The influence of the acyl-CoA:cholesterol acyltransferase-1 gene (-77G-->A) polymorphisms on plasma lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects.
BACKGROUND
Acyl-CoA:cholesterol acyltransferase (ACAT) plays important roles in cellular cholesterol homeostasis. Two isoforms of ACAT have been reported (ACAT-1 and ACAT-2). ACAT inhibitors cannot only prevent atherosclerosis formation, but may also induce its regression in animals. In humans, an ACAT inhibitor was shown to have a lipid-lowering effect. The present study was carried out to clarify the relationship between ACAT-1 gene variants and hyperlipidemia.


RESULTS
To identify genetic variants, we screened 30 subjects with hyperlipidemia by direct sequencing. As a result, a missense variant (R526G) and a variant in the 5' untranslated region (-77G-->A) were identified. The genotype frequencies of each variant were determined in 178 unrelated normolipidemic and 441 unrelated hyperlipidemic subjects. The alleles frequencies of the R526G variant in normolipidemic and hyperlipidemic subjects were 0.676 and 0.633, respectively. The alleles frequencies of the -77G-->A variant in normolipidemic and hyperlipidemic subjects were 0.503 and 0.515, respectively. Differences in allele frequencies between normolipidemic and hyperlipidemic subjects were not significant in both variants. R526G variant did not affect plasma concentrations of lipids or apolipoproteins in subjects studied. However, among hyperlipidemic subjects, plasma concentrations of HDL-C and apoA-I in subjects with -77G-->A variant were significantly higher than those in subjects without variant.


CONCLUSIONS
Two variants in ACAT-1 gene were identified in subjects with hyperlipidemia. -77G-->A variant affects plasma HDL concentrations only in hyperlipidemic subjects. These data suggest that the intracellular FC concentration might modulate plasma HDL concentrations.
Ohta
Takao
T
Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan. tohta@med.u-ryukyu.ac.jp
Takata
Kouki
K
Katsuren
Keisuke
K
Fukuyama
Shigeru
S
D016632:Apolipoprotein A-I / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood*; D005091:Exons; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D002785:Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D002785:Sterol O-Acyltransferase