka-u.ac.jp