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Arterioscler Thromb Vasc Biol. 2019 Jun;39(6):1182-1190. doi: 10.1161/ATVBAHA.118.311894.

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

Author information

1
From the Center for Lipid Metabolomics, Division of Preventive Medicine (A.O.A., P.R.L., R.J.G., P.M.R., D.I.C., S.M.), Department of Medicine, Brigham and Women's Hospital, Boston, MA.
2
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.O.A.).
3
Peter Munk Cardiac Centre, Toronto General Hospital, ON, Canada (P.R.L.).
4
Heart and Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, ON, Canada (P.R.L.).
5
Merck Research Laboratories, Boston, MA (A.Y.C.).
6
Department of Endocrinology & CVD, Quest Diagnostics Nichols Institute, San Juan Capistrano, CA (M.C., J.M.).
7
Medical Evidence & Observational Research, Global Medical Affairs (B.D., F.N.), AstraZeneca R&D, Mölndal, Sweden.
8
Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden (F.N.).
9
Department of Biostatistics, Harvard School of Public Health, Boston, MA (R.J.G.).
10
Cardiovascular Medicine (P.M.R., S.M.), Department of Medicine, Brigham and Women's Hospital, Boston, MA.
11
Cardiovascular & Metabolic Diseases, Innovative Medicines (E.H.-C.), AstraZeneca R&D, Mölndal, Sweden.
12
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden (E.H.-C.).

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

PMID:
31070471
PMCID:
PMC6534275
[Available on 2020-06-01]
DOI:
10.1161/ATVBAHA.118.311894

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