Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Rainwater, David L.; Kammerer, Candace M.; VandeBerg, John L.

doi:10.1161/01.atv.19.11.2696

Cited by 16 publications

(10 citation statements)

References 40 publications

(29 reference statements)

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“…LPA is the structural locus on chromosome 6 for the Lp(a)-specific protein apo(a). Previous studies in baboons (7,27,28) and humans (29) have demonstrated genetic variation at this locus accounts for the majority of variation in Lp(a) levels. In this study, the locus also appears to influence lipoprotein particles in V2-C size range (30-33 nm), which is the size range that would contain baboon Lp(a) particles.…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 94%

“…Concentrations of apolipoprotein AI (apoA1), apoB, and apoE were determined using an immunoturbidometric approach with commercial reagents in a clinical chemistry analyzer (5,6). Lp(a) concentrations were measured using a sandwichstyle ELISA (7).…”

Section: Measurement Of Lipid and Lipoprotein Traitsmentioning

confidence: 99%

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

Rainwater

Cox

Rogers

et al. 2009

Journal of Lipid Research

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“…It has been shown already in studies with non-human primates that the serum lipoprotein response to dietary manipulation has an important genetic component (Mahaney et al 1999;Rainwater et al 1999Rainwater et al , 2002aBaroukh et al 2001). Such genetic variability could have a marked impact on the success of public health policies and those of the National Cholesterol Education Program Adult Treatment Panel III (2002).…”

Section: Plasma Lipids: the First Of Many Risk Factorsmentioning

confidence: 99%

The quest for cardiovascular health in the genomic era: nutrigenetics and plasma lipoproteins

Ordovas

2004

Proc. Nutr. Soc.

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Nutrigenetics and nutrigenomics are promising multidisciplinary fields that focus on studying the interactions between nutritional factors, genetic factors and health outcomes. Their goal is to achieve more efficient individual dietary intervention strategies aimed at preventing disease, improving quality of life and achieving healthy aging. Our studies, and those of many other investigators, using population-based and intervention studies have found evidence for interactions between dietary factors, genetic variants and biochemical markers of CVD. Now, the characterization of individuals who may respond better to one type of dietary recommendation than another can be begun. Thus, a low-fat low-cholesterol strategy may be particularly efficacious in lowering the plasma cholesterol levels of those subjects carrying the apoE4 allele at the APOE gene. HDL-cholesterol (HDL-C) levels are also modulated by dietary, behavioural and genetic factors. It has been reported that the effect of PUFA intake on HDL-C concentrations is modulated by an APOA1 genetic polymorphism. Thus, subjects carrying the A allele at the -75 G/A polymorphism show an increase in HDL-C with increased intakes of PUFA, whereas those homozygotes for the more common G allele have the expected lowering of HDL-C levels with increased intake of PUFA. Variability at the hepatic lipase gene is also associated with interactions between intake of fat and HDL-C concentrations that could shed some light on the different abilities of certain ethnic groups to adapt to new nutritional environments. This knowledge should lead to successful dietary recommendations partly based on genetic factors that may help to reduce cardiovascular risk more efficiently than the current universal recommendations.

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“…15 Briefly, serum samples were treated with SDS under reducing conditions, and apo(a) isoform phenotypes were resolved by electrophoresis in acrylamide gradient gels and detected by using a system 16 that identifies 12 isoform sizes in baboons.…”

Section: Genotypesmentioning

confidence: 99%

“…Significance of the residual heritability and the covariate effects were assessed by comparing the likelihood of a submodel, in which the specific parameter to be tested was fixed at zero, with that of a model in which all parameters were estimated, with the use of the likelihood ratio test, as described in detail elsewhere. 15 This statistic is asymptotically distributed as a 2 with 1 df.…”

Section: Statistical Analysesmentioning

confidence: 99%

Locus Controlling LDL Cholesterol Response to Dietary Cholesterol Is on Baboon Homologue of Human Chromosome 6

Kammerer

Rainwater

Cox

et al. 2002

ATVB

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Objective-Cholesterolemic responses to dietary lipids are known to be heritable, but the genes that may affect thisresponse have yet to be identified. Using segregation analysis, we previously detected a potential quantitative trait locus (QTL) in baboons that influenced low density lipoprotein cholesterol response to dietary cholesterol. We performed linkage analyses to locate this QTL by using data on the baboon genetic linkage map. A n increased plasma level of LDL cholesterol (LDLC) is a well-known risk factor for the development of cardiovascular disease (CVD). Epidemiological studies have also shown that dietary factors increase the risk of CVD; however, there is considerable interindividual variability in cholesterolemic response to dietary lipid, 1 and a proportion of this variation in response is genetic. 2-4 Polymorphisms in some genes involved in lipid metabolism have been associated with cholesterolemic response to dietary change in humans, although these effects generally are small. 5 One of the current challenges in cardiovascular research is to identify genes that interact with environmental factors, such as diet, to affect the risk of developing CVD.Using segregation analysis on data from a large population of pedigreed baboons, we previously detected a major gene that affects LDLC response to increased dietary cholesterol (LDLC RC ). 6 In this case, LDLC refers to all apoB-containing lipoproteins that are predominantly particles in the LDL size interval in baboons. 7 This major gene (or quantitative trait locus [QTL]) accounted for much of the genetic variation in LDLC RC and also affected some of the variation in LDLC on the basal diet. To locate this potential QTL, we performed linkage analyses based on the recently developed genetic linkage map for baboons. 8 Methods AnimalsData were analyzed on a total of 760 pedigreed baboons (Papio hamadryas) consisting of 10 pedigrees ranging in size from 42 to 107 animals. These 2-and 3-generation pedigrees consisted of 218 founders (33 sires and 185 dams) and their 542 offspring. Serum lipid and lipoprotein, as well as genotypic, data were available on 632 of the pedigreed baboons. These families provided a large number of pairwise relationships for genetic analyses, including 1210 first-degree, 6546 second-degree, 1495 third-degree, and 62 fourth-degree relative pairs with data. The 216 males and 416 females with data had a meanϮSD age of 9.6Ϯ6.9 years (range 2.2 to 22.5 years) and a meanϮSD weight of 16.8Ϯ8.5 kg (range 5.2 to 45.2 kg) at the outset of the experiment.All animals were maintained at the Southwest Foundation for Biomedical Research, a facility certified by the Association for Assessment and Accreditation of Laboratory Animal Care International. The experimental protocol was approved by the Institutional Animal Care and Use Committee. Diet ProtocolAll baboons were subjected to the same 4-step dietary challenge as previously described. 6 Briefly, these steps were as follows: (1)

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Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Cited by 16 publications

References 40 publications

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

The quest for cardiovascular health in the genomic era: nutrigenetics and plasma lipoproteins

Locus Controlling LDL Cholesterol Response to Dietary Cholesterol Is on Baboon Homologue of Human Chromosome 6

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