Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.
OBJECTIVE
We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level.


RESULTS
We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08).


CONCLUSIONS
Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.
Lipid Metabolism Laboratory, JM-USDA-Human Nutrition Research Center on Aging at Tufts University and Department of Medicine, New England Medical Center, Boston, Mass 02111, USA. mbrousseau@hnrc.tufts.edu
Margaret E
ME
Brousseau
John J
JJ
O'Connor
Jose M
JM
Ordovas
Dorothea
D
Collins
James D
JD
Otvos
Tatyana
T
Massov
Judith R
JR
McNamara
Hanna B
HB
Rubins
Sander J
SJ
Robins
Ernst J
EJ
Schaefer
D000483:Alleles; D001053:Apolipoproteins / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D005215:Fasting / Q000097:blood; D015248:Gemfibrozil / Q000494:pharmacology / Q000627:therapeutic use; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006023:Glycoproteins; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D050356:Lipid Metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D012307:Risk Factors; D014481:United States; D014493:United States Department of Veterans Affairs
D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D005819:Genetic Markers; D006023:Glycoproteins; D000960:Hypolipidemic Agents; D008055:Lipids; D008077:Lipoproteins, LDL; D015248:Gemfibrozil