Sequence microheterogeneity in apolipoprotein(a) gene repeats and the relationship to plasma Lp(a) levels.
Lipoprotein(a) [Lp(a)] is a cholesterol ester-rich atherogenic lipoprotein that is composed of a particle of low density lipoprotein and a large glycoprotein, apolipoprotein(a) [apo(a)]. Apolipoprotein(a) varies in size over a approximately 500 kDa range due to inter-allelic differences in the number of tandemly repeated kringle 4 (K4)-encoding 5.5 kb sequences in the apo(a) gene. Only one of the 10 different types of K4 repeats in the apo(a) gene, the so-called type 2 K4 repeats, vary in number between apo(a) alleles. In this paper, we show that there is microheterogeneity within the sequence of the type 2 K4 repeat. DraIII restriction digestion and genomic blotting revealed that a subset of the type 2 K4-encoding sequences contained a DraIII site (K4-D). The proportion of apo(a) alleles that had at least one K4-D repeat ranged from 25% in Caucasians to 50% in the Chinese. K4-D repeats were clustered at the end(s) of the type 2 K4 tandem array and the number and patterns of the K4-D repeats were in linkage disequilibrium with flanking sequence polymorphisms; these features are remarkably similar to the minisatellite variant repeats (MVRs) found in variable number of tandem repeat sequences (VNTRs). In addition, a DraIII pattern that comprised 9% of the sample was invariably associated with low plasma levels of Lp(a) in Caucasians.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235, USA.
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Mancini
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Mooser
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Guerra
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Hobbs
D001053:Apolipoproteins / Q000235:genetics*; D053241:Apoprotein(a); D001483:Base Sequence; D004247:DNA; D015252:Deoxyribonucleases, Type II Site-Specific; D005006:Ethnicity / Q000235:genetics; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid
D001053:Apolipoproteins; D017270:Lipoprotein(a); D004247:DNA; C045449:endodeoxyribonuclease DraIII; D015252:Deoxyribonucleases, Type II Site-Specific; D053241:Apoprotein(a)