Low Serum Paraoxonase-1 Activity Associates with Incident Cardiovascular Disease Risk in Subjects with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein.

Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP-(LR; event rate 4.9%); low HDL-C/high CRP-(HR1; event rate 14.4%); and high HDL-C/high CRP-(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit-0.68, 95% CI 0.55-0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio-1.77, 95% CI 1.29-2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels.

Plasma ApoE elevations are associated with NAFLD: The PREVEND Study.

Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI ≥ 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: ß = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE ε3ε3 homozygotes, ApoE ε2 carriers, and ApoE ε3ε4 and ε4ε4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE genotypes. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD.

Compositional Features of HDL Particles Interact with Albuminuria to Modulate Cardiovascular Disease Risk.

Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was performed on participants of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study at the baseline screening with standard lipid/lipoprotein analyses and, three-to-four years later (second screen), with nuclear magnetic resonance lipoprotein analyses focusing on HDL parameters including HDL particle (HDL-P) and apolipoprotein A-I concentrations. These were used with UAE and derived measures of HDL apoA-I content (apoA-I/HDL-C and apoA-I/HDL-P) in risk models adjusted for gender, age, apoB, diabetes, past CVD history, CRP and GFR. Interaction analysis was also performed. Baseline screening revealed significant associations inverse for HDL-C and apoA-I and direct for apoA-I/HDL-C. The second screening demonstrated associations inverse for HDL-P, large HDL-P, medium HDL-P, HDL size, and apoA-I/HDL-P. Significant interactions with UAE included apoA-I/HDL-C at the baseline screening, and apoA-I/HDL-P and medium HDL-P but not apoA-I/HDL-C at the second screening. We conclude that features of HDL particles including apoA-I/HDL-P, indicative of HDL apoA-I content, and medium HDL-P modify associations of elevated UAE with CVD risk.

Insulin resistance involvement in prevalence of familial dysbetalipoproteinemia in ε2ε2 subjects by Bayesian network modeling.

OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all ε2 homozygotes develop FD indicating that additional factors play a role including insulin resistance (IR). The current study was undertaken to explore relationships and influences among factors, especially IR, that might elucidate FD progression pathways. METHODS: Bayesian network (BN) modeling, a probabilistic graphical exploratory data analysis tool that portrays relationships and influences among variables as simple diagrams, was applied to 52 e2e2 subjects. An algorithm based on apolipoprotein and lipid values identified 24 subjects having FD. BN modeling parameters included plasma apoE, HDL cholesterol (HDL-C), apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), apoA-I/HDL-C ratio, apoA-II/HDL-C ratio, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). RESULTS: Modeling resulted in twenty network graphs. Each graph revealed apoE and the apoA-II/HDL-C ratio as sole determinants of FD prevalence. BN results did not demonstrate a direct role for insulin and HOMA-IR. However, multiple graphs in the set did reveal indirect influence of IR on FD prevalence as conveyed through the apoA-II/HDL-C ratio; while all remaining graphs in the set demonstrated the apoA-II/HDL-C ratio as directly influencing insulin levels and HOMA-IR. For apoE, the other determinant of FD prevalence, results revealed no relationship with IR parameters. CONCLUSIONS: In so far as insulin levels and HOMA-IR are associated with IR in e2e2 subjects, IR may act indirectly in FD progression via the apoA-II/HDL-C ratio; and/or the apoA-II/HDL-C ratio acts directly to promote IR.

Roles of high apolipoprotein E blood levels and HDL in development of familial dysbetalipoproteinemia in ε2ε2 subjects.

OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is a mixed hyperlipidemia closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all homozygotes progress to FD. Unlike the polymorphism, few studies explore effects of apolipoprotein E (apoE) blood levels on FD development. Likewise, despite the known apoE2 lipoprotein binding preference for high-density lipoprotein (HDL); little work exists exploring HDL in FD. Accordingly, this study was undertaken to investigate potential roles in FD development for apoE and HDL. Additionally, insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were investigated in view of reports linking insulin resistance to FD. METHODS: APOE genotyping and levels of apoE, apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), insulin, HOMA-IR, lipids, and NMR lipoprotein analysis were determined in a cohort of healthy individuals (N=7169). A lipid-based algorithm identified FD in 24 of 52 e2e2 subjects. Logistic regression modeling assessed associations of FD development with measured variables. RESULTS: Univariate models revealed associations with FD significant and positive for apoE, apoA-II/apoA-I, apoA-I/HDL-C, apoA-II/HDL-C, and HOMA-IR. For HDL-C, association was significant but inverse. Results of multivariable models containing apoE with single parameters added revealed statistical significance only for the apoA-II/HDL-C ratio (OR 10.52, 95%CI 1.17-94.79, p=0.036) concurrent with significance for apoE (OR 2.21, 95%CI 1.06-4.65, p=0.035). Interaction was not demonstrated (p=0.36). NMR results revealed for FD versus nonFD subjects generally higher levels of VLDL and small HDL and for IDL few differences. CONCLUSION: High apoE and high apoA-II/HDL-C independently associate with FD development in ε2ε2 individuals.

Apolipoprotein E levels and apolipoprotein E genotypes in incident cardiovascular disease risk in subjects of the Prevention of Renal and Vascular End-stage disease study.

BACKGROUND: Apolipoprotein E (apoE) is a component of all major lipoprotein classes with multiple functions including clearance of circulating triglyceride-rich lipoprotein particles and hepatic production of triglyceride-rich lipoprotein, thus affording several avenues for apoE involvement in atherosclerosis development. ApoE has 3 isoforms (E2, E3, and E4) based on a common genetic polymorphism. Numerous studies have been performed assessing cardiovascular disease (CVD) risk relative to the 6 resulting genotypes; however, surprisingly, few studies have been performed assessing risk attributable to apoE plasma levels either alone or in addition also taking into account apoE genotypes. OBJECTIVE: To examine the role of apoE levels together with apoE genotypes on incident CVD risk in a large population-based cohort and also to afford preliminary characterization of atherogenic apoE-containing lipoprotein particles. METHODS: Cox multivariable proportional hazards modeling was performed on a cohort of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study as a function of apoE levels and apoE genotypes adjusted for age, gender, and past history of CVD. Further modeling was performed with single addition of clinical and biomarker parameters to elucidate the nature of apoE-associated risk. RESULTS: High apoE levels were demonstrated to be associated with CVD risk (hazard ratio per apoE standard deviation, 1.20; 95% confidence interval, 1.11-1.31; P < .0001) both overall and within the high-frequency apoE genotype groups (ε2ε3, ε3ε3, and ε3ε4). Only on addition of apoB-containing lipoprotein parameters to models, did apoE levels lose association with risk. CONCLUSIONS: ApoE levels positively associate with incident CVD risk with apoE-associated risk likely residing in apoB-containing lipoproteins.

Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling.

Data is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, "Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation" (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1]).

Influences on plasminogen activator inhibitor-2 polymorphism-associated recurrent cardiovascular disease risk in patients with high HDL cholesterol and inflammation.

BACKGROUND AND AIMS: Evidence continues to accumulate that athero-protective effects of high-density lipoprotein (HDL) depend to some degree on effective HDL functionality and that such functionality can become degraded in the setting of chronic inflammation. To investigate this issue, we have studied a group of post-myocardial infarction patients with high levels of C-reactive protein as an indicator of chronic inflammation and with concurrently high levels of HDL cholesterol. For these patients we have demonstrated high-risk for recurrent cardiac events as well as a strong association of risk with a polymorphism of the gene (SERPINB2) for plasminogen activator inhibitor-2 (PAI-2) presumptively reflective of an important role for fibrinolysis in risk. However, additional processes might be involved. The current work sought to characterize processes underlying how PAI-2 might be involved in the generation of risk. METHODS: Multivariate population data were leveraged using Bayesian network modeling, a graphical probabilistic approach for knowledge discovery, to generate networks reflective of influences on PAI-2 polymorphism-associated risk. RESULTS: Modeling results revealed three individual networks centering on the PAI-2 polymorphism with specific features providing information relating to how the polymorphism might associate with risk. These included racial dependency, platelet clot initiation and propagation, oxidative stress, inflammation effects on HDL metabolism and coagulation, and induction and termination of fibrinolysis. CONCLUSIONS: Beyond direct association of a PAI-2 polymorphism with recurrent risk in post-myocardial infarction patients, results suggest that PAI-2 likely plays a key role leading to risk through multiple pathophysiologic processes. Such knowledge could potentially be valuable with individualization of patient care.

Apolipoprotein B attenuates albuminuria-associated cardiovascular disease in prevention of renal and vascular endstage disease (PREVEND) participants.

Whether urinary albumin excretion relates to higher levels of atherogenic apolipoprotein B fractions in the nondiabetic population is uncertain. Such a relationship could explain, in part, the association of elevated urinary albumin excretion with cardiovascular disease risk. We assessed the relationship of urinary albumin excretion with apolipoprotein B fractions and determined whether the association of elevated urinary albumin excretion with incident cardiovascular events is modified by high apolipoprotein B fraction levels. We performed a prospective study on 8286 nondiabetic participants (580 participants with cardiovascular disease; 4.9 years median follow-up time) with fasting lipids, apolipoprotein B, and urinary albumin excretion determined at baseline. With adjustment for sex and age, micro- and macroalbuminuria were associated with increased apolipoprotein B fractions (non-HDL cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B). All four apolipoprotein B fractions modified associations of urinary albumin excretion with incident cardiovascular disease (hazard ratios for interaction terms ranged from 0.89 to 0.94 with 95% confidence intervals ranging from 0.84 to 0.99 and P values ranging from 0.001 to 0.02 by Cox proportional hazards modeling). These interactions remained present after additional adjustment for conventional risk factors, eGFR, cardiovascular history, and lipid-lowering and antihypertensive drug treatments. Such modification was also observed when urinary albumin excretion was stratified into normo-, micro-, and macroalbuminuria. We conclude that there is an association between elevated urinary albumin excretion and apolipoprotein B fraction levels and a negative interaction between these variables in their associations with incident cardiovascular events. Elevated urinary albumin excretion may share common causal pathways with high apolipoprotein B fractions in the pathogenesis of cardiovascular disease.

Plasminogen activator inhibitor-2 polymorphism associates with recurrent coronary event risk in patients with high HDL and C-reactive protein levels.

The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process.

Reactive Oxygen Species, SUMOylation, and Endothelial Inflammation.

Although the exact mechanism through which NADPH oxidases (Nox's) generate reactive oxygen species (ROS) is still not completely understood, it is widely considered that ROS accumulation is the cause of oxidative stress in endothelial cells. Increasing pieces of evidence strongly indicate the role for ROS in endothelial inflammation and dysfunction and subsequent development of atherosclerotic plaques, which are causes of various pathological cardiac events. An overview for a causative relationship between ROS and endothelial inflammation will be provided in this review. Particularly, a crucial role for specific protein SUMOylation in endothelial inflammation will be presented. Given that SUMOylation of specific proteins leads to increased endothelial inflammation, targeting specific SUMOylated proteins may be an elegant, effective strategy to control inflammation. In addition, the involvement of ROS production in increasing the risk of recurrent coronary events in a sub-group of non-diabetic, post-infarction patients with elevated levels of HDL-cholesterol will be presented with the emphasis that elevated HDL-cholesterol under certain inflammatory conditions can lead to increased incidence of cardiovascular events.

Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein.

BACKGROUND: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups. METHODOLOGY/PRINCIPAL: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I:A-II levels interacted with high apoE levels in establishing subgroup risk. CONCLUSIONS/SIGNIFICANCE: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein.

Although there is great interest in the notion that dysfunctional transformation of high-density lipoprotein (HDL) facilitates development of atherosclerosis and cardiovascular disease (CVD), few studies in human populations directly address this issue. As apolipoprotein E (apoE) is a constituent of HDL thought to be important for HDL antiatherogenic function, we sought to assess the role of apoE in CVD risk in subjects likely to display dysfunctional transformation of HDL. Association of apoE levels with incident CVD risk was investigated using Cox multivariable proportional hazards modeling. Analyses were performed in subgroups of women and men likely to display dysfunctional transformation of HDL deriving from previous subgroup identification based upon defining characteristics of concurrently high levels of HDL cholesterol and systemic inflammation as reflected by high C-reactive protein levels. Results revealed apoE levels (dichotomized as highest quartile vs combined 3 lowest quartiles) as predicting subgroup risk in women (hazard ratio, 4.52; 95% confidence interval, 1.07-19.12; P = .040) but not in men. Further sex differences were manifested in terms of the relationship of apoE levels with age. Analysis revealed positive correlation of apoE levels with age in women (r = 0.47, P < .0001) but not in men (r = 0.04, P = .43). Apolipoprotein E levels predict incident CVD risk in women with high levels of HDL cholesterol and C-reactive protein but not in men. Future studies should be oriented toward investigations of apoE as related to multiplicity of HDL functionality and toward assessment of potential roles for apoE in dysfunctional transformation of HDL.

Thrombospondin-4 polymorphism (A387P) predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and C-reactive protein levels.

Few studies are available in human populations investigating involvement of vascular inflammation and oxidative stress-related dysfunctional transformation of high-density lipoprotein (HDL) in establishing cardiovascular disease (CVD) risk. To this end, the current work investigated a subgroup of post-infarction patients at high-risk for recurrent events defined by high levels of HDL cholesterol (HDL-C) and concurrently high levels of C-reactive protein (CRP). Thrombospondin-4 (TSP-4), a matricellular protein of vessel walls associated with inflammation, was investigated in terms of CVD risk using multivariable modelling with a well-characterised functional genetic polymorphism of THBS4 (A387P, rs1866389) along with previously demonstrated risk-related functional genetic polymorphisms of CYBA (C242T, rs4673) and CETP (TaqIB, rs708272), and a set of blood markers. Results revealed risk-association for the gain-of-function P-allele of the THBS4 polymorphism (hazard ratio 2.00, 95% confidence interval 1.10-3.65, p=0.024). Additionally, von Willebrand factor was associated with D-dimer levels in the higher-risk P allele patients suggestive of a connection between endothelial dysfunction and thrombogenesis. In conclusion, TSP-4, a matricellular protein involved in regulating vascular inflammation, plays a role in establishing recurrent coronary risk in post-infarction patients with high levels of HDL-C and CRP. Further studies should focus on additional effects of vascular inflammatory processes on anti-atherogenic functionality of HDL particles.

Glycerol as a reference material for fecal fat quantitation using low-resolution time domain ¹H NMR spectroscopy.

OBJECTIVES: To assess glycerol as reference material for low-resolution time-domain (1)H NMR analysis of fecal fat. DESIGN AND METHODS: NMR analysis of fecal fat in stool samples with added glycerol was used to assess linearity, recovery, and relationship with NMR lipid signal. RESULTS: The study revealed for added glycerol excellent linearity (r=0.9998), recovery (101-104%), and linear relationship with simulated fecal fat content. CONCLUSIONS: Glycerol is an effective reference material for NMR fecal fat analysis.

An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients.

BACKGROUND: Transfusion of ABO non-identical plasma, platelets and cryoprecipitate is routine practice even though adverse effects can occur. METHODS AND MATERIALS: Our hospital changed transfusion practice in 2005 and adopted a policy of providing ABO-identical blood components to all patients when feasible. We retrospectively compared the transfusion requirements, length of stay and in-hospital mortality in relation to ABO blood group in surgical patients who received platelet transfusions before and after this change to determine whether it resulted in any benefit. RESULTS: Prior to the change in practice, both group B and AB patients received more ABO non-identical platelet transfusion (P=0·0004), required significantly greater numbers of red cell transfusions (P=0·04) and had 50% longer hospital stays (P=0·039) than group O and A patients. Following the policy change, there was a trend for fewer red cell transfusions (P=0·17) and length of stay in group B and AB patients than group O or A patients. Overall, the mortality rate per red cell transfusion decreased from 15·2 per 1000 to 11·0 per 1000 (P=0·013). CONCLUSIONS: These results, in the context of previous findings, suggest that providing ABO-identical platelets and cryoprecipitate might be associated with reduction in transfusion requirements and improve outcomes in surgical patients.

LPL polymorphism (D9N) predicts cardiovascular disease risk directly and through interaction with CETP polymorphism (TaqIB) in women with high HDL cholesterol and CRP.

OBJECTIVE: We sought to determine whether concurrently high levels of HDL cholesterol and CRP predict initial cardiovascular events in women, and to assess additional risk involving two genes encoding proteins involved in reverse cholesterol transport. METHODS: A graphical approach identified high-risk subgroups in a population-based female cohort. Polymorphism-associated risk was assessed for CETP (TaqIB [rs708272]) and LPL (D9N [rs1801177]) using multivariable analysis adjusted for clinical parameters and biomarkers. RESULTS: A high HDL-C/high CRP high-risk subgroup was identified. Multivariable modeling revealed D9N as predicting subgroup cardiovascular disease risk directly (minor allele-carriers versus major allele homozygotes: HR 5.16, 95% CI 1.43-18.54, p = 0.012) and through interaction with TaqIB (highest risk in minor allele carriers of both polymorphisms). CONCLUSIONS: In women with high HDL-C and high CRP levels, an LPL polymorphism associated with risk and interacted with a CETP polymorphism such that the highest risk occurred in subjects with presumably decreased activities of both proteins.

PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry.

BACKGROUND: Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. METHODS AND RESULTS: A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). CONCLUSIONS: Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

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

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.