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Regulation of cholesteryl ester transfer protein expression by upstream polymorphisms

reduced expression associated with rs247616

Suhy, Adam; Hartmann, Katherine; Papp, Audrey C.; Wang, Danxin; Sadee, Wolfgang

doi: 10.1097/FPC.0000000000000151
ORIGINAL ARTICLES
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Background Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport by exchanging cholesteryl esters for triglycerides between high-density lipoprotein and low-density lipoprotein particles, effectively decreasing high-density lipoprotein cholesterol levels. Variants within a large haplotype block upstream of CETP (rs247616, rs173539) have been shown to be significantly associated with reduced expression; however, the underlying mechanism has not been identified.

Methods We analyzed the linkage structure of our top candidate single-nucleotide polymorphism (SNP), rs247616, and assessed each SNP of the haplotype block for potential interactions with transcription factor binding sites. We then used a reporter gene assay to assess the effect of three SNPs (rs247616, rs173539, and rs1723150) on expression in vitro.

Results Several variants in the upstream haplotype, including rs247616, rs173539, and rs1723150, disrupt or generate transcription factor binding sites. In reporter gene assays, rs247616 and rs173539 were found to significantly affected expression in HepG2 cells, whereas rs17231506 had no effect. rs247616 decreased expression by 1.7-fold (P<0.0001), whereas rs173539 increased expression by 2.2-fold (P=0.0006).

Conclusion SNPs rs247616 and rs173539 are in high linkage disequilibrium (R2=0.96, D′=1.00) and have the potential to regulate CETP expression. Although opposing effects suggest that regulation of CETP expression could vary between tissues, the minor allele of rs247616 and SNPs in high linkage with it were found to be associated with reduced expression across all tissues.

Department of Pharmacology, Center for Pharmacogenomics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA

Correspondence to Wolfgang Sadee, 5078 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA Tel: +1 614 292 1597; fax: +1 614 292 7232; e-mail: wolfgang.sadee@osumc.edu

Received February 14, 2015

Accepted May 13, 2015

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