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

Abstract

Lipoprotein Lipase (LPL) plays a pivotal role in lipid metabolism by hydrolyzing triglyceride (TG) rich lipoprotein particles. Abnormalities in normal LPL function are associated with the risk of coronary artery disease (CAD). A number of genetic variants have been identified in the LPL gene that affects different functions of the LPL protein. A common HindIII polymorphism in intron 8 (T/ G) of the LPL gene has been found to be associated with altered plasma TG and HDL-cholesterol, and CAD risk in several studies, but its functional significance is unknown. It has been shown that certain intronic sequence contain regulatory elements that are important for transcription and translational regulation of a gene. In this study we tested the hypothesis that this polymorphism affects the binding site of a transcription factor that regulates the transcription of LPL gene. Electrophoretic mobility shift assays revealed that the HindIII site binds to a transcription factor and that the mutant allele has lower binding affinity than the wild type allele. Transcription assays containing the entire intron 8 sequence along with full-length human LPL promoter were carried out in COS-1 and human vascular smooth muscle cells. The mutant allele was associated with significantly decreased luciferase expression level compared to the wild type allele in both the muscle (3.394 ± 0.022 vs. 4.184 ± 0.028; P=4.7 × 10 −6 ) and COS-1 (11.603 ± 0.409 vs. 14.373 ± 1.096; P<0.0001) cells. In conclusion, this study demonstrates for the first time that the polymorphic HindIII site in the LPL gene is functional because it affects the binding of a transcription factor and it also has an impact on LPL expression.

Associations of three lipoprotein lipase gene polymorphisms, lipid profiles and coronary artery disease

“…These effects of the HindIII polymorphism on TG and HDL-C levels are consistent with the physiological role of LPL, which both hydrolyzes TG-rich lipoproteins and modulates plasma HDL-C levels. The HindIII polymorphism is located in intron 8 of the LPL gene, and therefore, should not be the cause of the observed effects (41).…”

Association of Three Lipoprotein Lipase Polymorphisms with Coronary Artery Disease in Chinese and Asian Indians

“…P+H+S was consistently associated with atherogenicity in Chinese and Indians, while P-H-X and P+H-S were associated with lowered CAD risk in the Chinese and similarly, P-H-S in Indians. The opposite effect of P+H+S and P+H-S on CAD susceptibility in the Chinese also suggests that HindIII may be an independent functional site, as shown recently [10].…”

“…Although HindIII is within an intronic region, it could affect the binding of a transcriptional factor and the LPL expression [10]. P+H+S was consistently associated with atherogenicity in Chinese and Indians, while P-H-X and P+H-S were associated with lowered CAD risk in the Chinese and similarly, P-H-S in Indians.…”

Association of lipase lipoprotein polymorphisms with high-density lipoprotein and triglycerides in elderly men

“…The S447X polymorphism is characterized by the substitution of cytosine (C) by guanine (G) at position 1595 in exon 9, resulting in a premature stop codon, which removes the last two amino acids of the protein. The X allele is associated with higher LPL activity (Hata et al, 1990;Kobayashi et al, 1992;Chen et al, 2008).…”