The effect of cholesteryl ester transfer protein -629C->A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides.
BACKGROUND
The -629C-->A cholesteryl ester transfer protein (CETP) promoter polymorphism is a determinant of HDL cholesterol (HDL-C). The effect of the closely linked CETP TaqIB polymorphism on HDL-C has been suggested to be modified by obesity and hyperinsulinemia.


OBJECTIVE
Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, we hypothesized that triglycerides modify the effect of the CETP -629C-->A promoter polymorphism on HDL-C.


METHODS
In 7083 nondiabetic subjects of the PREVEND population, the -629C-->A promoter polymorphism, HDL-C, serum triglycerides, waist circumference, and insulin resistance (HOMA(ir)) were determined. Serum apolipoprotein A-I was available in 6948 subjects. The TaqIB polymorphism was also assessed.


METHODS
The study is set in the general community.


RESULTS
HDL-C and serum apolipoprotein A-I were on average 0.14 mmol/liter and 0.05 g/liter higher in -629AA (22.9%) compared to -629CC (26.8%) homozygotes (P < 0.001 for both). This genotype effect on HDL-C was on average 0.15 mmol/liter in the lowest triglyceride tertile but only 0.08 mmol/liter in the highest tertile (P < 0.01). Multiple regression analysis showed that HDL-C was determined by the CETP promoter variant (P < 0.001), gender (P < 0.001), triglycerides (P < 0.001), and interactions between triglycerides and genotype (P < 0.05), between triglycerides and gender (P < 0.05), and between genotype and gender (P < 0.05), independently from waist, HOMA(ir), alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The -629C-->A promoter polymorphism did not interact with obesity and HOMA(ir) on HDL-C.


CONCLUSIONS
The HDL-C-raising effect of the CETP -629A allele is diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides.
Borggreve
Susanna E
SE
Department of Endocrinology, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. s.e.borggreve@int.umcg.nl
Hillege
Hans L
HL
Wolffenbuttel
Bruce H R
BH
de Jong
Paul E
PE
Bakker
Stephan J L
SJ
van der Steege
Gerrit
G
van Tol
Arie
A
Dullaart
Robin P F
RP
D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014280:Triglycerides / Q000097:blood*
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D014280:Triglycerides