Group IIA Secretory Phospholipase A 2 , Vascular Inflammation, and Incident Cardiovascular Disease

Abstract

Objective— Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA 2 -IIA (group IIA secretory phospholipase A 2 ) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA 2 -IIA in secondary prevention, we prospectively evaluated sPLA 2 -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 sPLA 2 -IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA 2 -IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA 2 -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 sPLA 2 -IIA) had the strongest effect on sPLA 2 -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, sPLA 2 -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 sPLA 2 -IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.