|Lai, Chao Qiang|
Submitted to: Nutrition Metabolism and Cardiovascular Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2009
Publication Date: 4/11/2009
Citation: Junyent, M., Arnett, D.A., Tsai, M.Y., Kabagambe, E.K., Straka, R.J., Province, M., An, P., Smith, C., Shen, J., Borecki, I., Parnell, L.D., Lai, C., Lee, Y., Ordovas, J.M. 2009. The effect of a novel intergenic polymorphism (rs11774572) on HDL cholesterol concentrations depends on the TaqIB polymorphism in the cholesterol ester transfer protein gene. Nutrition Metabolism and Cardiovascular Disease.20:34-40. Interpretive Summary: Blood plasma lipid levels are determined in part by genetic components and many different genetic loci affect lipoprotein metabolism in humans. Because genes and gene components interact and often work in concert, investigations of gene-gene interactions may provide additional predictive value and mechanistic insight into newly identified lipid related genes. The objective of this study was to ascertain whether three newly discovered genetic variants, which have recently been associated with blood lipid levels, interact in a genetic manner with the well characterized variant of the CETP gene, encoding the key enzyme in cholesterol metabolism, to affect blood lipid levels. These four genetic variants were assayed in 1002 Whites and blood lipids were measured by standard methods. Individuals carrying the C version of genetic variant rs11774572 significantly associated with lower HDL-cholesterol and higher triglyceride and insulin levels than persons carrying two copies of the T version. Furthermore, this genetic variant showed an interaction with a common variant of the CETP gene, which altered HDL-cholesterol, LDL and VLDL levels. In summary, genetic variant rs11774572 exerts influence on blood lipid regulation and insulin resistance, both important in metabolic syndrome. Importantly, this genetic variant, although mapping to a region of the human genome distinct from CETP, acts synergistically with a CETP variant to alter blood lipids.
Technical Abstract: Background: Plasma lipid levels have a strong genetic component and many different loci, including those identified by genome-wide association studies, affect lipoprotein metabolism in humans. Hence, the study of gene-gene interactions may be useful to provide additional predictive value as well as mechanistic insight into newly identified lipid related loci. Objective: To test associations of three single nucleotide polymorphisms (SNPs) (rs11774572, rs7819412, and rs6995374) at novel lipid loci with the SNP rs708272 in the cholesterol ester transfer protein (CETP) gene, in determining blood lipid and metabolic syndrome (MetS) traits. Design - The aforementioned SNPs were genotyped in 1002 subjects who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Lipids were measured by standard procedures and lipoprotein subfractions, by proton nuclear magnetic resonance spectroscopy. Results: Polymorphism rs11774572 was significantly associated with MetS (P=0.020), mainly driven by association of the C allele with lower HDL-C (P=0.043) and higher triglyceride (P=0.049) and insulin (P=0.040) concentrations than TT subjects. A significant interaction between SNPs rs11774572 and CETP-TaqIB was found for HDL-C (P=0.006), HDL (P=0.008) and LDL particle sizes (P=0.009), small LDL (P=0.004), and VLDL concentrations (P=0.021), in which TT homozygotes displayed higher HDL-C, HDL and LDL particle size, and lower small LDL and VLDL concentrations than C carriers, if they were CETP B2 allele carriers (P values ranging from <0.001 to 0.001). Conclusions: The rs11774572 polymorphism plays a key role in the dyslipidemia and insulin resistance that characterize MetS. The interaction between rs11774572 and CETP-TaqIB SNPs on HDL-C concentrations provides evidence that these variants function in concert to regulate blood lipid levels.