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

Abstract

The lipoprotein lipase (LPL) enzyme plays a major role in lipid metabolism, primarily by regulating the catabolism of triglyceride (TG)-rich lipoprotein particles. The gene for LPL is an important candidate for affecting the risk of atherlosclerosis in the general population. Previously, we have shown that the HindIII polymorphism in intron 8 of the LPL gene is associated with plasma TG and HDL-cholesterol variation in Hispanics and non-Hispanic whites (NHWs). However, this polymorphism is located in an intron and hence may be in linkage disequilibrium with a functional mutation in the coding region or intron-exon junctions of the LPL gene. The aim of this study was to initially screen the LPL coding region and the intron-exon junctions by single-strand conformation polymorphism (SSCP) analysis for mutation detection in a group of 86 individuals expressing the phenotype of high TG/low HDL, followed by association studies in a population-based sample of 1,014 Hispanics and NHWs. Four sequence variations were identified by SSCP and DNA sequencing 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 analyses, including these four mutations and the HindIII polymorphic site, indicate that the association of the HindIII site with plasma TG (P=0.001 in NHWs and P=0.002 in Hispanics) and HDL-cholesterol (P=0.007 in NHWs and P=0.127 in Hispanics) is independent of all other LPL variable sites examined. These observations reinforce the concept that the intronic 8 HindIII site is functional by itself and provide a strong rationale for future comprehensive functional studies to delineate its biological significance.

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

“…Other identified SNPs in the ApoC3 (À482, À2854), ApoA5 (À3, 56, IVS3 þ 476,1259) and LPL (N291S, D9N, V108v, HindIII) genes have been shown to influence lipid metabolism and/ or cardiovascular risk outcomes in some studies. 7,[21][22][23][24] Furthermore, other genes such as the ApoE, ApoA1, ApoB, hepatic lipase and PPAR genes have been investigated for their association with lipid levels and/or cardiovascular disease outcomes. 4,10,[25][26][27] Since weight gain and BMI are significantly correlated with serum triglycerides and cholesterol levels, it is possible that genetic variants which may influence the extent of weight gain during treatment with antipsychotics, such as the polymorphisms in the 5-HT2C receptor (À759 T/C), 28,29 polymorphisms of the leptin gene, 28,30 and polymorphisms in the a2A receptor (À1291 C/G) 31 may also be related to deferential drug  gene effects on serum lipids.…”

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

“…Since the HindIII polymorphism is located in the middle of intron 8, it is not considered to be functional but rather in linkage disequilibrium with a putative functional variant. Some groups, including ours, have attempted to find such a functional variant and identified coding SNPs, including D9N, N291S and S447X [6,[19][20][21]. Among these, only the S447X was common with a frequency of about 9% in Caucasians.…”

“…Several common LPL genetic variants have been widely studied, and among them HindIII in intron 8 (T→G at position 481), and S447X in exon 9 are of particular interest because of their common occurrence (25% and 9% of the less common alleles, respectively in most populations) and their associations with plasma lipid profile [6][7][8][9][10][11] and susceptibility to CAD [10][11][12][13][14][15] in several studies, although some inconsistent results have also been reported [16][17][18]. Since the HindIII polymorphism is located in the middle of intron 8, it is not considered to be functional but rather in linkage disequilibrium with a putative functional variant.…”

Variation near the Region of the Lipoprotein Lipase Gene and Hypertension or Blood Pressure Levels in Chinese.

“…This suggests that there may be common underlying genetic determinants between BP regulation and lipid metabolism. Human lipoprotein lipase (LPL) plays a major role in the determination of the plasma lipid and lipoprotein profile, and is a ratelimiting enzyme responsible for the hydrolysis of triglycerides (TG) in chylomicrons (CM) and very-low-density lipoprotein (VLDL) (3). The LPL gene may be one of these genetic determinants.…”