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 ap olipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inve rsely related to the number of kringle 4 (K4)-encoding sequences in th e 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 rep eats, affect plasma levels of Lp(a). To identify sequences in the apo( a) gene that contribute to plasma Lp(a) levels, we characterized the r elationship 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 t he 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 pl asma Lp(a) levels (less than or equal to 3 mg/dl). To determine whethe r this association was due to the effect of the 11 TTTTA copies on apo (a) gene transcription, we measured the ability of fragments containin g 11 or eight TTTTA repeats to promote transcription when introduced i nto cultured human hepatocarcinoma cells. No difference was found in t he transcriptional activity of the two fragments. The TTTTA repeat con stitutes the first sequence polymorphism at the apo(a) locus, other th an the number of K4 repeats, which is associated with plasma concentra tions of Lp(a).