Type 2 diabetes mellitus interacts with obesity and common variations in PLTP to affect plasma phospholipid transfer protein activity.

BACKGROUND: Phospholipid transfer protein (PLTP) is an emerging cardiometabolic risk marker that is important in high-density lipoprotein (HDL) and triglyceride metabolism. Plasma PLTP activity is elevated in type 2 diabetes mellitus, whereas glucose may regulate PLTP gene transcription in vitro. Of interest, common PLTP variations that predict cardiovascular disease have been identified recently. We investigated whether the diabetic state is able to amplify relationships between obesity and PLTP gene variations with circulating PLTP levels. SUBJECTS AND METHODS: Plasma PLTP activity (using a phospholipid vesicles-HDL system), PLTP gene score [number of PLTP activity-decreasing alleles based on two tagging polymorphisms (rs378114 and rs60- 65904)] and waist circumference were determined in two Dutch cohorts comprising 237 patients with type 2 diabetes and 78 control subjects. RESULTS: Patients with diabetes were more obese (P < 0.001 for prevalence of increased waist circumference) and had 13% higher plasma PLTP activity (P < 0.001). PLTP gene score was not different in diabetic and control subjects (P = 0.40). PLTP activity was highest in patients with diabetes with an enlarged waist and lowest in control subjects with a normal waist circumference (P < 0.001). Multiple linear regression analysis revealed a positive interaction between diabetes status and waist circumference on PLTP activity (ß = 0.200, P = 0.005). Furthermore, diabetes status (ß = -0.485, P = 0.046) or HbA1c (ß = -0.240, P = 0.035) interacted with PLTP gene score to affect PLTP activity. CONCLUSIONS: Type 2 diabetes and enlarged waist circumference interact to impact on plasma PLTP activity. Diabetes may also amplify the association between plasma PLTP activity and common PLTP gene variations. Our findings support the hypothesis that diabetes-environment and diabetes-gene interactions govern plasma PLTP activity.

Apolipoprotein B/A-I and total cholesterol/high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein.

BACKGROUND: the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and apolipoprotein (apo) B/A-I ratios predict major adverse cardiovascular events (MACEs). The extent to which these associations are modified by high-sensitivity C-reactive protein (hs-CRP) and albuminuria is largely unknown. We compared the strength of these ratios with first MACE in the general population and determined whether these associations remain when taking account of these risk markers. SUBJECTS AND METHODS: a prospective case-cohort study was performed among 6948 subjects (PREVEND cohort) without previous cardiovascular disease and who did not use lipid-lowering drugs initially. Fasting serum TC, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, apoB, apoA-I, triglycerides, hs-CRP and albuminuria were measured at baseline. The composite endpoint was incident MACE. RESULTS: a total of 362 first cardiovascular events occurred during 7.9 years of follow-up. All pro- and anti-atherogenic measures of lipoproteins and apos predicted MACEs in age- and sex-adjusted Cox proportional hazard analyses (P = 0.018 to P < 0.001). The age- and sex-adjusted hazard ratio (HR) was 1.37 [95% confidence interval (CI), 1.26-1.48] for the apoB/apoA-I ratio and 1.24 (95% CI, 1.18-1.29) for the TC/HDL-C ratio (both P < 0.001). These relationships were essentially unaltered after additional adjustment for triglyceride levels. Pair-wise comparison revealed that these ratios were of similar importance in age- and sex-adjusted analysis (P = 0.397). The HRs of apoB/apoA-I (P < 0.001) and TC/HDL-C (P < 0.001) for risk of MACEs were only marginally attenuated by additional controlling for traditional risk factors (hypertension, diabetes, obesity and smoking), hs-CRP and albuminuria. CONCLUSIONS: first MACE is associated with both the fasting serum apoB/apoA-I ratio and the TC/HDL-C ratio in the general population, independently of triglycerides, hs-CRP and albuminuria.

Plasma lecithin: cholesterol acyltransferase activity modifies the inverse relationship of C-reactive protein with HDL cholesterol in nondiabetic men.

Lecithin:cholesterol acyltransferase (LCAT) is instrumental in high-density lipoprotein (HDL) maturation, but high LCAT levels do not predict low cardiovascular risk. LCAT may affect antioxidative or anti-inflammatory properties of HDL. We determined the relationship of plasma high-sensitivity C-reactive protein (CRP) with LCAT activity and evaluated whether LCAT activity modifies the decreasing effect of HDL cholesterol (HDL-C) on CRP, as an estimate of its anti-inflammatory properties. Plasma HDL-C, apolipoprotein (apo) A-I and LCAT activity (exogenous substrate method) were measured in 260 nondiabetic men without cardiovascular disease. CRP was correlated inversely with HDL-C and apo A-I, and positively with LCAT activity (P<0.01 to 0.001). Multivariate regression analysis demonstrated that age- and smoking-adjusted plasma CRP levels were associated negatively with HDL-C (beta=-0.224, P<0.001) and positively with LCAT activity (beta=0.119, P=0.034), as well as with the interaction between HDL-C and LCAT activity (beta=0.123, P=0.026). There was also an interaction between apo A-I and LCAT activity on CRP (beta=0.159, P=0.005). These relationships remained similar after adjustment for apo B-containing lipoproteins. In conclusion, the inverse relationship of HDL-C with CRP is attenuated by LCAT activity at higher HDL-C levels. It is hypothesized that LCAT could mitigate HDL's anti-inflammatory or antioxidative properties at higher HDL-C concentrations.