Group IIA Secretory Phospholipase A2, Vascular Inflammation, and Incident Cardiovascular Disease

Abstract

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

Keywords: cardiovascular disease; inflammation; primary prevention; risk factor; secondary prevention.

Conflict of interest statement

Disclosures: Dr. Caulfield is an employee of Quest Diagnostics. Dr. Chu is employed by Merck Research Laboratories. Drs. Hurt-Camejo, Ding, and Nyberg are employees of AstraZeneca. Dr. Nyberg holds shares in AstraZeneca. Dr Ridker has received research grant support from AstraZeneca, Novartis, Amgen, Kowa, and the National Heart, Lung, and Blood Institute and has served as a consultant to Genzyme, Janssen, Aegerion, ISIS, Vascular Biogenics, Boehringer, Pfizer, and Merck. Dr Ridker is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in CVD that have been licensed to AstraZeneca and Siemens. Dr Mora has received institutional research support from AstraZeneca, Atherotech Diagnostics, and NIH; served as a consultant to Genzyme, Quest Diagnostics, Pfizer, and Cerenis Therapeutics; and received speaker honoraria from AstraZeneca, and the National Lipid Association for educational (nonpromotional) activities. The other authors report no conflicts.

Figures

Figure 1.

Baseline to 1-year median percent change in sPLA2-IIA according to randomized treatment. Values obtained from individuals with both baseline and 1 year measurements (n=9 620). hsCRP indicates high-sensitivity C-reactive protein.*P values from the Wilcoxon signed rank test comparing baseline and year 1 values were statistically significant (P <0.0001) ¶P values from the Wilcoxon rank sum test comparing the change among the rosuvastatin group with the change among the placebo group were <0.0001.

Figure 2.

Fully adjusted Hazard ratios (95% CI) for the primary event according to sPLA2-IIA levels and treatment assignment, relative to subjects on placebo with the lowest quartile of baseline sPLA2-IIA levels.

Figure 3.

Efficacy of rosuvastatin for the primary event, stratified by baseline sPLA2-IIA mass.