Effects of selection for serum cholesterol concentrations on serum lipid concentrations and body weight in baboons

Kammerer, Candace M.; Mott, Glen E.; Carey, K. Dee; McGill, Henry C.

doi:10.1002/ajmg.1320190216

Cited by 22 publications

(11 citation statements)

References 24 publications

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“…Although we cannot rule out this possibility, we have not observed, in density gradient analyses, 13,17,21 apo(a) proteins in density fractions more buoyant than Lp(a). Furthermore, baboons tend to have relatively low plasma triglyceride concentrations (Ϸ52 mg/dL on the basal diet and Ϸ37 mg/dL on the HFHC diet 35 and, consequently, low levels of TRLs.…”

Section: Discussionmentioning

confidence: 99%

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

Rainwater

Kammerer

VandeBerg

1999

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Abstract-We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fat and cholesterol in 633 baboons fed a series of 3 diets: a basal diet low in cholesterol and fat, a high-fat diet, and a diet high in fat and cholesterol. Measurement of serum concentrations in samples taken while the baboons were sequentially fed the 3 diets allowed us to analyze 3 Lp(a) variables: Lp(a) Basal , Lp(a) RF (response to increased dietary fat), and Lp(a) RC (response to increased dietary cholesterol in the high-fat environment). On average, Lp(a) concentrations significantly increased 6% and 28%, respectively, when dietary fat and cholesterol were increased (PϽ0.001). As expected, most of the variation in Lp(a) Basal was influenced by genes (h 2 ϭ0.881). However, less than half of the variation in Lp(a) RC was influenced by genes (h 2 ϭ0.347, PϽ0.0001), whereas the increase due to dietary fat alone was not significantly heritable (h 2 ϭ0.043, Pϭ0.28). To determine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkage analyses by using LPA genotypes inferred from the apo(a) isoform phenotypes. All of the genetic variance in Lp(a) Basal concentration was linked to the LPA locus (log of the odds [LOD] score was 30.5). In contrast, linkage analyses revealed that genetic variance in Lp(a) RC was not linked to the LPA locus (LOD score was 0.036, PϾ0.5). To begin identifying the non-LPA genes that influence the Lp(a) response to dietary cholesterol, we tested, in bivariate quantitative genetic analyses, for correlation with low density lipoprotein cholesterol [LDLC; ie, non-high density lipoprotein cholesterol less the cholesterol contribution from Lp(a)]. LDLC Basal was weakly correlated with Lp(a) Basal ( P ϭ0.018). However, LDLC RC and Lp(a) RC were strongly correlated ( P ϭ0.382), and partitioning the correlations revealed significant genetic and environmental correlations ( G ϭ0.587 and E ϭ0.251, respectively). The results suggest that increasing both dietary fat and dietary cholesterol caused significant increases in Lp(a) concentrations and that the response to dietary cholesterol was mediated by a gene or suite of genes that appears to exert pleiotropic effects on LDLC levels as well. The gene(s) influencing Lp(a) response to dietary cholesterol is not linked to the LPA locus.

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Section: Discussionmentioning

confidence: 99%

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

Rainwater

Kammerer

VandeBerg

1999

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“…Both the basal and challenge levels of LDL and HDL were highly heritable. 4 Subsequent studies focused on detecting and identifying the responsible genes by molecular [5][6][7][8] and statistical 9 -11 genetic strategies. A previous study suggested that the response to dietary cholesterol and to dietary saturated fat might be controlled by separate genes in baboons.…”

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confidence: 99%

Two Major Loci Control Variation in β-Lipoprotein Cholesterol and Response to Dietary Fat and Cholesterol in Baboons

Rainwater

Kammerer

Hixson

et al. 1998

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Abstract-We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in ␤-lipoproteins (low density lipoprotein cholesterol [LDLC]) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels (LDLC Base ), we analyzed two variables for diet response: LDLC RF , which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLC RC , which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities (h 2 ) of the 3 traits were 0.59 for LDLC Base , 0.14 for LDLC RF , and 0.59 for LDLC RC . In addition, LDLC Base and LDLC RC had a significant genetic correlation (ie, G ϭ0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLC RC and some genetic variation in LDLC Base and LDLC RF and confirmed the presence of a different major locus that influences LDLC Base alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations. (Arterioscler Thromb Vasc Biol. 1998;18:1061-1068.)

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“…The HDL-C levels of the juvenile baboons, offspring of selectively bred high-and low-responding parents, were observed to diverge from birth through 2 years of age while they were fed identical diets. 30,31 Although affecting HDL-C levels in these baboons, neither an unidentified major locus nor the LCAT structural locus exerted an effect on lipemic response 32,33 ; however, another major locus for apoA1 was found to account for 33% of the variance in apoA1 response to diet. 34 Studies in humans and nonhuman animals alike strongly support the notion that genes influence lipemic response of HDL-C or its subfractions.…”

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confidence: 79%

Pleiotropy and Genotype by Diet Interaction in a Baboon Model for Atherosclerosis

Mahaney¹,

Blangero²,

Rainwater³

et al. 1999

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Abstract-We investigated dietary effects on pleiotropic relationships among 3 HDL cholesterol (C) subfractions(HDL 1 -C, HDL 2 -C, and HDL 3 -C; levels quantified by gradient gel electrophoresis) for 942 pedigreed baboons (Papio hamadryas) who were fed a basal (Chow) diet and a high cholesterol, saturated fat (HCSF) challenge diet. Using multivariate maximum likelihood methods we estimated heritabilities for all 6 traits, genetic and environmental correlations ( G and E ) between them, and the additive genetic variance of each subfraction's response to the diets. On the Chow diet, genetic correlations between the 3 subfractions were significant, and we observed complete pleiotropy between HDL 1 -C and HDL 3 -C ( G ϭϪ0.81). On the HCSF diet, only the genetic correlation between HDL 1 -C and HDL 3 -C ( G ϭϪ0.61) was significant. Genetic correlations between individual subfractions on the Chow and HCSF diets did not differ significantly from 1.0, indicating that the same additive genes influenced each subfraction's levels regardless of diet. However, the additive genetic variance of response to the diets was highly significant for HDL 1 -C and HDL 2 -C, but not for HDL 3 -C. Similar sets of genes influence variation in the 3 HDL subfractions on the Chow diet, and the same set influences variation in each subfraction on the HCSF diet. However, the expression of genes influencing HDL 1 -C and HDL 2 -C is altered by the HCSF diet, disrupting the pleiotropy observed between the 3 subfractions on the Chow diet.

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Effects of selection for serum cholesterol concentrations on serum lipid concentrations and body weight in baboons

Cited by 22 publications

References 24 publications

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

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

Two Major Loci Control Variation in β-Lipoprotein Cholesterol and Response to Dietary Fat and Cholesterol in Baboons

Pleiotropy and Genotype by Diet Interaction in a Baboon Model for Atherosclerosis

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