Human Molecular Genetics, Vol 7, 257-264, Copyright © 1998 by Oxford University Press
HG Kraft, M Windegger, HJ Menzel and G Utermann
Lipoprotein(a) [Lp(a)] is a quantitative genetic trait in human plasma
associated with atherothrombotic disease. The major determinant of Lp(a)
concentration is the apolipoprotein(a) [apo(a)] gene locus. Variation in
the number of kringle IV repeats (K-IV VNTR) in apo(a) has a direct effect
on Lp(a) concentrations but explains only a fraction of the large intra-
and inter-population variance in Lp(a) levels. Effects on Lp(a) of other
intragenic polymorphisms including a pentanucleotide repeat (PNRP) in the
promoter likely reflect allelic associations with as yet unidentified
sequence variation in the apo(a) gene. We have studied a candidate C-->T
transition in two European and two African populations. This polymorphism
in the 5' region of the apo(a) gene creates an ATG start codon thereby
reducing apo(a) translation in vitro by 60%. All samples were also analyzed
for the K-IV VNTR and the PNRP to stratify for their effects and to
consider allelic associations. Consistent with the in vitro effect the
C-->T transition was associated with a significant reduction in Lp(a)
levels in both African populations ( P < 0.0056). In Caucasians,
however, the effect was not significant. This was explained by linkage
disequilibrium of the +93 T with apo(a) alleles of intermediate length
(K-24-K-34) and with nine PNRs. In Europeans these alleles are associated
with low Lp(a) which makes any potential effect of the +93 T undetectable
in the total sample. From our results we conclude (i) that the +93 C/T
polymorphism is the second known intragenic apo(a) polymorphism which
affects Lp(a) levels directly in vivo ; (ii) that allelic associations may
mask the effect of a mutation; and (iii) that heterogeneity of an effect of
a mutation across populations does not disprove causality.
ARTICLES
Significant impact of the +93 C/T polymorphism in the apolipoprotein(a) gene on Lp(a) concentrations in Africans but not in Caucasians: confounding effect of linkage disequilibrium
Institut fur Medizinische Biologie und Humangenetik, University of Innsbruck, Schopfstrasse 41, 6020 Innsbruck, Austria. hans- georg.kraft@uibk.ac.at
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