Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma.
Most of the interindividual variations in plasma levels of lipoprotein(a) [Lp(a)] can be attributed to sequence differences linked to the apolipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inversely related to the number of kringle 4 (K4)-encoding sequences in the apo(a) gene, but there are several exceptions to this general trend. Other aspects of the apo(a) gene, in addition to the number of K4 repeats, affect plasma levels of Lp(a). To identify sequences in the apo(a) gene that contribute to plasma Lp(a) levels, we characterized the relationship between a length polymorphism [(TTTTA)n] located 1.3 kb 5' of the first exon of the apo(a) gene, the number of K4 repeats in the gene, and the plasma levels of Lp(a). There was significant linkage disequilibrium between the number of TTTTA repeats and the number of K4 repeats. All of the apo(a) alleles with 11 TTTTA repeats contained fewer than 24 K4 repeats and were paradoxically associated with low plasma Lp(a) levels (< or = mg/dl). To determine whether this association was due to the effect of the 11 TTTTA copies on apo(a) gene transcription, we measured the ability of fragments containing 11 or eight TTTTA repeats to promote transcription when introduced into cultured human hepatocarcinoma cells. No difference was found in the transcriptional activity of the two fragments. The TTTTA repeat constitutes the first sequence polymorphism at the apo(a) locus, other than the number of K4 repeats, which is associated with plasma concentrations of Lp(a).
Mooser
V
V
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75235, USA.
Mancini
F P
FP
Bopp
S
S
Pethö-Schramm
A
A
Guerra
R
R
Boerwinkle
E
E
Müller
H J
HJ
Hobbs
H H
HH
D000483:Alleles; D001054:Apolipoproteins A / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D004247:DNA; D005091:Exons; D005192:Family Health; D017930:Genes, Reporter; D015894:Genome, Human; D006801:Humans; D007438:Introns; D017270:Lipoprotein(a) / Q000097:blood* / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D014158:Transcription, Genetic; D044465:White People / Q000235:genetics
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D004247:DNA; D008156:Luciferases