A pleiotropic QTL on 2p influences serum Lp-PLA2 activity and LDL cholesterol concentration in a baboon model for the genetics of atherosclerosis risk factors

Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245, United States.
Atherosclerosis (Impact Factor: 3.99). 03/2008; 196(2):667-73. DOI: 10.1016/j.atherosclerosis.2007.07.014
Source: PubMed


Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), the major portion of which is bound to low-density lipoprotein, is an independent biomarker of cardiovascular disease risk. To search for common genetic determinants of variation in both Lp-PLA(2) activity and LDL cholesterol (LDL-C) concentration, we assayed these substances in serum from 679 pedigreed baboons. Using a maximum likelihood-based variance components approach, we detected significant evidence for a QTL affecting Lp-PLA(2) activity (LOD=2.79, genome-wide P=0.039) and suggestive evidence for a QTL affecting LDL-C levels (LOD=2.16) at the same location on the baboon ortholog of human chromosome 2p. Because we also found a significant genetic correlation between the two traits (rho(G)=0.50, P<0.00001), we conducted bivariate linkage analyses of Lp-PLA(2) activity and LDL-C concentration. These bivariate analyses improved the evidence (LOD=3.19, genome-wide P=0.015) for a QTL at the same location on 2p, corresponding to the human cytogenetic region 2p24.3-p23.2. The QTL-specific correlation between the traits (rho(Q)=0.62) was significantly different from both zero and 1 (P[rho(Q)=0]=0.047; P[rho(Q)=1]=0.022), rejecting the hypothesis of co-incident linkage and consistent with incomplete pleiotropy at this locus. We conclude that polymorphisms at the QTL described in this study exert some genetic effects that are shared between Lp-PLA(2) activity and LDL-C concentration.

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    • "Here, we describe an important first step toward identifying genetic determinants of atherosclerosis in the rhesus macaque by characterizing the contribution of genes (i.e., heritability) to spontaneous variation in circulating lipids. We elected to study lipid levels first because lipids are well-established risk factors for human atherosclerosis, and because heritability for lipid levels has been demonstrated previously in both humans and in other NHP species [15,16]. Additionally, because significant gender differences in the genetic architecture of lipid levels and lipid metabolism have been demonstrated recently in humans [17-19], and implicated in rhesus macaques [20], we also wanted to investigate potential differences in heritability between male and female macaques for all lipids measured in this study. "
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