Genetic screening of the lipoprotein lipase gene for mutations associated with high triglyceride/low HDL-cholesterol levels

The lipoprotein lipase (LPL) enzyme plays a major role in lipid metabolism, primarily by regulating the catabolism of triglyceride (TG)-rich lipoprote in particles. The gene for LPL is an important candidate for affecting the risk of atherosclerosis in the general population. Previously, we have show n that the HindIII polymorphism in intron 8 of the LPL gene is associated w ith plasma TG and HDL-cholesterol variation in Hispanics and non-Hispanic w hites (NHWs). However, this polymorphism is located in an intron and hence may be in linkage disequilibrium with a functional mutation in the coding r egion or intron-exon junctions of the LPL gene. The aim of this study was t o initially screen the LPL coding region and the intron-exon junctions by s ingle-strand conformation polymorphism (SSCP) analysis for mutation detecti on in a group of 86 individuals expressing the phenotype of high TG/low HDL , followed by association studies in a population-based sample of 1014 Hisp anics and NHWs, Four sequence variations were identified by SSCP and DNA se quencing in the coding region of the gene, including two missense mutations (D9N in exon 2 and N291S in exon 6), one samesense mutation (V108V in exon 3), and one nonsense mutation (S447X in exon 9). Multiple regression analy ses, including these four mutations and the HindIII polymorphic site, indic ate that the association of the HindIII site with plasma TG (P=0.001 in NHW s and P=0.002 in Hispanics) and HDL-cholesterol (P=0.007 in NHWs and P=0.12 7 in Hispanics) is independent of all other LPL variable sites examined. Th ese observations reinforce the concept that the intronic 8 HindIII site is functional by itself and provide a strong rationale for future comprehensiv e functional studies to delineate its biological significance.