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Biomedical subjects

M C Mahaney

Publications and source records attributed to M C Mahaney.

At least 55 records · Page 3Linked to original sources
PubMed1996

Genetic correlations between lipoprotein phenotypes and indicators of sex hormone levels in Mexican Americans.

Previous studies have shown that the inverse relationship between HDL cholesterol (HDL-C) and triglyceride (TG) levels, risk factors for cardiovascular disease, is due largely to the effects of shared genes. HDL-C and TG are also known to be related to endogenous sex hormone levels, however the nature of the relationships is unclear. The objective of this study is to ascertain the extent to which these relationships are determined by shared genes. We conducted a multivariate quantitative genetic analysis of HDL-C, TG, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) in 635 people from 27 pedigrees participating in the San Antonio Family Heart Study. Heritabilities (h2) and genetic and environmental correlations (rho G and rho E) were estimated simultaneously by maximum likelihood methods. All four traits showed significant (P < 0.05) heritabilities: h2HDL-C = 0.38, h2TG = 0.54, h2DHEAS = 0.43, h2SHBG = 0.26. Significant genetic correlations were detected between HDL and each of the other traits: rho G(HDL-TG) = -0.56, rho G(HDL-DHEAS) = 0.23 and rho G(HDL-SHBG) = -0.56. However, there were no significant genetic correlations between TG and either measure of sex hormones. Thus, at least three separate groups of genes influence HDL-C levels in Mexican Americans: one group that has pleiotropic effects on HDL and TG, one group influences both HDL-C and SHBG and a third influences both HDL-C and DHEAS.

Adipose Tissue↗
PubMed1996

Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures.

Insulin resistance is part of a metabolic syndrome that also includes non-insulin-dependent diabetes mellitus, dyslipidemia, obesity, and hypertension. It has been hypothesized that insulin resistance represents the primary physiological defect underlying this syndrome. Since insulin resistance is at least partially genetically determined, we hypothesized that genes influencing insulin resistance would have pleiotropic effects on a number of other traits, including triglyceride (TG) and HDL cholesterol levels, body mass index (BMI) and body fat distribution, and blood pressure levels. To investigate this hypothesis, we analyzed data obtained from individuals in 41 families enrolled in the San Antonio Family Heart Study. Statistical methods that take advantage of the relatedness among individuals were used to differentiate between genetic and nongenetic (ie, environmental) contributions to phenotypic variation between traits. Serum levels of fasting and 2-hour insulin (measured in 767 and 743 nondiabetic family members, respectively) were used as a measure of insulin resistance. The genetic correlations were high between insulin levels (both fasting and 2-hour) and each of the following: BMI, HDL level, waist-to-hip ratio, and subscapular-to-triceps ratio, indicating that the same gene, or set of genes, influences each pair of traits. In contrast, the genetic correlations of insulin levels with systolic and diastolic blood pressures were low. We have previously shown that a single diallelic locus accounts for 31% of the phenotypic variation in 2-hour insulin levels in this population. We conducted a bivariate segregation analysis to see if the common genetic effects on insulin and these other traits could be attributable to this single locus. These results indicated a significant effect of the 2-hour insulin locus on fasting insulin levels (P = .02) and BMI (P = .05), with the "high" insulin allele associated with higher levels of fasting insulin but lower levels of BMI. There was no detectable effect of this locus on HDL level, TG level, subscapular-to-triceps ratio, or blood pressure. Overall, these results suggest that a common set of genes influencing insulin levels also influences other insulin resistance syndrome-related traits, although for the most part this pleiotropy is not attributable to the 2-hour insulin level major locus.

Adult↗
PubMed1996

Triiodothyronine exerts a major pleiotropic effect on reverse cholesterol transport phenotypes.

The thyroid hormone triiodothyronine (T3) is known to be a potent mediator of APOA1 gene expression. With the use of multivariate quantitative genetic analysis, we have assessed the magnitude of shared effects of T3 on plasma concentrations of apolipoprotein AI (apo AI) and three related phenotypes: HDL-C, apo AII, and LpAI (which is a concentration of apo AI that contains HDL particles). Maximum likelihood techniques were used to simultaneously estimate mean effects and variance components in large, extended Mexican American families living in San Antonio, Tex. We found that T3 accounted for 16%, 23%, 21%, and 37% of the additive genetic variance in HDL-C, apo AI, apo AII, and LpAI, respectively, while explaining virtually none of the random environmental variance in these phenotypes. T3 also has a pronounced effect on the pairwise genetic correlations among the four phenotypes: After the pleiotropic effects of T3 concentrations are controlled for, the genetic correlations are reduced by 6% in the case of HDL-C and apo AI and 97% for apo AII and LpAI. Thus, genes that influence T3 have a significant effect on HDL-C, apo AI, apo AII, and LpAI and also on the correlations among these phenotypes.

Adolescent↗
PubMed1996

Effects of a major gene for apolipoprotein A-I concentration are thyroid hormone dependent in Mexican Americans.

Apolipoprotein A-I (apoA-I) is the principal protein component of HDL cholesterol. The thyroid hormone triiodothryonine (T3) is known to be a potent mediator of expression of the apoA-I structural gene (APOA1). Using complex segregation analysis, we detected a major gene influencing plasma concentration of apoA-I and examined its interaction with T3 serum level in Mexican Americans participating in the San Antonio Family Heart Study. Strong evidence for a major locus with two alleles (A and a) determining apoA-I level was obtained when interaction with T3 was allowed. The major gene appears not to be linked to the APOA1 structural locus. Genotypes differed significantly in their relationships to T3 level. The AA and Aa genotypes showed a positive relationship with T3 level, while the rarer aa homozygote showed a strong negative relationship with T3. The relative variance in apoA-I concentration due to this major gene varied from 56% to 18%, depending on T3 level. On average, the major gene accounts for 30% of apoA-I variation, and shared-household effects account for an additional 11%. These findings suggest that thyroid hormone has an important role in the genetic control of lipoprotein metabolism.

Adult↗
PubMed1996

Genetic and environmental correlations among hormone levels and measures of body fat accumulation and topography.

In this study we partition the phenotypic correlations between body fat measures and serum levels of hormones with known, or suspected, lipolytic effects into their genetic and environmental components. Using variance decomposition techniques, we are able to estimate the pleiotropic effects of genes and/or shared environmental factors that give rise to the phenotypic correlations previously reported between these traits. We used data from a large sample of randomly ascertained Mexican-American families living in San Antonio, TX. Data were available for 582 individuals in 26 pedigrees. Levels of sex hormone-binding globulin, dehydroepiandrosterone sulfate, insulin, insulin-like growth factor I, total T4, and total T3 were assayed. The measures of body fat accumulation and topography included body mass index, subscapular/triceps ratio, and relative fat patterning index. The results of this analysis demonstrate that significant phenotypic correlations among these traits can arise from three underlying conditions: 1) entirely from shared genetic effects (pleiotropy), 2) entirely from shared random environmental effects, or 3) a combination of both effects. However, we also show that it is possible for significant genetic and environmental correlations to interact in such a way as to produce a phenotypic correlation that itself would not be considered significant.

Adipose Tissue↗
PubMed1995

Plasma HDL cholesterol, triglycerides, and adiposity. A quantitative genetic test of the conjoint trait hypothesis in the San Antonio Family Heart Study.

BACKGROUND: The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study. METHODS AND RESULTS: We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h2), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (P < .001) for all traits (h2HDL-C = 0.55, h2TG = 0.53, h2FM% = 0.37, h2BMI = 0.44) but significant genetic correlations (P < .001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (PG = -0.52) and fat mass and BMI (PG = 0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (P > .05). CONCLUSIONS: Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.

Adipose Tissue↗
PubMed1995

Major gene with sex-specific effects influences fat mass in Mexican Americans.

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype x sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing.

Adolescent↗
PubMed1995

Statistical genetics of normal variation in family data for oligogenic diseases.

A quadrivariate quantitative genetic analysis detected significant heritabilities for four simulated quantitative traits (Q1-Q4) with additive genetic pleiotropy between traits Q1, Q2, and Q3. Using univariate segregation analysis, we tentatively detected five major loci: one each for Q2, Q3, and Q4 and two, at different maxima, for Q1. Bivariate one-locus segregation analysis identified significant major locus pleiotropy for Q1, Q2, and Q3 only; and suggested identity between one of Q1's major genes and that for Q2, and between the second Q1 major gene and that for Q3. Patterns of linkage, supportive of inferences from the bivariate segregation analyses, were detected between three candidate genes and the major genes for Q1, Q2 and Q4.

Alleles↗
PubMed1995

A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio Family Heart Study. Segregation and linkage analyses.

To detect and measure the effects of a single locus on quantitative variation in plasma concentrations of HDL cholesterol (HDL-C), we conducted statistical genetic analyses on data from 526 Mexican American individuals in 25 randomly ascertained pedigrees. By using maximum-likelihood complex segregation analysis, we found evidence for a major locus with a codominant mixture model that included the phenotypic means, standard deviations, relative frequency of a low HDL-C allele, and heritability for plasma HDL-C levels, plus the effects of sex (genotype specific), age-by-sex, age2-by-sex, plasma concentrations of apolipoprotein (apo)AI and triglycerides (genotype specific), exogenous sex hormone use, and menopausal status under an unrestricted general model. Inclusion of the four covariates (in addition to the sex and age-by-sex effects) accounted for nearly 79% of the variance in total plasma HDL-C levels. Of the remaining 21% of the variance, the detected major locus accounted for approximately 55% in men and 21% in women; the total genetic contributions to the variance by genes were approximately 82% in men and 69% in women. Linkage analyses with penetrance parameter estimates from the segregation analysis excluded tight linkage between the detected major locus and markers for the following candidate loci: the apoAI/apoCIII genomic region (P < .05), apoB (P < .01), hepatic lipase (P < .001), lipoprotein lipase (P < .001), and the LDL receptor (P < .001). While not excluding the apoE locus (LOD = -0.348, P < .21), the analysis provided no support for tight linkage between it and the detected major locus.

Adolescent↗
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

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

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↗
PubMed1991

Phenotypic evolution in prehistoric Ohio Amerindians: natural selection versus random genetic drift in tooth size reduction.

Many anthropologic investigations involve measurement and analysis of polygenic skeletal and dental traits in prehistoric populations from which genetic details cannot be inferred. However, population genetics concepts can be applied productively to analyses of phenotypic variation in prehistoric human populations. One potentially useful approach, derived from basic quantitative genetics (Lande 1976, p. 314), models the effects of natural selection and random genetic drift on the evolution of the average phenotype in a population. We apply this model to the problem of dental size reduction in three prehistoric Amerindian populations from Ohio. Conversion of mean log-transformed buccolingual diameters for six permanent teeth (maxillary and mandibular I1, M1, and M2) to phenotypic standard deviation units reveals significant size reduction in the maxillary teeth only. By assuming 40 generations (t) between the 2 populations and a narrow heritability (h2) range of 0.30-0.70, the estimated minimum selective mortality required to produce the reductions is 1.8 deaths per 100 persons per generation. Given the same t and h2 values, the effective population size (Ne) needed to reject the neutral hypothesis (i.e., random genetic drift) with 95% confidence is approximately 150. Because paleodemographic and ethnographic studies suggest minimum effective sizes of this magnitude for these populations, we tentatively reject random genetic drift and conclude that selective mortality is most probably responsible for the maxillary tooth size reduction observed.

Biological Evolution↗
PubMed1990

Dental agenesis in the Dariusleut Hutterite Brethren: comparisons to selected Caucasoid population surveys.

We report the results of a study of the prevalence of nonsyndromic dental agenesis among a sample of 208 individuals (105 females, 103 males) between the ages of 15 and 29 years from a North American religious and genetic isolate, the Dariusleut Hutterites of Western Canada. Direct examination of dental casts, oral examination reports, dental treatment records, and a limited number of dental radiographs reveals congenital absence and/or obvious morphometric reduction of at least one tooth (excluding third molars) in 98 subjects (55 females, 43 males), yielding a prevalence estimate of approximately 47%. This estimate is nearly four times those reported for nonisolate Caucasoid populations of European descent and substantially higher than the elevated prevalences observed in several other isolated populations. Although the prevalence of dental agenesis in the Dariusleut is indeed high, neither the incidence of bilateral agenesis (exhibited at least once in 58% of affected dentitions), number of affected teeth per person (mean, 2.4), morphologic tooth classes affected, or combinations of tooth classes affected ostensibly distinguish them from other populations with similar geographic origins. We conclude that the dental agenesis observed in this North American genetic isolate does not represent a private polymorphism or rare developmental variant. Consequently, the results of further study in these Dariusleut Brethren will be directly relevant to critically testing as yet unresolved hypotheses for the mode of gene action and the relative contributions of hereditary and environmental factors to the reduction of tooth numbers in human dentitions.

Adolescent↗
PubMed1990

Stature estimation in prehistoric Native Americans of Ohio.

In the present report we investigate stature estimation techniques in a sample of 64 (35 male, 29 female) prehistoric Native Americans from Ohio. Because living stature is unknown for these 64 individuals, we use Fully's (1956) anatomical method to provide the best estimates of living stature. In this method all osseous components of skeletal height are measured and soft tissue correction is added. Comparisons of regression equations commonly used for stature estimation in prehistoric Eastern Woodland Native American populations, but developed for East Asian and East Asian-derived populations (using lower extremity components), show that these commonly used equations consistently yield stature estimates 2 to 8 cm in excess of the best estimates from Fully's method. Based on the skeletal height measures of the 64 individuals in the present sample, we develop regression equations for the estimation of stature. These equations yield stature estimates virtually identical to estimates from Fully's method and may prove useful for stature reconstruction in other prehistoric Eastern Woodland Native American populations.

Body Height↗
PubMed1986

Delayed dental development and pulmonary disease severity in children with cystic fibrosis.

The relationships among development of the succedaneous mandibular dentition, chronologic age, a clinically-derived prognostic score and duration of therapeutic intervention were studied in 23 females and 27 males with cystic fibrosis (CF). Radiographically-determined dental age was significantly delayed. Although significant correlations were obtained between dental and chronologic age, none were observed between delays in dental development and either the measure of pulmonary disease severity or age at CF diagnosis. The findings are not consistent with a pathologic aetiology for the reported dental delays or with being a secondary consequence of the stresses of the disease. The delay seems to be an endocrine-mediated pleiotropic effect of the cystic fibrosis locus.

Adolescent↗
PubMedDate not supplied

Cross-sectional growth standards for captive baboons: I. Organ weight by chronological age.

We present the first cross-sectional organ weight reference standards for captive baboons (Papio hamadryas). Organ weight data were obtained from necropsy reports for 634 healthy, pedigreed, captive female and male baboons. From summary statistics we calculated and fit cross-sectional, sex-specific percentile curves for: adrenals, brain, eyes, heart, kidneys, liver plus gall bladder, lungs, pancreas, pituitary gland, spleen, and thyroid gland in two year age class intervals and summary statistics by sex for each organ in one year age classes.

Animals↗