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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:985.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Point Mutation (-69 GA) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

Makoto Nagano; Shizuya Yamashita; Ken-ichi Hirano; Takeshi Kujiraoka; Mayumi Ito; Yukiko Sagehashi; Hiroaki Hattori; Norimichi Nakajima; Takao Maruyama; Naohiko Sakai; Tohru Egashira; Yuji Matsuzawa

From the Research Department, R&D Center, BML, Saitama (M.N., T.K., M.I., Y.S., H.H., T.E.); the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka (S.Y., K.H., T.M., N.S.); and Nakajima Clinic, Akita (N.N.), Japan.

Correspondence to Shizuya Yamashita, MD, PhD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail shizu{at}imed2.med.osaka-u.ac.jp

Abstract—Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo) B–containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the -69 nucleotide of the promoter region (-69 GA), corresponding to the second nucleotide of the PEA3/ETS binding site (CGGAA) located upstream of the putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked HALP (HDL cholesterol 2.59 mmol/L=100 mg/dL) were revealed to be heterozygous for the -69 GA mutation, and the allelic frequency of the mutant was 0.0102 in the subjects with a marked HALP. The subjects with the -69 GA mutation had low plasma CETP levels. Reporter gene assay showed that this mutation markedly reduced the transcriptional activities in HepG2 cells (8% of wild type). These results suggested that this mutation would be dominant negative. In conclusion, a novel -69 GA mutation in the CETP gene causes the decreased transcriptional activity leading to HALP.

Key Words: cholesteryl ester transfer protein deficiency • hyperalphalipoproteinemia • mutation • promoter • PEA3/ETS binding site

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