ObjectivesThis study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.BackgroundHigher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.MethodsWe conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.ResultsPLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.ConclusionsReducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

APOA5 is probably the gene with the strongest effect on triglyceride (TG) metabolism. APOA5 is almost exclusively expressed in the liver, and its product apoAV has a very low circulating concentration. New physiological roles of apoAV have been recently elucidated, such as control of chylomicron production in the intestine and TG accumulation in adipose tissue. The key role of APOA5 in TG metabolism has been largely shown through genetic studies in association with either severe or moderate hypertriglyceridemia. Studies suggest that APOA5 variants affect not only total TG concentrations but also the entire lipoprotein subclass distribution, shifting them toward atherogenic dyslipidemia in high-risk subjects. Environmental interactions and epigenetic factors are also crucial in regulating these processes. Delineation of the mechanisms involved in the transcriptional control of the gene, combined with determination of biological significance of the SNPs in the APOA5 locus, would help to fully understand the effect of APOA5 on TGs. In summary, APOA5 variants cause hypertriglyceridemia. In high cardiovascular risk patients (e.g., patients with metabolic syndrome or type 2 diabetes), APOA5 variants elevate TG levels and shift the entire lipoprotein subclass distribution toward atherogenic dyslipidemia. At a physiological level, apoAV seems to encompass more roles than those initially suggested after its discovery.

No abstract

No abstract

No abstract

No abstract

No abstract

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene regulates cholesterol homoeostasis by accelerating low-density lipoprotein receptor (LDLR) degradation resulting in the decreased catabolism of low-density lipoprotein (LDL) leading to hypercholesterolaemia. PCSK9 has also been related to other metabolic risk factors such as triglycerides (TGs) and glucose levels and body mass index (BMI). Therefore, our aim was to study the relationship between the PCSK9 and the lipid and lipoprotein profile. We studied 267 diabetic and metabolic syndrome patients who were not receiving any lipid-lowering therapy. We measured circulating lipids, cholesterol in remnant lipoproteins (RLPc) and PCSK9 levels. A detailed lipoprotein profile was determined based on NMR. Plasma PCSK9 levels were significantly and positively correlated with TG (r=0.136, P=0.033), total cholesterol (r=0.219, P<0.001) and apoB (apolipoprotein B; r=0.226, P=0.006) circulating levels and with an atherogenic profile of lipoprotein subclasses. In further detail, circulating PCSK9 levels were positively correlated with large very-low density lipoprotein (VLDL) particles, (r=0.210, P=0.001) and with their remnants, the intermediate-density lipoprotein (IDL) particles (r=0.206, P=0.001); positively correlated with smaller LDL particles (for small LDL: r=0.224, P<0.001; for medium small LDL: r=0.235, P<0.001; and for very small LDL: r=0.220, P<0.001); and with high-density lipoprotein (HDL) particles (r=0.146, P<0.001), which is mainly explained by the PCSK9 correlation with the smallest HDL particles (r=0.130, P=0.037). In addition, circulating PCSK9 levels were positively correlated with the pro-atherogenic circulating RLPc levels (r=0.171, P=0.006). All of the correlations were adjusted by age, gender and BMI. PCSK9 levels are significantly and positively correlated with atherogenic lipoproteins such as large VLDL, IDL, the smallest LDL, the smallest HDL particles and RLPc levels.