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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-PLA 2  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-PLA 2  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-PLA 2  activity, cardiovascular outcomes, and interaction with the Lp-PLA 2  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-PLA 2  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-PLA 2  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-PLA 2  inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52.    Summary   SCARB1  rs10846744 is significantly associated with Lp-PLA 2  activity, atherosclerosis, and CVD events, but Lp-PLA 2  activity is not a mediator in the association of rs10846744 with cIMT in MESA.

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