Genotype-by-diet effects on co-variation in Lp-PLA2 activity and LDL-cholesterol concentration in baboons fed an atherogenic diet

Vinson, Amanda; Mahaney, Michael C.; Diego, Vincent P.; Cox, Laura A.; Rogers, Jeffrey; VandeBerg, John L.; Rainwater, David L.

doi:10.1194/jlr.m800020-jlr200

Cited by 12 publications

(10 citation statements)

References 49 publications

(45 reference statements)

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Heritability of Spontaneous Lipid Levels in an Extended Pedigree of Indian-Origin Rhesus Macaques (Macaca mulatta)

et al. 2013

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The rhesus macaque is an important model for human atherosclerosis but genetic determinants of relevant phenotypes have not yet been investigated in this species. Because lipid levels are well-established and heritable risk factors for human atherosclerosis, our goal was to assess the heritability of lipoprotein cholesterol and triglyceride levels in a single, extended pedigree of 1,289 Indian-origin rhesus macaques. Additionally, because increasing evidence supports sex differences in the genetic architecture of lipid levels and lipid metabolism in humans and macaques, we also explored sex-specific heritability for all lipid measures investigated in this study. Using standard methods, we measured lipoprotein cholesterol and triglyceride levels from fasted plasma in a sample of 193 pedigreed rhesus macaques selected for membership in large, paternal half-sib cohorts, and maintained on a low-fat, low cholesterol chow diet. Employing a variance components approach, we found moderate heritability for total cholesterol (h2=0.257, P=0.032), LDL cholesterol (h2=0.252, P=0.030), and triglyceride levels (h2=0.197, P=0.034) in the full sample. However, stratification by sex (N=68 males, N=125 females) revealed substantial sex-specific heritability for total cholesterol (0.644, P=0.004, females only), HDL cholesterol (0.843, P=0.0008, females only), VLDL cholesterol (0.482, P=0.018, males only), and triglyceride levels (0.705, P=0.001, males only) that was obscured or absent when sexes were combined in the full sample. We conclude that genes contribute to spontaneous variation in circulating lipid levels in the Indian-origin rhesus macaque in a sex-specific manner, and that the rhesus macaque is likely to be a valuable model for sex-specific genetic effects on lipid risk factors for human atherosclerosis. These findings are a first-ever report of heritability for cholesterol levels in this species, and support the need for expanded analysis of these traits in this population.

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Section: Introductionmentioning

confidence: 99%

Sex-Specific Heritability of Spontaneous Lipid Levels in an Extended Pedigree of Indian-Origin Rhesus Macaques (Macaca mulatta)

et al. 2013

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“…While we cannot exclude the possibility that Type 1 and Type 2 errors were responsible for apparent diet differences, a likely interpretation is genotype-by-diet interaction, wherein the effects of different genes predominate depending on dietary environment. In fact, some of our previous baboon studies have reported evidence of diet-by-genotype interaction for HDL-and LDL-related traits (13,(24)(25)(26). However, additional explorations of novel diet-by-genotype interactions developed in this study await future analyses.…”

Section: Discussionmentioning

confidence: 95%

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

Rainwater

Cox

Rogers

et al. 2009

Journal of Lipid Research

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We employed a novel approach to identify the key loci that harbor genes influencing lipoprotein metabolism in approximately 2,000 pedigreed baboons fed various diets differing in levels of fat and cholesterol. In this study, 126 overlapping traits related to both LDL and HDL metabolism were normalized and subjected to genome-wide linkage screening. As was expected, the traits were highly, but not completely, correlated. We exploited the information in these correlated traits by focusing on those genomic regions harboring quantitative trait loci (QTL) for multiple traits, reasoning that the more influential genes would impact a larger number of traits. This study identified five major QTL clusters (each with at least two significant logarithm of the odds scores .4.7), two of which had not been previously reported in baboons. One of these mapped to the baboon ortholog of human chromosome 1p32-p34 and influenced concentrations of LDL-cholesterol on Basal and high-fat, low-cholesterol diets. The other novel QTL cluster mapped to the baboon ortholog of human chromosome 12q13.13-q14.1 and influenced LDL size properties on highfat, low-cholesterol and high-fat, high-cholesterol, but not Basal, diets. Confirming the value of this approach, three of the QTL clusters replicated published linkage findings for the same or similar traits.-Rainwater, D. L., L. A. Cox, J. Rogers, J. L. VandeBerg, and M. C. Mahaney. Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons.

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“…To assess diet effects on genetic control of lipoprotein metabolism, we first investigated effects on individual traits measured on two diets. Not surprisingly [7,10,18,33], traits were very strongly correlated across diets; ρ G ranged from 0.97 to 1.00 for traits measured on basal and HFLC diets (differing in level of fat) and from 0.84 to 0.98 for traits measured on HFLC and HFHC diets (differing in level of cholesterol). Highly significant genetic correlations notwithstanding, we found evidence of diet-genotype interaction for HDLC with changing levels of fat and for all but Hmed with changing levels of cholesterol, suggesting the metabolic pathways responsible for variation in each of these traits are governed both by common and, to some extent, unique sets of genes in the contrasting dietary environments.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a locus on chromosome 1 exerted significant effects on LDLC levels on the two low cholesterol diets, but not the HFHC diet (the primary QTL in this case was located on chromosome 19; see http://baboon.sfbrgenetics.org/Bab_SupplementalData/Rainwater2009.php). Furthermore, we localized a pleiotropic QTL for LDLC and Lp-PLA 2 (i.e., lipoprotein-associated phospholipase A 2 ) to the baboon orthologue of human chromosome 2p when animals were fed basal diet, but to chromosome 19 when fed HFHC diet [33,37]. Teasing out a gene whose expression is responsive to dietary environment may provide useful insights into lipoprotein metabolism and potential methods to modify CVD risk associated with dyslipidemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of diet on genetic regulation of lipoprotein metabolism in baboons

2010

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Several measures of lipoprotein phenotype are significant predictors of cardiovascular risk. Although such lipoprotein phenotypes are under strong genetic control, it is not clear to what extent they are controlled by the same - and by different - genes and whether these relationships may be altered in different dietary environments. Therefore, we measured six lipoprotein traits (three LDL traits - LDLC and apoB concentrations and LDL size - and three HDL traits - HDLC and apoA1 concentrations and HDL size) on each of three diets differing in level of fat and cholesterol. In bivariate analyses, all but two metabolically related trait pairs were genetically correlated, though none were completely correlated, implying additive genetic effects by both pleiotropic and unique genes. In comparing genetic correlations for the same pair of traits across diet, we detected evidence of diet effects on genetic control of these metabolically related traits; specifically, increasing level of dietary cholesterol was associated with a significant decrease in the genetic correlation of apoA1 with HDL size, and a significant increase in the genetic correlations of LDL size with LDLC and apoB. The results suggest a complex network of genes affecting lipoprotein metabolism: the genes may exert both unique and pleiotropic effects; the genes may exert detectable effects in many or only in specific dietary environments.

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Genotype-by-diet effects on co-variation in Lp-PLA2 activity and LDL-cholesterol concentration in baboons fed an atherogenic diet

Cited by 12 publications

References 49 publications

Sex-Specific Heritability of Spontaneous Lipid Levels in an Extended Pedigree of Indian-Origin Rhesus Macaques (Macaca mulatta)

Sex-Specific Heritability of Spontaneous Lipid Levels in an Extended Pedigree of Indian-Origin Rhesus Macaques (Macaca mulatta)

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

Effects of diet on genetic regulation of lipoprotein metabolism in baboons

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