CETP deficiency due to a novel mutation in the CETP gene promoter and its effect on cholesterol efflux and selective uptake into hepatocytes.

OBJECTIVES: To identify the genetic variant in the CETP gene of the proband with high HDL-C and low CETP activity and to investigate whether HDL from the CETP-deficient subject was dysfunctional in the reverse cholesterol transport (RCT) pathway.
METHODS: We sequenced the CETP gene and assessed its promoter activity. Cholesterol efflux and hepatic cholesteryl ester delivery studies were also performed using the proband's HDL.
RESULTS: A proband was a compound heterozygote for a known D459G variant and a novel 18-bp deletion mutation in the CETP promoter. This promoter mutation markedly reduced the transcriptional activity in HepG2 cells. HDL2 from this subject increased SR-BI-mediated cholesterol efflux, whereas cholesteryl ester delivery into hepatocytes was maintained.
CONCLUSION: A novel deletion mutation in the CETP promoter is associated with high HDL-C and decreased promoter activity. HDL from this CETP-deficient subject was not dysfunctional in mediating two main steps of RCT assessed in vitro.