Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels

Abstract

Objective: To investigate the roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing high-density lipoprotein cholesterol (HDL-C) level.

Methods and results: A novel graphical exploratory data analysis tool allowed the examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein levels. Results demonstrated a high-risk subgroup, defined by high HDL-C and C-reactive protein levels, exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA(2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). In the high-risk subgroup, multivariable modeling revealed greater risk for B2 allele carriers (less CETP activity) versus B1 homozygotes (hazard ratio, 2.41; 95% CI, 1.04 to 5.60; P=0.04). Within the high-risk subgroup, B2 allele carriers had higher serum amyloid A levels than B1 homozygotes. Evidence also demonstrates that CETP genotypic differences in HDL subfraction distributions regarding non-HDL-C and lipoprotein-associated phospholipaseA(2) may potentially relate to impaired HDL remodeling.

Conclusions: Postinfarction patients with high HDL-C and C-reactive protein levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and at elucidating the mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving an increase in HDL-C level.

Figure 1

Outcome event mapping of estimated coronary event rate over the risk domain of HDL-C and CRP ranks for the study population. Full-scale outcome rate along z-axis is 0.40. The red iso-contour at peak base corresponds to mean event rate for the total population (0.159). For reference, HDL ranks 480, 660, and 730 correspond approximately to: HDL-C of 1.04 mmol/l (40mg/dL), 1.30 mmol/l (50 mg/dL), and 1.55 mmol/l (60 mg/dL), respectively; while CRP ranks 195 and 465 correspond to CRP of 1 mg/L and 3 mg/L, respectively.

Figure 2

Outcome event mappings of estimated coronary event rates over the risk domain of HDL-C and CRP ranks as a function of the dichotomized TaqIB polymorphism of CETP for: A. B1 homozygotes and B. B2 allele carriers. Full-scale outcome rate along z-axis is 0.50. See Figure 1 legend for correspondence of HDL-C and CRP ranks with levels.