Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

Rainwater, David L.; Cox, Laura A.; Rogers, Jeffrey; VandeBerg, John L.; Mahaney, Michael C.

doi:10.1194/jlr.m800583-jlr200

Cited by 38 publications

(17 citation statements)

References 49 publications

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“…As was expected [7], each of the six traits was strongly heritable, with genes explaining approximately half the total phenotypic variance in this study. This approximate level of heritability held for each of three diets – differing in levels of fat and cholesterol – that were tested in this study.…”

Section: Discussionsupporting

confidence: 86%

“…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%

“…A number of years ago, our group initiated studies of diet-genotype interactions using a dietary paradigm that employed a standardized shift in level of dietary fat and cholesterol [6,7]. The ultimate goal of this research has been to improve our understanding of the complex network of factors, particularly genetic, that influence the traits and their responses to specific dietary changes.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of diet on genetic regulation of lipoprotein metabolism in baboons

2010

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“…With this approach, we confi rmed known candidate genes. For instance, the HDL QTL on chromosome 18 has been identifi ed in multiple mouse crosses ( 26 ); in addition, it is located in orthologous regions in baboons and humans ( 33,34 ). A difference in expression in Lipg explained the chromosome 18 HDL QTL in at least three mouse crosses (B6×D2, NZB×SM, B6×C3H) ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ × SM/J intercross

Leduc

Blair

Verdugo

et al. 2012

Journal of Lipid Research

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A higher incidence of coronary artery disease (CAD) is associated with a lower level of HDL-cholesterol ( 1, 2 ), which is determined by multiple environmental and genetic factors. In the past few years, new therapeutic approaches have focused on fi nding ways to increase HDL ( 3, 4 ). To date, however, only a few environmental interventions, such as diet and exercise, have been successful in raising HDL level ( 5 ), whereas drug therapy development is still ongoing and has targeted only a limited number of proteins such as CETP ( 3, 4 ). In the search for a potential drug target to raise HDL and decrease CAD, the identifi cation of new genes involved in HDL determination is essential.The genetic basis of HDL-cholesterol variation has been widely studied in various animal models. In humans, recent genome-wide association studies (GWAS) have identifi ed known HDL genes such as LIPG and CETP in addition to new genes such as GALNT2 ( 6 ). These known genes, however, explain only a small proportion of the total variation, indicating that additional genes are yet to be discovered. Mouse models are a powerful strategy for identifying such genes. A large overlap exists among species for quantitative trait loci (QTL) and genes involved in lipid metabolism ( 7 ). Many study methodologies are similar between human and mouse, but mouse studies offer advantages by capitalizing on genomics tools that are not available and practical for studies of human populations. To date, our laboratory and those of others have identifi ed over 35 mouse HDL QTL (as reviewed in Wang et al., Refs. 7,8 ). In addition, we and others have developed bioinformatics tools to narrow the QTL interval to just a few candidate genes ( 9, 10 ). Application of these tools has led to the discovery of single genes underlying QTL for HDL and

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“…This fi gure has been modifi ed from Ref. 13 . Approximately 20-30 mg of frozen liver was cut on an aluminum plate on dry ice and homogenized in 1ml Trizol Reagent using a PowerGen 125 Homogenizer (Thermal Scientifi c, Pittsburgh, PA).…”

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confidence: 99%