title: Prevalence and phenotypic spectrum of cholesteryl ester transfer protein gene mutations in Japanese hyperalphalipoproteinemia.
abstract: A patient with cholesteryl ester transfer protein (CETP) deficiency presents with marked hyperalphalipoproteinemia (HALP). To investigate the contribution of CETP deficiency to the cause of HALP (HDL-C> or =1.94 mmol/l, 75 mg/dl), we investigated the CETP activities and the prevalence of genetic CETP mutations among 624 Japanese HALP subjects. The subjects were screened for four known genetic CETP mutations (intron 14 splicing defect (In14), exon 15 missense mutation (Ex15), intron 10 splicing defect (In10) and exon 6 nonsense mutation (Ex6)). We found the frequency of the patients with reduced CETP activity (<75% of normal controls) to be 55.5 and 64.1% in a high HDL group (1.94< or =HDL-C<2.59 mmol/l) and a marked HALP group (HDL-C> or =2.59 mmol/l, 100 mg/dl), respectively. At least one of the four mutations was identified in 65.7% of subjects with reduced CETP activities and 57.5% of subjects with marked HALP. The In14 and Ex15 mutations were very common in HALP subjects and the frequency of In10 mutation and Ex6 mutation was quite low. To investigate the impact of genetic CETP mutation on the phenotypes, we compared the plasma lipid levels and CETP activities between the subjects with two common mutations. All In14 homozygotes showed marked HALP, while marked HALP is less frequent (64.3%) in Ex15 homozygotes. HDL-C levels in Ex15 heterozygotes were significantly higher than those of In14 heterozygotes, suggesting the mutation has dominant negative effects on CETP activity in vivo. Some cases with In14 (5.7%) or Ex15 (7.2%) mutation showed low HDL-C levels. We conclude that CETP deficiency is a major cause of HALP; nevertheless CETP deficiency is not necessarily HALP.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, B5, Suita, Osaka 565-0871, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Maruyama
authors.forename: Naohiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Masato
authors.initials: M
authors.lastname: Ishigami
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Arai
authors.forename: Sugako
authors.initials: S
authors.lastname: Okada
authors.forename: Eiko
authors.initials: E
authors.lastname: Okuda
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohya
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakajima
authors.forename: Ken
authors.initials: K
authors.lastname: Kadowaki
authors.forename: Etsuko
authors.initials: E
authors.lastname: Fushimi
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000328:Adult; D000368:Aged; D001053:Apolipoproteins / Q000097:blood*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins; D005260:Female; D006023:Glycoproteins; D006801:Humans; D006951:Hyperlipoproteinemias / Q000453:epidemiology / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D015995:Prevalence
chemical_list: D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D002784:Cholesterol