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.

• Authors: Akintunde O Akinkuolie, Patrick R Lawler, Audrey Y Chu, Michael Caulfield, Jianying Mu, Bo Ding, Fredrik Nyberg, Robert J Glynn, Paul M Ridker, Eva Hurt-Camejo, Daniel I Chasman, Samia Mora
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 39 Issue 6 Pg. 1182-1190 (06 2019) ISSN: 1524-4636 [Electronic] United States
• PMID: 31070471 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Rosuvastatin Calcium
• Group II Phospholipases A2
• PLA2G2A protein, human

Topics

• Aged
• Anti-Inflammatory Agents (therapeutic use)
• Cardiovascular Diseases (enzymology, epidemiology, genetics, prevention & control)
• Double-Blind Method
• Dyslipidemias (drug therapy, enzymology, epidemiology, genetics)
• Female
• Genetic Predisposition to Disease
• Group II Phospholipases A2 (blood, genetics)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Incidence
• Inflammation (drug therapy, enzymology, epidemiology, genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Primary Prevention
• Prospective Studies
• Risk Assessment
• Risk Factors
• Rosuvastatin Calcium (therapeutic use)
• Time Factors
• Treatment Outcome