The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity

Samir S Deeb,Reiling Peng

doi:10.1016/s0022-2275(20)32086-1

Abstract

Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups. The T and A alleles at positions −514 and −250, respectively, were observed to be associated with decreased hepatic lipase (HL) activity and increased triglyceride content of HDL and LDL particles. We investigated whether these polymorphisms have any effect on transcriptional activity of the proximal promoter (−639 to +29) in transient transfection assays. We found that the promoter with T at position −514 had approximately 30% lower activity than the one with C at the same position (P < 0.0005) regardless of the genotype at position −250. In conclusion, these data indicate that the −514T allele may contribute significantly to decreased HL activity and the resultant increase in plasma levels of triglyceride-rich HDL2 and large buoyant LDL particles. In addition, this promoter variant may explain the finding that its presence attenuates the increase in HL activity with increasing intra-abdominal fat in women. —Deeb, S. S., and R. Peng. The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity.

Highlights

Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups
These polymorphisms may alter promoter activity and hepatic lipase (HL) levels or they may be in linkage disequilibrium with other polymorphisms of the gene that may impact these variables. We addressed this question by determining the effect of the polymorphisms at positions Ϫ250 and Ϫ514 on activity of the proximal LIPC promoter in transient transfection assays
We investigated the activity of the promoter in the murine hepatocyte cell line AML12

Summary

Introduction

Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups. The T and A alleles at positions ؊514 and ؊250, respectively, were observed to be associated with decreased hepatic lipase (HL) activity and increased triglyceride content of HDL and LDL particles. We found that the promoter with T at position ؊514 had approximately 30% lower activity than the one with C at the same position (P Ͻ 0.0005) regardless of the genotype at position ؊250 These data indicate that the ؊514T allele may contribute significantly to decreased HL activity and the resultant increase in plasma levels of triglyceride-rich HDL2 and large buoyant LDL particles. This promoter variant may explain the finding that its presence attenuates the increase in HL activity with increasing intra-abdominal fat in women.—Deeb, S. All these observations indicate that the LIPC promoter polymorphisms are potentially of clinical significance as genetic markers for the above traits

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Conclusion