Updated pooled analysis finds the CETP B2 allele may raise, not lower, cardiovascular risk in the general population despite higher HDL cholesterol (Pharmacogenomics 2008)

Human plasma contains cholesteryl ester transfer protein (CETP) which, besides other functions, enables the transfer of cholesteryl esters in plasma from high-density lipoproteins (HDL) towards triglyceride-rich lipoproteins, thereby contributing to lower HDL cholesterol. Variations in the CETP gene, including the intronic TaqIB polymorphism (rs708272), are common in the population. Although HDL cholesterol is approximately 10% higher in TaqIB B2B2 than in B1B1 carriers, the association of this polymorphism with cardiovascular disease has not been unequivocally established. We present an updated pooled analysis concerning the association of cardiovascular disease with the TaqIB polymorphism, including only studies that predominantly comprise Caucasian subjects. The distribution of this CETP genotype was observed to be different in population-based studies (n = 10,526) compared with studies in populations selected by high cardiovascular risk (n = 10,947), with B2B2 carriers being less frequent among cases from high-risk populations compared with cases from population-based studies (p = 0.0009 for the difference in genotype distribution). In population-based studies, the odds ratio (OR) for cardiovascular disease was found to be 1.45 (95% CI: 1.07-1.95) in B2B2 compared with B1B1 carriers, contrasting the lower OR of 0.84 (95% CI: 0.74-0.96) in B2B2 versus B1B1 carriers from high-risk populations. Thus, it is possible that in the general population, the B2 allele is associated with higher cardiovascular risk, despite higher HDL cholesterol. Our analysis agrees with the contention that selection towards a lower frequency of B2B2 homozygotes may have occurred in selected populations, which would result in a apparently protective effect of the B2 allele when determined in high-risk populations. We also evaluated whether the TaqIB polymorphism would predict efficacy of lipid-lowering treatment with respect to plasma lipids and cardiovascular outcome, but the results of published studies were contradictory. Likewise, no definite conclusion can be made at present concerning the effect of this CETP polymorphism on the lipid response to diet intervention.