Abstract
Both lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes. We previously reported a quantitative trait locus (QTL) corresponding to HSA2p24.3-p23.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-cholesterol (LDL-C) concentration in baboons fed a basal diet. Here, our goal was to locate pleiotropic QTLs influencing both traits in the same baboons fed a high-cholesterol, high-fat (HCHF) diet, and to assess whether shared genetic effects on these traits differ between diets. We assayed Lp-PLA(2) activity and LDL-C concentration in 683 baboons fed the HCHF diet. We used a bivariate maximum likelihood-based variance components approach in whole-genome linkage screens to locate a QTL [logarithm of odds (LOD) = 3.13, genome-wide P = 0.019] corresponding to HSA19q12-q13.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-C levels in the HCHF diet. We additionally found significant evidence of genetic variance in response to diet for Lp-PLA(2) activity (P = 0.0017) and for LDL-C concentration (P = 0.00001), revealing a contribution of genotype-by-diet interaction to covariation in these two traits. We conclude that the pleiotropic QTLs detected at 2p24.3-p23.2 and 19q12-q13.2 on the basal and HCHF diets, respectively, exert diet-specific effects on covariation in Lp-PLA(2) activity and LDL-C concentration.
Highlights
Both lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes
All summary statistics for Lp-PLA2 activity and LDL-C concentration increased from the basal to the HCHF diet
The simultaneous increases observed in Lp-PLA2 activity and LDL-C concentration in baboons fed an HCHF diet is consistent with reports by others of associations between both traits [3, 4, 7], and with what is known of the functional biological relationship between Lp-PLA2 and the LDL particle
Summary
Both lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes. This study was made possible by research grants from the National Institutes of Health (P01 HL-028972, R01 HL-068922, R01 RR-008781); a base grant from the National Center of Research Resources (NCRR) to the Southwest National Primate Research Center (SNPRC; P51 RR-013986); and was conducted in facilities constructed with support from NCRR Research Facilities Improvement Program Grants (C06 RR-014578, C06 RR-13556, C06 RR-15456, C06 RR-017515) Both lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, a biomarker of inflammation, and LDL-cholesterol (LDL-C) concentration are associated with early onset atherosclerosis, endothelial dysfunction, and future cardiac events [1, 2]. We recently reported a genetic correlation between Lp-PLA2 activity and LDL-C concentration in baboons fed a basal diet, and presented evidence for a quantitative trait locus (QTL) on chromosome 2p that influences covariation in these traits [9]. This article is available online at http://www.jlr.org
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