ABCC6 gene polymorphism associated with variation in plasma lipoproteins.

The ATP cassette-binding (ABC) gene superfamily contains more than 40 members, many of which are involved in cellular lipid transport. The most prominent example is ABCA1, mutations in which affect plasma high-density lipoprotein (HDL) cholesterol concentration. ABCC6 is another member of the ABC gene family, and mutations in ABCC6 were recently shown to cause pseudoxanthoma elasticum (PXE). A Canadian patient with PXE was referred for assessment of moderately severe type IV hyperlipoproteinemia with hypoalphalipoproteinemia, which was refractory to pharmacological treatment. We identified intron-exon boundaries of ABCC6 to sequence genomic DNA from this patient to find the disease mutation. We report (1) identification of a set of amplification primers for the 31 exons of ABCC6; (2) identification of the ABCC6 R>X1164 nonsense mutation in the PXE subject with dyslipidemia; (3) identification of common amino acid variants and silent nucleotide variants in ABCC6, with a range of allele frequencies across ethnic groups; (4) evidence consistent with a possible pseudogene encoding 9 exons with sequence homology to ABCC6; and (5) association of the ABCC6 R>Q1268 variant with plasma triglyceride and HDL cholesterol. The results suggest that ABCC6 may be a determinant of plasma lipoproteins.