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Biomedical subjects

J Blangero

Publications and source records attributed to J Blangero.

At least 163 records · Page 9Linked to original sources
PubMed1994

Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

The Lpb5 apolipoprotein B (apoB) allele occurs in pigs with spontaneous hypercholesterolemia. Low-density lipoprotein (LDL) from these pigs binds to the LDL receptor with a lower affinity and is cleared from the circulation more slowly than control pig LDL. However, the severity of hypercholesterolemia in pigs with the mutant apoB allele is highly variable. This study aimed to determine the metabolic basis for the phenotypic heterogeneity among Lpb5 pigs. Lpb5 pigs were divided into two groups: those with plasma cholesterol greater than 180 mg/dL (Lpb5.1) and those with plasma cholesterol less than 180 mg/dL (Lpb5.2). LDL from both Lpb5.1 and Lpb5.2 pigs was catabolized in vivo and in vitro at a similarly reduced rate. The difference in plasma cholesterol between the two phenotypic groups was in part due to a higher buoyant LDL production rate in Lpb5.1 pigs than in Lpb5.2 pigs. The in vivo LDL receptor status was evaluated by measuring the catabolism of LDL chemically modified to abrogate LDL receptor binding. Approximately 50% of LDL clearance in normal and Lpb5.2 pigs was via the LDL receptor; in Lpb5.1 pigs, 100% of LDL clearance was LDL receptor independent. Quantitative pedigree analysis of the segregation of the plasma cholesterol phenotype suggested that two major gene loci (the apoB locus and a second apparently unlinked locus) contribute to the determination of plasma cholesterol levels in this pig population.

Animals↗
PubMed1994

Genetic and environmental correlations among skinfold measures.

A bivariate genetic analysis, utilizing variance decomposition techniques based on maximum likelihood methods, was undertaken to examine the genetic and environmental correlations among eight skinfolds in a large pedigreed sample of Mexican Americans from San Antonio, Texas. The resulting correlation coefficients reveal significant values for both the genetic and environmental components among the traits examined. The genetic correlation coefficients showed the highest values between skinfolds from the same region (i.e., triceps, biceps, and forearm), while the environmental correlation remained fairly constant between all traits. These findings are further supported by a principal component analysis of the phenotypic, genetic, and environmental correlation matrices. This represents the first study to partition the phenotypic correlation between these traits into their genetic and environmental components. An examination of the graphical representations of the eigenvectors of these correlation matrices reveals that the patterns of central versus peripheral fat distribution seen in the phenotypic correlation matrix are largely a function of the genetic correlation structure. All these findings are interpreted as evidence of a global pleiotropic effect in the genetic expression of these traits, with what might be secondary regional pleiotropic effects among specific subsets of the skinfolds. In addition it appears that these pleiotropic effects exist against a background of a relatively constant shared environmental effect. It is concluded that these traits are not independent with respect to either shared genetic or environmental influences.

Adolescent↗
PubMed1993

Genotype by sex interaction in measures of lipids, lipoproteins, and apolipoproteins.

Genotype by sex (GxS) interaction in a quantitative trait indicates that the sexual dimorphism exhibited in that trait is heritable. GxS interaction has implications for the modeling of traits in segregation analyses and for the assessment of disease risk in males and females. Thirteen quantitative measures of lipids, lipoproteins, and apolipoproteins from 203 to 301 individuals in 25 to 27 kindreds were examined for evidence of GxS interaction. These measures included serum concentrations of total cholesterol, triglycerides, LDL-C, HDL-C, apo B, and apo AI, and peak LDL particle diameter, small LDL mass, large LDL mass, IDL mass, VLDL mass, HDL3 mass, and HDL2 mass. GxS interaction was indicated for transformed values of LDL-C and small LDL mass by an additive genetic correlation between males and females significantly less than 1.0, and GxS interaction was indicated for transformed values of HDL3 mass and HDL2 mass by males and females having significantly different additive genetic variances.

Adult↗
PubMed1993

Multivariate genetic analysis of apo AI concentration and HDL subfractions: evidence for major locus pleiotropy.

A major locus influencing apolipoprotein AI (apo AI) serum levels was detected using data from the Donner Laboratory Family Study. This locus accounts for 46% of the phenotypic variability in apo AI levels. Multivariate segregation analysis revealed that this major locus also has significant pleiotropic effects on the relative distribution of high density lipoproteins.

Apolipoprotein A-I↗
PubMed1993

Multivariate quantitative genetic simulations in anthropology with an example from the South Pacific.

Computer simulation is a commonly used tool both in genetic epidemiology and in anthropological genetics. We describe here various methods for simulating multivariate quantitative genetic evolution and apply these methods in an analysis of craniometrics from two Pacific island samples. The results of this application indicate that the two samples (one from the Tolai and one from the Moriori) are significantly different, even when allowing for founder effect, intense selection on founders, and genetic drift. The simulation methods we describe and use are commonly applied in animal breeding studies and are much more efficient and general than the multilocus gene-dropping technique usually used in anthropological genetics simulations.

Animals↗
PubMed1993

Statistical genetic approaches to human adaptability.

The genetic determinants of physiological and developmental responses to environmental stress are poorly understood. This has been primarily due to the difficulty of direct measurement of response and the lack of appropriate statistical genetic methods. Here, I present a unified statistical genetic methodology for human adaptability studies that permits evaluation of the inheritance of quantitative trait response to environmental stressors. The foundation of this approach is the mathematical relationship between genotype-environment interaction and the genetic variance of response to environmental challenge. I describe two basic methods that can be used for either discrete or continuous environments. Each method allows for major loci, residual polygenic variation, and genotype-environment interaction at both the major genic and the polygenic levels. The first method is based on multivariate segregation analysis and is appropriate for situations in which data are available for each individual in each environment. The second method is appropriate for the more common case when response to the environment cannot be observed directly. This method is based on an extension of a mixed major locus/variance component model and can be used when singly measured related individuals are observed in different environments. Three example applications using data on lipoprotein variation in pedigreed baboons are provided to show the utility of these methods.

Adaptation, Physiological↗
PubMed1993

Quantitative genetics of relative organ weight variation in captive baboons.

Anthropoid phylogeny has been characterized by dramatic increases in relative brain size. Given the importance of genetic mechanisms in evolution, quantitative genetic analyses of the biological concomitants of relative brain size variation should greatly augment our understanding of this phylogenetic phenomenon. In humans the brain is often linked metabolically with three other organs--heart, kidneys, and liver--that together account for most of the total basal metabolic rate. Because the weights of these four organs are proportional to their individual organ metabolic rates, their summed weights have been used by previous researchers as a proxy measure for their composite organ metabolic rate. We have conducted a quantitative genetic analysis of variation in the relative weights of these four organs in a population of captive baboons from the Southwest Foundation for Biomedical Research. These analyses were performed on loge-transformed organ weights available for 601 animals, 307 of which were assigned to 25 pedigrees containing 2 to 49 members; the remaining 294 animals were treated as independent individuals. Moderate but statistically significant (p < 0.005) heritabilities were estimated for all four organ weights: h2brain = 0.409 +/- 0.147, h2heart = 0.386 +/- 0.184, h2kidneys = 0.468 +/- 0.152, and h2liver = 0.600 +/- 0.160. Significant (p < 0.05) additive genetic correlations were estimated between brain and liver weights (rho G = 0.568) and between liver and kidney weights (rho G = 0.858). Significant (p < 0.05) environmental correlations were identified for heart and kidney weights (rho E = 0.551) and for liver and kidney weights (rho E = 0.684). Our results clearly demonstrate that the four organ weights have substantial heritable components that, because of their similar magnitudes, are probably equally susceptible to selection. However, the patterns of intercorrelation revealed by our analyses of the genetic and environmental correlation matrices indicate that, of the four organs composing the proxy measure of organ metabolic rate, only the liver and the kidneys are likely to exhibit correlated responses to selection for increased relative brain size such as that observed in the anthropoid fossil record.

Analysis of Variance↗
PubMed1992

A DNA polymorphism for LCAT is associated with altered LCAT activity and high density lipoprotein size distributions in baboons.

A polymorphic Pvu II site was mapped to intron 5 of LCAT, the gene encoding baboon lecithin: cholesterol acyltransferase (LCAT). In a study of 83 baboons, heterozygous baboons (Pv1/Pv2) had significantly higher LCAT enzyme activity levels than did baboons homozygous for the more common allele (Pv1/Pv1). LCAT genotype explained 6% of the total variation in LCAT enzyme activity. To test for allelic effects on cholesterol metabolism, we compared serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I). We also compared distributions of cholesterol and apo A-I among three HDL size classes (HDL1, HDL2, and HDL3). All measurements were obtained for each baboon after long-term feeding of a basal diet low in cholesterol and fat and again after 7 weeks on an atherogenic diet. Heterozygous baboons had significantly lower serum levels of total cholesterol than did homozygotes. In addition, we detected significant effects of LCAT genotype on size distributions of HDL cholesterol and apo A-I on both diets but did not detect any genotype-by-diet interaction. Heterozygotes had increased amounts of cholesterol and apo A-I in HDL3 particles and lower amounts of cholesterol and apo A-I in the larger HDL size classes by comparison with homozygotes. Overall, the LCAT polymorphism explained a significant proportion of total variation in cholesterol (4-10%) and apo A-I (13%) distributions on both diets. Thus, the results indicate that the LCAT polymorphism is associated with significant differences in LCAT enzyme activity and with alterations in HDL compositions.

Animals↗
PubMed1992

Quantitative genetic analysis of skin reflectance: a multivariate approach.

Skin color is a polygenically determined quantitative trait. Although it has been used extensively in studies of between-population variation, there have been relatively few studies of the inheritance of skin color. In this article we use measurements on 359 members of the Jirel population of eastern Nepal to assess the heritabilities and additive genetic correlations of three skin reflectance measures. Skin color was measured at the upper inner arm site at three wavelengths. A maximum likelihood approach was used to estimate sex and age effects on skin reflectance, heritabilities, and phenotypic variances at each wavelength and both additive genetic and environmental correlations between wavelengths. This technique incorporated information from 36 pedigrees with 2-25 members and 173 independent individuals. Likelihood ratio tests were used to assess the significance of specific variance/covariance components. The results indicate that skin reflectances are moderately heritable at all three wavelengths. The pairwise phenotypic correlations ranged from 0.76 to 0.88. The observed additive genetic correlations were not significantly different from 1.00, suggesting that the same loci influence variation at each wavelength. This evidence for relatively complete pleiotropy implies that measurements at multiple wavelengths yield little additional genetic information, although they may be useful for reducing measurement error. Based on estimates of the genetic and phenotypic covariance matrices, we determined that skin reflectance measurements are expected to provide only as much information for assessing local between-population genetic variation as a single two-allele polymorphic marker. Therefore microevolutionary studies based on skin color variation should be viewed with caution.

Adolescent↗
PubMed1991

Skin color variation in eastern Nepal.

The purpose of this paper is to provide skin color data on several endogamous groups of eastern Nepal and to demonstrate genetic microdifferentiation in skin color. Skin reflectance measures were taken at the upper inner arm and forehead sites, using the British DSL Model 99 Reflectance Spectrophotometer fitted with blue, green, and red filters. Measurements on 484 males representing six endogamous groups (Jirel, Sunwar, Sherpa, Tamang, Brahman, Chetri) were utilized. After adjusting for group-specific age effects, multivariate likelihood ratio permutation tests were used to assess ethnic differences in skin reflectance means and covariance matrices. Ethnic group membership had a highly significant effect on skin color at the upper inner arm site and at the forehead site. Differential tanning responses among groups were also detected and may represent the influence of genotype-environment interaction on reflectance traits. Mahalanobis distance analysis revealed patterns of microdifferentiation that are inconsistent with oral historical accounts. Little support was found for the ethnohistorical belief that Jirels are a hybrid group descended from Sunwars and Sherpas, even though this scenario is supported by linguistic, anthropometric, and dermatoglyphic data. We suggest that while reflectometric studies of skin pigmentation may be useful in assessing the macrodifferentiation of human populations, the use of skin color in differentiation studies at the local population level needs to be carefully evaluated.

Adolescent↗
PubMed1991

Mixed model segregation analysis of LDL-C concentration with genotype-covariate interaction.

Mixed model complex segregation analyses have in the past ignored the possibility of genotype-covariate interaction. Only in the nonmixed model with polygenic heritability equal to zero have segregation analyses been performed that allowed for genotype specific regression of the phenotype on covariates. We present an extension of Hasstedt's [1982] mixed model likelihood approximation which does allow for genotype-covariate interaction in the mixed model. Following description of this approximation, we validate the likelihood calculation by a Monte Carlo procedure based on the actual pedigree and missing data structure used in a complex segregation analysis of low density plus very low density lipoprotein cholesterol (LDL-C + VLDL-C) in baboons. The observed averages of the bootstrap parameter estimates adequately recover the generating values, which included parameters specifying genotype-covariate interaction. We then applied both a traditional complex segregation analysis and an analysis with genotype-covariate interaction to test for the presence of a major locus affecting LDL-C levels in baboons. The model including genotype-covariate interaction was significantly different from the model without interactions, and strongly supported the hypothesis that there is a segregating Mendelian locus as opposed to a random environmental factor. This major locus accounts for approximately 46% of the variance in LDL-C levels, as compared to 40% explained by a locus with no genotype-covariate interaction.

Animals↗
PubMed1991

Multivariate segregation analysis using the mixed model.

Most major genes involved in the etiology of complex diseases are likely to have pleiotropic effects on a number of intervening quantitative traits. Methods of segregation analysis that incorporate the additional information from such multiple traits will exhibit greater power for detecting the effects of major genes and allow explicit tests of major locus pleiotropy hypotheses. In this study, we present a new method for multivariate segregation analysis that utilizes a multivariate generalization of Hasstedt's [1982] technique for calculating approximate mixed model likelihoods on pedigrees. The method is based on a simplification of the multivariate conditional likelihood via a transformation that simultaneously orthogonalizes the residual additive genetic and environmental covariance matrices. This transformation allows the multivariate conditional likelihood to be factored into the product of independent univariate conditional likelihoods. Resulting computations are relatively fast, making it feasible to analyze multiple traits in extended pedigrees. We demonstrate our method with a bivariate analysis of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) serum levels in 585 pedigreed baboons.

Apolipoprotein A-I↗
PubMed1991

Genetic epidemiology of non-insulin-dependent diabetes mellitus in north India: preliminary analyses of some genetic markers in Punjabis.

Studies on monozygotic (MZ) twins and admixed populations show that the predisposition to non-insulin-dependent diabetes mellitus has a large genetic component. We have examined the distribution of some genetic polymorphisms (ABO, GLO, ESD, AK, ACPA, and GPI) in control and diabetic Punjabis from north India. The distribution of various genetic markers indicate that the differences between the control and diabetic samples are statistically not significant. Moreover, a contingency chi-square analysis over all loci suggests nonsignificant genetic differentiation (p = 0.50) between the Punjabi samples.

Adult↗
PubMed1990

Genetic analysis of apolipoprotein A-I in two dietary environments.

Although of great clinical and biological importance, the role of genotype-diet interaction in lipoprotein metabolism and atherosclerosis is still poorly understood. We analyzed serum apolipoprotein A-I (apo A-I) concentrations of approximately 600 pedigreed baboons that were fed two dietary regimens: (1) a basal diet and (2) an atherogenic (high-cholesterol, saturated-fat) diet. Complex segregation analysis was performed separately for apo A-I concentrations in each dietary environment. A major locus model with a recessive allele for high levels of apo A-I and a polygenic component best fit the family data for both diets. Using bivariate segregation analysis, we showed that the major genes detected in the univariate analyses represent two distinct loci that act additively to determine apo A-I concentrations. These two loci accounted for approximately 40% of the total phenotypic variance in apo A-I levels in each dietary environment and were also responsible for 33% of the variation in apo A-I response to the atherogenic diet. Both major loci were influenced by genotype-diet interaction in which the two-locus genotypes exhibited heterogeneous responses to the atherogenic diet. Most genotypes responded to the atherogenic diet with an increase in apo A-I, but two genotypes showed a decrease that can be traced to the effect of one of the major loci. The presence of two major loci and genotype-diet interaction may be responsible for the equivocal results obtained in human pedigree studies of apo A-I.

Animals↗
PubMed1990

Effects of population structure on within-group variation in the Jirels of Nepal.

The impact of population structure on phenotypic differentiation is most frequently considered in terms of between-subdivision variation. However, the demographic and social structures of a population also induce changes in within-group variation. We analyze the intragenerational dynamics of within-group variation for the Jirels, a tribal population of eastern Nepal. In the analyses we utilized age- and sex-corrected cranial measures (head length, head breadth, bizygomatic diameter, minimum frontal diameter, and head circumference) available for 526 adults (ages 15-54 years). We used a multivariate measure of variance, the standardized generalized variance, to assess levels of within-village variability, quantifying the sampling variance for this statistic by using a jackknife methodology. To generate null expectations of within-group variation, we used permutation procedures, which permit robust testing of significance without distributional assumptions. We also compared the within-birthplace variation in adults to the observed within-residence variation to examine migration effects. Contrary to expectation, some villages with high rates of in-migration have less variability than those with few migrants. When differences between the sexes at birth are controlled for, females in some villages exhibit greater variance than males, reflecting known differences in sex-specific dispersal.

Adolescent↗