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 roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing HDL cholesterol (HDL-C). Methods and Results A novel graphical exploratory data analysis tool allowed examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein (CRP). Results demonstrated a high-risk subgroup defined by high HDL-C and CRP exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA2 (Lp-PLA2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). Multivariable modeling revealed in the high-risk subgroup greater risk for B2 allele-carriers (less CETP activity) versus B1 homozygotes (hazard ratio 2.41, 95% CI 1.04-5.60, p=0.041). Within the high-risk subgroup, B2 allele-carriers had higher serum amyloid A levels than B1 homozygotes. Evidence is also presented demonstrating CETP genotypic differences in HDL subfraction distributions regarding nonHDL-C and Lp-PLA2 potentially relating to impaired HDL remodeling. Conclusions Postinfarction patients with high HDL-C and CRP levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and elucidating mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving raising HDL-C.

Increased Coronary Heart Disease Risk Determined by High High-Density Lipoprotein Cholesterol and C-Reactive Protein: Modulation by Variation in the CETP Gene

“…Although CETP activity was not measured, this would suggest that cholesteryl ester transfer from HDL toward apoB-containing lipoproteins is impaired consequent to lower CETP action. Altogether, the data provided in this article 11 agree with the hypothesis that dysfunctional HDL (probed by a proinflammatory state [high CRP and serum amyloid A levels] combined with high HDL cholesterol) increases the risk of recurrent CVD. Variation in the CETP gene, which is associated with lower CETP mass and activity, may contribute to recurrent risk, possibly via abnormal HDL remodeling and impairment of HDL's antiinflammatory properties.…”

“…11 Among 767 nondiabetic subjects (77% male and 79% white), a high-risk subgroup (nϭ166, 56% male) was identified (recurrence rate 23.5% during a mean follow-up period of 26 months versus 13.8% in the background population). Besides 29% higher HDL cholesterol and 3-fold higher CRP levels, the high-risk subgroup individuals were also characterized by larger HDL particles, higher apolipoprotein (apo)A-I and serum amyloid A levels.…”

“…16 Thus, it appears that common variations in the CETP gene, giving rise to lower CETP levels and higher HDL cholesterol, could interact with other genes, as well as with nongenetic factors, including dysfunctional HDL, in modulating CVD risk. Obviously, the mechanisms responsible for an increased CVD risk despite high HDL cholesterol need to be defined more precisely, and the association of increased risk with the CETP B2 allele, as observed in the THROMBO study, 11 should be replicated in other cohorts.…”

“…11 Among 767 nondiabetic subjects with established coronary heart disease (THROMBO cohort), a subgroup comprising 166 individuals (21.6%) at high risk for recurrent coronary heart disease is identified, which is characterized by high HDL cholesterol and CRP levels (hazard ratio 1.81, Pϭ0.0022). The combination of high HDL cholesterol with high CRP is considered to be suggestive of dysfunctional HDL.…”

Serum high density lipoprotein cholesterol level and risk of death: let’s avoid the extremes

“…A series of recent investigations have indicated that there are certain instances where elevated levels of serum HDL-C are not only not associated with improved outcomes, but paradoxically increased risk of CV and all-cause mortality. These include patients with inflammation, polymorphisms in certain genes (such as CETP, lipoprotein lipase, hepatic lipase and scavenger receptor B-I), end stage renal disease (ESRD), diabetes, and coronary artery disease (6)(7)(8)(9)(10)(11)(12)(13).…”