Lp-PLA2, scavenger receptor class B type I gene (SCARB1) rs10846744 variant, and cardiovascular disease

作者：Ani Manichaikul, Xin-Qun Wang, Li Li, Jeanette Erdmann, Guillaume Lettre, Joshua C. Bis, Dawn Waterworth, Mary Cushman, Nancy S. Jenny, Wendy S. Post, Walter Palmas, Michael Y. Tsai, Lars Wallentin, Harvey D. White, Heribert Schunkert, Christopher J. O’Donnell, David M. Herrington, Stephen S. Rich, Michelle L. O’Donoghue, Annabelle Rodríguez · 发表于：PLoS ONE · 年份：2018 · DOI：10.1371/journal.pone.0204352 · 被引用次数：8 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Protein Kinase Regulation and GTPase Signaling、Peroxisome Proliferator-Activated Receptors

BACKGROUND: We previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis. METHODS: We first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies. RESULTS: SCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), do...