Submitted on December 19, 2006
Accepted on May 21, 2007
CETP genotypes and HDL-cholesterol phenotypes in the HERITAGE Family Study
Nadine Spielmann1, Arthur S. Leon2, D.C. Rao3, Treva Rice4, James S. Skinner5, Claude Bouchard6, and Tuomo Rankinen6*
1 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
2 School of Kinesiology, University of Minnesota, Minneapolis, Minnesota, United States
3 Division of Biostatistics and Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States
4 Division of Biostatistics and Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis,, Missouri, United States
5 Kinesiology, Indiana University, Bloomington, Indiana, United States
6 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, United States
* To whom correspondence should be addressed. E-mail: rankint{at}pbrc.edu.
Associations between CETP polymorphisms and high-density lipoprotein cholesterol (HDL-c) levels before and after 20 weeks of endurance training were investigated in the HERITAGE Family Study. Plasma HDL-c, HDL2-c, HDL3-c and Apolipoprotein A1 (ApoA1) levels were measured and 13 CETP single nucleotide polymorphisms (SNPs) were genotyped in 265 Blacks and 486 Whites. Three haplotypes defined by SNPs at the -1337, -971 and -629 sites were strongly associated with baseline HDL-c levels in Whites. Both the C>-1337>T and C>-629>A were associated with baseline HDL-c (p<0.001) and ApoA1 (p<0.01) when tested separately. However, only the C>-629>A remained significant in a combined model. The G>-971>A was not associated with HDL phenotypes, but showed significant interactions with C>-629>A (p=0.002) on baseline traits. Genotype-by-sex interactions were observed at the -629 locus for HDL3-c (p=0.004) and ApoA1 (p=0.02) training responses in Whites. In women, the -629 A/A homozygotes showed greater increases in HDL3-c (p=0.02) and ApoA1 (p=0.02) levels than the other genotypes. Finally, APOE genotype and the CETP C>-629>A locus contributed independently and in additive fashion to the HDL traits, explaining 6.0% to 8.8% of the variance.
The CETP -1337>T and -629>A alleles are associated with higher baseline HDL-c and ApoA1 levels. The beneficial effects of endurance training on plasma HDL3-c and ApoA1 levels are evident in White women homozygous for the -629>A allele. The CETP and APOE genotypes account up to 9% of the variance in HDL-c phenotypes in the HERITAGE Family Study.
