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M C Mahaney

Publications and source records attributed to M C Mahaney.

At least 37 records · Page 2Linked to original sources
PubMed2000

Plasma levels of extracellular superoxide dismutase in an Australian population: genetic contribution to normal variation and correlations with plasma nitric oxide and apolipoprotein A-I levels.

Extracellular superoxide dismutase (EC-SOD) is a major superoxide scavenger and may be important to normal vascular function and cardiovascular health. We analyzed family data from 610 healthy Australians to detect and quantify the effects of genes on normal variation in plasma levels of EC-SOD and to test for pleiotropy with plasma nitric oxide (NO) and apolipoprotein A-I (apoA-I). Using maximum-likelihood-based variance decomposition methods, we determined that sex, age, and plasma levels of HDL cholesterol, apoA-I, and creatinine accounted for 38.6% of the variance in plasma EC-SOD levels and that additive genes accounted for 35% (P<0.00002). Multivariate analyses of plasma levels of EC-SOD, NO(x) (a measure of basal NO production), and apoA-I detected significant genetic correlations, indicating pleiotropy between EC-SOD and apoA-I (genetic correlation [rho(G)]=-0.45) and between NO(x) and apoA-I (rho(G)=0.58) but not between EC-SOD and NO(x). Genes shared by EC-SOD and apoA-I account for 20% of the genetic variance and, respectively, 7% and 9% of the phenotypic variance in both traits. Shared genes also account for >33% of the genetic variance and 5% and 15% of the respective phenotypic variance in NO(x) and apoA-I. In healthy individuals, over a third of the variance in EC-SOD plasma levels is due to the additive effects of genes. Some genes influence EC-SOD and apoA-I levels. The same is true of NO(x) and apoA-I but not of EC-SOD and NO(x). These patterns of pleiotropy can guide subsequent attempts to identify the genes and physiological mechanisms underlying them.

Adult↗
PubMed1999

Quantitative trait linkage mapping in anthropology.

Recent years have seen rapid progress in several areas of both biomedical and anthropological genetics. While genetic analyses have come to play a significant role in biological anthropology, there has been little use of modern methods for linkage mapping of quantitative trait loci (QTLs). It is now feasible to design research studies to investigate the quantitative genetics of complex phenotypes that are of primary importance to traditional questions in biological anthropology. Complex traits such as functionally significant morphological features, physiological characteristics or aspects of behavior can be examined to estimate the influence of genetic variation on within-species phenotypic variation. In addition, new methods for mapping quantitative trait loci provide opportunities to identify the regions within chromosomes that contain the functional genes of interest. This review summarizes molecular genetic and statistical genetic approaches to QTL mapping, and presents examples of how this approach can expand the scope of anthropological genetics to include mapping and identifying individual genes that influence complex phenotypic traits relevant to fundamental questions in biological anthropology.

Animals↗
PubMed1999

Genetic analysis of personality traits and alcoholism using a mixed discrete continuous trait variance component model.

Bivariate analyses can improve power to detect linkage. This paper describes one application of a bivariate variance component method for estimating joint likelihoods of a continuous and a discrete trait. This method is applied to the Collaborative Study on the Genetics of Alcoholism data set to investigate the relationship between personality traits derived from the tridimensional personality questionnaire (TPQ) and alcoholism. The results indicate that the novelty-seeking subscale of the TPQ and alcoholism share a strong and significant genetic correlation (rho G = 0.83) and modest environmental correlation (rho E = 0.31). When both traits are considered jointly in a multipoint linkage model compared with the alcoholism trait alone, there is an improvement in the ability to detect and localize a quantitative trait locus on chromosome 4.

Age Factors↗
PubMed1999

Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism.

Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C-namely, unesterified HDL2a-C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes.

Adult↗
PubMed1999

Pleiotropic genetic effects on LDL size, plasma triglyceride, and HDL cholesterol in families.

The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (P<0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (P<0.001) additive genetic correlations (rho(G)), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG rho(G)=-0.87, for LDL size and HDL-C rho(G)=0.65, and for HDL-C and TG rho(G)=-0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families.

Adult↗
PubMed1999

Pleiotropy and genotype by diet interaction in a baboon model for atherosclerosis: a multivariate quantitative genetic analysis of HDL subfractions in two dietary environments.

We investigated dietary effects on pleiotropic relationships among 3 HDL cholesterol (C) subfractions (HDL1-C, HDL2-C, and HDL3-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 (rhoG and rhoE) 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 HDL1-C and HDL3-C (rhoG=-0.81). On the HCSF diet, only the genetic correlation between HDL1-C and HDL3-C (rhoG=-0.61) 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 HDL1-C and HDL2-C, but not for HDL3-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 HDL1-C and HDL2-C is altered by the HCSF diet, disrupting the pleiotropy observed between the 3 subfractions on the Chow diet.

Animals↗
PubMed1999

Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC.

We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.

Chromosome Mapping↗
PubMed1999

Potential effects of ethnicity in genetic and environmental sources of variability in the stature, mass, and body mass index of children.

We examined sources of variability in stature, body mass, and body mass index (BMI) in families of black and white elementary schoolchildren from Philadelphia, Pennsylvania. The sample consisted of 445 black and 379 white children, 7-13 years old, and their parents (total n = 2016). The sample was distributed among 596 nuclear families, each representing an independent pedigree. Maximum-likelihood-based variance decomposition methods were used to simultaneously estimate ethnic group-specific effects of genes, sex, age by sex, and unmeasured environmental factors on stature, body mass, and BMI. Likelihood ratio tests were performed to assess the significance of h2 estimates and differences in sigma g and sigma e between black and white families. Genes account for moderate proportions of the phenotypic variance (h2) of these traits in black and white children. In black and white children, respectively, h2 estimates were 0.37 and 0.53 for stature, 0.37 and 0.31 for body mass, and 0.38 and 0.24 for BMI (p < 0.0005). Although the differences in h2 between ethnic groups were not significant (stature, p = 0.23; body mass, p = 0.49; BMI, p = 0.14), black children exhibited a significantly greater total residual phenotypic standard deviation (sigma e and sigma g) in body mass and BMI and a significantly greater sigma e for stature compared with white children. The larger residual phenotypic variance in the black sample is likely due to exposure to unmeasured environmental factors that are not accounted for in this model. Given that sigma g for stature is not significantly different between ethnic groups, the slightly lower estimates in black children are due to the increased contribution of the environment to the phenotypic variance in this trait.

Adolescent↗
PubMed1997

Serum leptin levels are independently correlated with two measures of HDL.

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.

Adult↗
PubMed1997

Exploiting pleiotropy to map genes for oligogenic phenotypes using extended pedigree data.

We investigated the utility of two approaches for exploiting pleiotropy to search for genes influencing related traits. To do this we first assessed the genetic correlations among a set of five closely related quantitative traits (Q1, Q2, Q3, Q4, Q5). We then used the genetic correlations among these five traits both to remove the common genetic effects of the four remaining traits, thereby identifying the unique genetic contribution to each trait, and to extract a synthetic phenotype which exploits the shared genetic information (pleiotropy) among these five traits. After obtaining these conditional traits, we then searched for evidence of quantitative trait loci (QTLs) (using variance component linkage) influencing the unique residual genetic component for each trait as well as those influencing the expression of the synthetic traits. From this work, we conclude that the removal of the common genetic effects of other traits in a group may be of greater utility when the majority of the pleiotropy initially detected between traits is attributable to the shared additive effects of polygenes, rather than to those of major loci. By contrast, decomposition of the genetic covariance matrix to its principal components is a greater utility when the majority of pleiotropy is attributable to major loci.

Chromosome Mapping↗
PubMed1997

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Adipose Tissue↗
PubMed1997

Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.

Adolescent↗
PubMed1997

Genetic relationship between measures of HDL phenotypes and insulin concentrations.

We used data from the San Antonio Family Heart Study to determine the HDL correlates of the insulin resistance syndrome (IRS), as reflected by insulin concentrations in nondiabetic subjects. We measured insulin concentrations both in the fasting state and 2 hours after a glucose challenge (2-hour insulin) and we assessed seven aspects of HDL phenotype, including size and concentration of both lipid and protein components. Measurements were obtained from 1202 nondiabetic members of 42 families. Initial quantitative genetic analyses revealed that a substantial portion of phenotypic variation in the nine variables was due to genes (heritabilities, h2, ranged from 0.32 to 0.47). We then conducted a series of bivariate genetic analyses, which indicated that there were significant additive genetic correlations (ie, pleiotropy) between the two measures of insulin and five of seven HDL measures tested, including concentrations of HDL cholesterol (fasting insulin only) and triglyceride, and HDL size distributions of apoAI, apoAII, and cholesterol; concentrations of apoAI and apoAII were not genetically related to either insulin measure. Increased insulin levels were associated with relatively smaller HDL phenotypes, and considering a similar association with small, dense LDLs, this finding suggests a common effect of insulin resistance on particle size distributions for these lipoproteins. Thus, these results suggest the existence of genes that pleiotropically influence variation in both HDLs and insulin levels and therefore contribute to the clustering of proatherogenic traits in the IRS.

Adult↗
PubMed1997

Shared and unique genetic effects among seven HDL phenotypes.

The purpose of this study was to investigate the genetic control of various HDL measures and to determine the proportion of genetic variance explained by shared genes (ie, pleiotropy) and the proportion unique to each trait. The data used were drawn from large, randomly ascertained pedigrees of Mexican Americans participating in the San Antonio Family Heart Study. Data were available for 655 individuals (258 men and 397 women) in 26 families. We performed a multivariate quantitative genetic analysis to simultaneously estimate both the additive genetic and random environmental correlations among seven HDL phenotypes. These seven HDL phenotypes can be divided into two categories: measures of concentration and estimates of particle size. Concentration was measured for apo A-I, apo A-II, esterified cholesterol, and unesterified cholesterol, and particle size was estimated for apo A-I, apo A-II, and esterified cholesterol. The heritabilities (h2) for each of the seven traits were significantly greater than zero (P<.05) and ranged from 0.2 to 0.6. When considered in a pairwise fashion, all combinations of these traits showed marked genetic correlations (rho(G)=0.33 to 0.87) and all were significantly greater than zero (P<.05), indicative of pleiotropic effects. However, we found substantial unique genetic variance for each of these traits even after accounting for the effects shared in common with all the remaining measures. We conclude that the genetic variation in these HDL phenotypes is a result of the action of common as well as unique genes.

Adult↗
PubMed1997

Spontaneous pathology of the gray short-tailed opossum (Monodelphis domestica).

The gray short-tailed opossum, Monodelphis domestica, is a newly established laboratory animal that is becoming increasingly important to biomedical research. Because little disease information is available for this species, we reviewed records for spontaneous gross and histologic lesions and microbiologic results in 150 M. domestica necropsies during an 11-year period. We identified 150 (91 female, 59 male) animals from 441 necropsy cases which were controls in experimental protocols or were members of the breeding colony. Initial statistical examinations indicated that the sample was representative of the living members of the breeding colony with respect to age, sex, and range of inbreeding. Causes of death and types of tumors were specifically evaluated. Females died earlier than males (22.6 +/- 13.0 months versus 30.9 +/- 11.9 months), but this difference was not associated readily with diet or inbreeding levels. The organ systems with the greatest lesion prevalences, in decreasing order, were the digestive, urogenital, cardiovascular, and respiratory systems. The most probable causes of all deaths were associated with the digestive system, followed by the cardiovascular and integumentary systems. The principal disease problems were rectal prolapse, congestive heart failure, and dermatitis. Neoplasia was found in 39 of the animals. The prevalence of neoplasia was greatest in the digestive system, followed by the endocrine, urogenital, integumentary, and hematopoietic systems. Pituitary adenoma was the most common neoplasm, followed by uterine leiomyoma and cutaneous lipoma. Specific microbially-induced diseases were not recognized, and endo- and ectoparasites were not found in colony-born M. domestica.

Animal Diseases↗
PubMed1996

Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study.

BACKGROUND: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Adult↗