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

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...

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Vydáno v:	PloS one Ročník 13; číslo 10; s. e0204352
Hlavní autoři:	Manichaikul, Ani, Wang, Xin-Qun, Li, Li, Erdmann, Jeanette, Lettre, Guillaume, Bis, Joshua C., Waterworth, Dawn, Cushman, Mary, Jenny, Nancy S., Post, Wendy S., Palmas, Walter, Tsai, Michael Y., Wallentin, Lars, White, Harvey, Schunkert, Heribert, O’Donnell, Christopher J., Herrington, David M., Rich, Stephen S., O’Donoghue, Michelle L., Rodriguez, Annabelle
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 05.10.2018 Public Library of Science (PLoS)
Témata:	1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism Aged Arteriosclerosis Atherosclerosis Biology and Life Sciences Biomarkers - metabolism Cardiology Cardiovascular disease Cardiovascular diseases Cardiovascular Diseases - ethnology Cardiovascular Diseases - genetics Cardiovascular Diseases - metabolism Consortia Coronary artery Coronary artery disease Docosahexaenoic acid Eicosapentaenoic acid Fatty acids Female Genetic Predisposition to Disease Genome-Wide Association Study Genomes Genomics Health sciences Heart Heart attacks Heart diseases Homocysteine Humans Infarction Inflammation Inhibitors Laboratories Lipoproteins Lipoproteins (low density) Low density lipoprotein Male Medicine Medicine and Health Sciences Middle Aged Minority & ethnic groups Myocardial infarction Pathology People and places Phospholipase A2 Phospholipids Physical Sciences Polymorphism, Single Nucleotide Public health Research and Analysis Methods Risk analysis Risk Factors Scavenger receptors Scavenger Receptors, Class B - genetics Single-nucleotide polymorphism Stability Stabilization Studies Thrombolysis Canada Montreal Quebec Canada United States > US Germany Quebec Canada
ISSN:	1932-6203, 1932-6203
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Popis
Shrnutí:	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. 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. 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), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52. SCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 Competing Interests: LL is employed by PAREXEL International. DW is employed by GlaxoSmithKline. MC reports institutional grant support from Diadexus. LW reports institutional research grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Merck, Pfizer and Roche Diagnostics. HW reports grant support from GlaxoSmithKline, Sanofi Aventis, Eli Lilly and Company, National Institute of Health, AstraZeneca, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc., DalGen, and grants and consultancy fees from AstraZeneca outside the submitted work. MLO reports grant support from GlaxoSmithKline, Eisai, Janssen, Merck, and AstraZeneca. AR retains inventorship rights to the SCARB1 rs10846744 molecular diagnostic issued patent and she is the founder of Lipid Genomics. Our competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0204352