Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: do they add up yet?

Hepatic lipase. The HL gene (or LIPC), located on chromosome 15 (15q21-23), spans over 60 kb, contains 9 exons and 8 introns (3), and has substantial homology with lipoprotein lipase (LPL). Together with endothelial and pancreatic lipases, they process 150 g of dietary triglyceride daily (1,2). In contrast to LPL, the synthesis, location, and function of HL are restricted to the liver. The LPL is responsible for the first phase of lipolysis of very-low density lipoproteins (VLDL) and chylomicrons. As particle size decreases, HL plays an increasing role; HL also hydrolyzes core triglycerides and phospholipids in HDL2 and HDL3 (high-density lipoprotein), being most efficient for Lp(AI, AII)-containing particles. The HL activity negatively correlates with HDL cholesterol (HDL-C) levels. CETP. The CETP gene, located on chromosome 16 (16q21) (4), specifies a 66 to 74 kDa hydrophobic glycoprotein, which is expressed in liver, spleen, adipose tissue, kidney, and skeletal muscle (1,2). The CETP is localized primarily on larger, Lp(AI)-containing HDL particles, and its principal role is to catalyze the exchange of triglycerides from apoB-containing particles (e.g., LDL, VLDL) for cholesteryl esters from HDL (1). Common reduced-function variants of HL and CETP. Both loss of function mutations, which are rare, and the more common reduced-function allelic variants of HL and CETP structural or regulatory domains have been described (3,4). As Andersen et al. (5) summarize in this issue of the Journal, four linked single nucleotide polymorphisms (SNPs) in the HL promoter have been discovered and are associated with reduced HL activity. These variant alleles are common, such that almost 40% of Caucasians are heterozygous or homozygous carriers (5). A common SNP for CETP has been extensively studied, which creates a TaqI restriction site. Although this SNP is located within intron 1, the TaqIB2 allele has been associated with reduced CETP activity. Strong linkage association with the C 629A CETP promoter polymorphism, which influences gene expression and CETP activity, may provide an explanation (6). In this issue of the Journal, Blankenberg et al. (7) examine further the C 629A polymorphism and a linked structural-domain variant, I405V.