© 1995 American Heart Association, Inc.
Articles |
C/T Polymorphism in the 5' Untranslated Region of the Apolipoprotein(a) Gene Introduces an Upstream ATG and Reduces In Vitro Translation
From the Falk Cardiovascular Research Center (B.R.Z., G.E.L., D.P.W., R.M.L.), Stanford University Medical School, Stanford, Calif, and MRC Lipoprotein Team (B.L.K.), Hammersmith Hospital, Ducane Road, London, England.
Correspondence to Richard M. Lawn, Falk Cardiovascular Research Center, Stanford University Medical School, Stanford, CA 94305-5246.
Abstract Elevated plasma levels of lipoproteinz(a) [Lp(a)] are a significant independent risk factor for arteriosclerosis. Interindividual levels of Lp(a) vary nearly 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. A search was made for sequence variants in the 5' flanking region of the apo(a) gene that affect its expression. A C to T transition at position +93 from the transcription start site was found with a frequency of 14% in the study population. In transient transfection assays in HepG2 cells, luciferase reporter gene constructs with a T at this position were associated with a 58% reduction in luciferase activity compared with the more common allele. This single base variant had no significant effect on the binding of nuclear regulatory proteins; however, it introduced an additional upstream ATG initiation codon with its own in-frame stop codon. Furthermore, equivalent levels of mRNA were produced in HepG2 cells transfected with reporter gene constructs containing either a T or a C at position +93. In vitro translation experiments using transcripts derived from either variant apo(a) promoter revealed a 60% reduction in translation associated with the T allele. Hence, the additional ATG created by the T at position +93 in the 5' flanking region of the apo(a) gene impairs the efficiency of translation from the bona fide ATG initiation codon.
Key Words: apolipoprotein • ATG initiation codon • lipoprotein(a) • polymorphism • atherosclerosis • translation
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