DNA sequence variation in human apolipoprotein C4 gene and its effect on plasma lipid profile.

Human apolipoprotein C-IV (apoC-IV, protein; APOC4, gene) is a new member of the APO E/C1/C2 gene cluster. In transgenic mice, human apoC-IV is predominantly associated with very low-density lipoprotein (VLDL) and thus may play an important role in lipid metabolism. To our knowledge, the extent and nature of APOC4 genetic variation and its role in lipid metabolism are unknown. In this study we have assessed the presence of genetic variation in all three exons of APOC4 and their flanking intronic sequence by SSCP and DNA sequencing. A total of five point mutations were observed, including two in the non-coding part of exon 1 (A609G and G620A), two in exon 2 (codons 36 and 52) and one in exon 3 (codon 96). The three mutations in exons 2 and 3 predict amino acid substitutions, Leu36Pro, Gly52Asp, and Leu96Arg. The frequencies of the variant alleles were: 0.010 for 609G, 0.039 for 620A, 0.502 for Pro36, 0.003 for Asp52 and 0.357 for Arg96. Significant pairwise linkage disequilibrium was observed between five of the ten APOC4 pairs, including nt. 620/codon 36, nt. 620/codon 96, codon 36/codon 52, codon 36/codon 96 and codon 52/codon 96. A general linear model analysis reveled a significant association of the Leu36Pro and the Leu96Arg polymorphisms with triglyceride levels in women. This is consistent with the proposed role of apoC-IV in triglyceride metabolism. The characterization of APOC4 genetic variation may lead to the identification of a specific role of apoC-IV in lipid metabolism or in other physiologic pathways.