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      Pentanucleotide Repeat and Size Polymorphisms in the Apolipoprotein(a) Gene Are Associated with the Lipoprotein(a) Concentration in Chronic Hemodialysis Patients

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          The elevation of serum or plasma lipoprotein(a) [Lp(a)] levels is regarded as an independent risk factor for cardiovascular disease, and many previous reports demonstrated that Lp(a) levels in hemodialysis patients were significantly higher than in controls. The purpose of this study was to investigate the effect of a pentanucleotide repeat polymorphism [(TTTTA)n] in the 5′-flanking region of the apolipoprotein(a) [apo(a)] gene and of a size polymorphism of apo(a) for elevated Lp(a) concentrations observed in chronic hemodialysis patients. We studied 172 patients on chronic hemodialysis and 199 healthy adults. For analysis of the pentanucleotide repeat polymorphism, polymerase chain reaction products were loaded on polyacrylamide gel for electrophoresis. apo(a) size phenotyping was performed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The median level of Lp(a) in the patients was 14.2 mg/dl which was significantly higher than that in controls (12.0 mg/dl; p < 0.05). In the genotype of (TTTTA)8/8, the median Lp(a) level in the patients (15.9 mg/dl) was significantly higher than that in controls (13.0 mg/dl; p < 0.05). In the genotype of (TTTTA)8/8 with large-sized apo(a) isoforms (A16–A25), the patients had significantly higher Lp(a) levels than the controls (p < 0.05). In conclusion, increased Lp(a) levels in chronic hemodialysis patients were mainly attributed to the combination of eight repeats of the pentanucleotide polymorphism and large-sized isoforms of apo(a).

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          Atherogenesis in transgenic mice expressing human apolipoprotein(a)

          Elevated plasma levels of the lipoprotein Lp(a) are associated with increased risk for atherosclerosis and its manifestations, myocardial infarction, stroke and restenosis (for reviews, see refs 1-3). Lp(a) differs from low-density lipoprotein by the addition of the glycoprotein apolipoprotein(a), a homologue of plasminogen that contains many tandemly repeated units which resemble the fourth kringle domain of plasminogen, and single homologues of its kringle-5 and protease domain. As plasma Lp(a) concentration is strongly influenced by heritable factors and is refractory to most drug and dietary manipulation, the effects of modulating it are difficult to mimic experimentally. In addition, the absence of apolipoprotein(a) from virtually all species other than primates precludes the use of convenient animal models. Here we show that transgenic mice expressing human apolipoprotein(a) are more susceptible than control mice to the development of lipid-staining lesions in the aorta, and that apolipoprotein(a) co-localizes with lipid deposition in the artery walls.
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            Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.

            Lipoprotein (a) (Lp(a)) is a complex of low density lipoprotein (LDL) with apolipoprotein (apo) (a). To examine the size distribution of Lp(a), plasma was separated by fast flow gel filtration and Lp(a):B complexes were determined in the eluate by enzyme immunoassays, in which detection was performed with monoclonal antibodies specific for apoB. Lp(a):B particles displayed apparent molecular masses (M(r)) of 2 x 10(6) to at least 10 x 10(6). Lp(a) size isoforms differed by the expression of apoB epitopes and their interaction with cultured human skin fibroblasts. LDL was more effective in inhibiting binding, uptake, and degradation of low M(r) Lp(a) than of high M(r) Lp(a). In contrast, Glu-plasminogen, alpha 2-macroglobulin and tissue-type plasminogen activator were more effective in competing for the cellular degradation of high M(r) Lp(a) than of low M(r) Lp(a). Ligand blotting revealed that Lp(a) bound to the low density lipoprotein receptor, the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and to two other endosomal membrane proteins. We propose that the LDL receptor preferentially internalizes low M(r) Lp(a), whereas LRP may have a role in the clearance of high M(r) Lp(a).

              Author and article information

              S. Karger AG
              April 1999
              31 March 1999
              : 81
              : 4
              : 414-420
              aInstitute of Community Medicine, bInstitute of Basic Medical Sciences, and cInstitute of Clinical Medicine, University of Tsukuba, Tsukuba; dDepartment of Medicine, Nakano General Hospital, Tokyo; eDepartment of Medicine, Kasukabe Shuwa Hospital, Kasukabe, Japan
              45325 Nephron 1999;81:414–420
              © 1999 S. Karger AG, Basel

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              Figures: 1, Tables: 3, References: 45, Pages: 7
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