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Biomedical subjects

M C Mahaney

Publications and source records attributed to M C Mahaney.

At least 19 recordsLinked to original sources
PubMed2006

Bone ALP and OC reference standards in adult baboons (Papio hamadryas) by sex and age.

BACKGROUND: Serum bone-specific alkaline phosphatase (bone ALP) and intact osteocalcin (OC) are markers of bone formation of interest because of easy measurability and potential utility as identifiers of those at risk for fractures associated with bone metabolism disorders. The baboon (Papio hamadryas) exhibits extensive biological similarities to humans making it particularly well suited to studies of bone maintenance and turnover. METHODS: We measured serum bone ALP and OC in 591 baboons. RESULTS: We report significant sex and age effects and present reference ranges and percentile distributions for these markers. CONCLUSIONS: This study is the first to characterize normal variation in bone ALP and OC levels in baboons and to assess the age and sex effects on this variation. The results provide much-needed reference standards to allow researchers to evaluate the status of their animals in cross-sectional studies and assess the meaning of changes in bone ALP and OC levels in longitudinal studies.

Age Factors↗
PubMed2005

Cross-species replication of a serum osteocalcin quantitative trait locus on human chromosome 16q in pedigreed baboons.

Osteocalcin (OC), a serum marker of bone formation, in its intact form reflects osteoblast activity. It is of interest to clinicians and bone biologists due to easy measurability and potential utility as an identifier of those at risk for fracture and other complications associated with bone metabolism disorders. The only published linkage study in humans shows significant evidence for a quantitative trait locus (QTL) affecting OC levels on 16q. We used the baboon, a primate model for skeletal maintenance and turnover, to detect and quantify the effects of genes on serum OC levels and to localize chromosomal regions harboring the responsible loci. We assayed OC levels in 591 pedigreed animals, assessed OC heritability, and conducted a genomewide linkage scan for evidence of QTLs affecting this phenotype. Heritability in these baboons is 0.24. Suggestive linkage is evident with markers in a region homologous to human chromosome 16q. This first genomewide linkage scan in a nonhuman primate for QTLs affecting bone formation as reflected by OC levels provides cross-species replication of the QTL on chromosome 16q previously localized in humans. Given the concordance of results of the only two genome scans for this trait in two primate species, further studies of this region are warranted.

Animals↗
PubMed2005

A quantitative trait locus for normal variation in forearm bone mineral density in pedigreed baboons maps to the ortholog of human chromosome 11q.

Baboons share many anatomical, physiological, and developmental characteristics with humans that make them excellent models for human bone maintenance and turnover. We conducted statistical genetic analyses, including a whole-genome linkage screen, of dual-energy x-ray absorptiometry-acquired measures of areal bone mineral density (aBMD), currently the most reliable single predictor of susceptibility to osteoporotic fracture in humans, from three forearm sites on the radius and ulna of 667 pedigreed baboons. We used a maximum likelihood-based variance decomposition approach to detect and quantify the effects of genes on normal variation in aBMD in the forearm of these baboons and to localize these effects to chromosomal regions. We estimated significant heritability for aBMD at all three sites and found evidence for a quantitative trait locus (QTL) contributing significantly to the genetic effects on this trait in a region of the baboon genome homologous to human chromosome 11q12-13. This first reported genome-wide linkage screen in a nonhuman primate for QTLs affecting forearm aBMD provides important cross-species replication of a QTL found in humans. The concordance of our results in a nonhuman primate with those reported for humans provides strong evidence that a gene (or genes) in this region affects normal variation in BMD.

Animals↗
PubMed2005

Genome-wide scan of resistin mRNA expression in omental adipose tissue of baboons.

INTRODUCTION: The hormone resistin was recently discovered in adipose tissue of mice. Functional tests suggest a role for resistin in the regulation of insulin sensitivity. However, human studies have reported controversial results on the metabolic function of this hormone. METHODS: A 1 g omental adipose tissue biopsy was obtained from 404 adult baboons. Resistin mRNA expression was assayed by real-time, quantitative RT-PCR, and univariate and bivariate quantitative genetic analyses were performed, via the variance decomposition approach. A genome scan analysis was conducted using resistin mRNA abundance in omental adipose tissue as a quantitative phenotype. RESULTS: A significant heritability of h2 = 0.23 (P = 0.003) was found for resistin mRNA abundance in omental adipose tissue. A genome scan detected a quantitative trait locus for resistin expression with an LOD score of 3.8, in the region between markers D19S431 and D19S714, corresponding to human chromosome 19 p13. This chromosomal region contains genes related to insulin resistance phenotypes, such as resistin, insulin receptor, angiopoietin-like 4 protein and LDL receptor. CONCLUSIONS: Individual variation in resistin mRNA expression has a significant genetic component, and a gene or genes on chromosome 19 p13 may regulate resistin mRNA levels in baboon omental adipose tissue.

Adipose Tissue↗
PubMed2004

Genotype-by-sex and environment-by-sex interactions influence variation in serum levels of bone-specific alkaline phosphatase in adult baboons (Papio hamadryas).

While more than 77% of the people in the US with osteoporosis are women, the contributions of genotype-by-sex (G x S) and environment-by-sex interactions to sex differences in osteoporosis risk factors have not been studied. To address this issue, we conducted a statistical genetic analysis of serum concentrations of bone-specific alkaline phosphatase (Bone ALP), a highly specific marker of osteoblast function that is elevated in persons with conditions like osteoporosis characterized by excessive bone turnover or rapid bone loss. We assayed Bone ALP from 657 pedigreed baboons using a commercially available ELISA kit. Using a maximum likelihood variance decomposition approach, we treated sex as an environmental milieu in which genes influencing Bone ALP levels are expressed. We modeled the genetic covariance in Bone ALP between all relative pairs conditional on their sex so that the covariance is the product of the kinship, the genetic correlation between trait levels in the two sexes, and the genetic variances in the two sexes. Sex-specific maximum likelihood estimates (MLE) of residual heritability for Bone ALP were greater for females than for males (h2 = 0.44 vs. h2 = 0.26, respectively), but likelihood ratio tests revealed only a marginally significant difference in sex-specific genetic variances (P = 0.057). In contrast, the between-sex genetic correlation (rhoG = 0.43) was significantly less than 1.0 (P = 0.037), and the difference in sex-specific environmental variances was highly significant (P = 0.00006). We report the first evidence for G x S interactions influencing variation in an osteoporosis risk factor. The diminished between-sex genetic correlation implies that different genes influence Bone ALP levels in the two sexes. The significant differences between environmental variances suggest that unmeasured factors, including those from the internal, biological environments of the two sexes, account for a greater proportion of the Bone ALP variation in males.

Alkaline Phosphatase↗
PubMed2004

Effects of diabetes on plasma nitrotyrosine levels.

BACKGROUND: Oxidative stress plays a major role in disease processes such as atherosclerosis and diabetes. Peroxynitrite is a reaction product of nitric oxide (NO) and superoxide and a potent oxidant. The peroxynitrite-mediated tyrosine nitration, which forms nitrotyrosine (NT), is associated with several pathological conditions. METHODS: We measured plasma NT levels using the HPLC method in 40 Mexican Americans with diabetes, but not taking medications, and 40 age- and sex-matched euglycaemic controls. RESULTS: Plasma-free NT levels were not different between subjects with diabetes (11.0 +/- 1.7 nmol/l, n = 40) and with non-diabetes (10.4 +/- 1.5 nmol/l, n = 40). There was also no association with levels of fasting glucose (r = -0.049, P = 0.663) or 2-h glucose (r = -0.099, P = 0.390). However, females had significantly lower free NT level (7.6 +/- 1.4 nmol/l, n = 40) than males (13.8 +/- 1.7 nmol/l, n = 40, P = 0.005), which were not affected by age, smoking status, BMI and glucose levels. CONCLUSIONS: In contrast to some earlier reports, our study shows that diabetes has no effect on plasma NT levels in Mexican Americans. We have also demonstrated lower free NT levels in females than males, which may partly explain the lower risk profile to vascular disease in women.

Blood Glucose↗
PubMed2004

White monkey syndrome in infant baboons (Papio species).

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.

Alopecia↗
PubMed2003

Pleiotropic effects on cardiovascular risk factors within and between the fourth and sixth decades of life: implications for genotype x age interactions.

We used an approach for detecting genotype x environment interactions to detect and characterize genotype x age interaction in longitudinal measures of three well known cardiovascular risk factors: total plasma cholesterol (TC), systolic blood pressure (SBP), and body weight (Wgt). Our objectives were to determine if the same gene or suite of genes influences quantitative variation in each of these phenotypes in the 4th and 6th decades of life, to assess the impact of additive gene effects in these two decades, and to evaluate the stability of pleiotropic relationships among these phenotypes. Using the Framingham Heart Study data, we constructed two cross-sectional samples comprising individuals on whom these phenotypes were measured at ages 30-39 years (Original Cohort: exam 1, Offspring Cohort: exam 2) and at ages 50-59 years (Original Cohort: exam 11, Offspring Cohort: exam 5). We also constructed a longitudinal sample from the cross-sectional sample members for whom measures on these traits were available at both ages (i.e., 4th and 6th decades of life). Patterns of pleiotropy, inferred from genetic correlations between traits, differ between the two age classes. Further, additive genetic variance in SBP during the 4th decade of life is attributable to a different gene or suite of genes than during the 6th. The magnitude of the effect increases for SBP. Variation in TC and Wgt appear to be influenced by the same gene or genes in both decades. The magnitude of the effect is stable for TC, but increases dramatically with age for Wgt.

Adult↗
PubMed2003

A quantitative trait locus on chromosome 16q influences variation in plasma HDL-C levels in Mexican Americans.

OBJECTIVE: We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). METHODS AND RESULTS: After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)=3.73 (P=0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LOD=2.73, P=0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). CONCLUSIONS: A QTL influencing plasma levels of HDL-C in Mexican Americans from San Antonio maps to a region of human chromosome 16q near LCAT and CETP.

Adolescent↗
PubMed2003

Bone mineral density reference standards in adult baboons (Papio hamadryas) by sex and age.

Osteoporosis is a progressive condition involving structural deterioration of bone tissue, leading to skeletal fragility and an increased susceptibility to fractures due to low bone mass and high rates of bone turnover. Areal bone mineral density (aBMD) serves as the most reliable predictor of susceptibility to osteoporotic fracture. The development of animal models, including Old World Monkeys, has been essential to studies of bone mineral density. These animals, including the baboon, exhibit many biological similarities with our own species relevant to the variation in age-related changes and pathology in bone that may make them an excellent model for studies of skeletal structure and maintenance in humans. The baboon has been shown to exhibit extensive biological similarities to humans regarding skeletal biology, but little is known about the range of normal variation in skeletal traits, such as bone mineral density, in this species. Our data, collected on baboons (Papio hamadryas) that are part of a large breeding colony at the Southwest Foundation for Biomedical Research and the Southwest National Primate Research Center (San Antonio, TX), involve 466 females and 210 males, ranging in age from 5.5 to 30 years. Student's t tests, bivariate correlations, and likelihood ratio tests show sex and age effects at all spinal sites. Age effects are minimal or absent in the forearm sites. This study is the first to characterize normal variation in aBMD in baboons, to assess the effect of age and sex on this variation, and to compare this variation to those data currently available from experimental control animals. As such, it provides much-needed reference standards that will allow researchers to evaluate the status of their animals in cross-sectional studies and more fully assess the meaning of aBMD changes in longitudinal studies.

Absorptiometry, Photon↗
PubMed2003

Hematology and blood biochemistry in infant baboons (Papio hamadryas).

Although published normative reference standards for hematologic and clinical chemistry measures are available for adult baboons, their applicability to infants has not been addressed. We analyzed these measures in 110 infant baboons (55 females and 55 males) from a large breeding colony at the Southwest Regional Primate Research Center in San Antonio, Texas. The sample consists of olive baboons and olive/yellow baboon hybrids, 1 week to 12 months of age. We produced cross-sectional reference values and examined the effects of age, sex, and subspecies on these variables. Hematology reference ranges for infant baboons are similar to, but wider than, those for adults. Reference ranges for blood biochemistry measures are generally more dissimilar to adults, indicating that for many variables, reference ranges for adult baboons are not adequate for infants. Although sex and subspecies differences are rare, age accounts for more than 10% of the variance in many of the variables.

Aging↗
PubMed2001

A quantitative trait locus influencing estrogen levels maps to a region homologous to human chromosome 20.

Estrogen, a steroid hormone, regulates reproduction and has been implicated in several diseases. We performed a genome-wide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in estrogen levels in baboons. A microsatellite polymorphism, D20S171, located on human chromosome 20q13.11, showed strong evidence of linkage with a LOD score of 3.06 (P = 0.00009). This region contains several potential candidate genes including melanocortin 3 receptor (MC3R), cytochrome P-450 subfamily XXIV (CYP24), and breast carcinoma amplified sequence (BCAS1). This is the first evidence of a quantitative trait locus with a significant effect on estrogen.

Aging↗
PubMed2001

The effect of pedigree complexity on quantitative trait linkage analysis.

Due to the computational difficulties of performing linkage analysis on large complex pedigrees, most investigators resort to simplifying such pedigrees by some ad hoc strategy. In this paper, we suggest an analytical method to compare the power of various pedigree simplification schemes by using the asymptotic distribution of the likelihood-ratio statistic. We applied the method to the large Hutterine pedigree. Our results indicate that the breaking and reduction of inbreeding loops can greatly diminish the power to localize quantitative trait loci. We also present an efficient Monte Carlo method for estimating identity-by-descent allele sharing in large complex pedigrees. This method is used to facilitate a linkage analysis of serum IgE levels in the Hutterites without simplifying the pedigree.

Adult↗
PubMed2001

Sodium-lithium countertransport activity is linked to chromosome 5 in baboons.

The genes involved in the regulation of cellular sodium transport characteristics, which are correlated with some forms of essential hypertension, have not yet been identified. We are studying the genes and environmental factors that affect red blood cell sodium-lithium countertransport (SLC) activity and intracellular sodium (ICNa) concentration in 634 baboons that comprise 11 pedigrees of 2 and 3 generations each. To detect and locate possible quantitative trait loci (QTLs) that affect SLC activity and ICNa concentration, we performed a genome screen by using a maximum likelihood-based variance-components linkage analysis program (SOLAR). SLC and ICNa phenotypes as well as genotypes on 281 microsatellite loci were available for all pedigreed animals. Both SLC and ICNa traits were highly heritable (residual heritability 0.593+/-0.083 [P<0.0001] and 0.739+/-0.082 [P<0.0001], respectively). We obtained evidence that a possible QTL for SLC activity is located on the baboon homologue of human chromosome 4 between D4S2456 and D4S2365 with a maximum multipoint lod score of 9.3 (P<10(-)(10)) near D4S1645. This QTL accounts for approximately two thirds of the total additive genetic variation in SLC activity in baboons. Although ICNa concentration was highly heritable, we found no evidence for linkage to a QTL with use of this methodology. Thus, we have evidence that a gene located on the baboon homologue of human chromosome 4 (baboon chromosome 5) affects cell sodium transport in baboons.

Animals↗
PubMed2001

Genetic contributions to plasma total antioxidant activity.

Oxidative stress plays important roles in a wide spectrum of pathological processes, such as atherosclerosis. Although several environmental factors are documented to influence redox metabolism, relatively little is known about genetic effects. In the present study, we evaluated genetic contributions to variation in plasma total antioxidant status (TAS), a measure of peroxyl-scavenging capacity, in 1337 members of 40 Mexican American families. TAS levels were significantly lower in women than in men (1.675+/-0.004 versus 1.805+/-0.005 mmol/L, respectively; P<0.001), and there was a significant decline of TAS levels with age in men but not in women (P<0.01 for the interaction). Quantitative genetic analysis indicated the heritability of TAS levels to be 0.509+/-0.052; ie, approximately 51% of the residual variance (after covariate adjustment) in TAS levels was due to the additive effects of genes (P<0.001). We have further observed a significant gene-by-smoking interaction (P<0.05). Additive genetic effects account for 83% of the residual phenotypic variance in TAS levels among smokers, but they account for only 49% in nonsmokers. However, genes contributing to TAS variation are the same in smokers and nonsmokers. Our study for the first time demonstrates that TAS, an indicator of redox homeostasis, is under strong genetic control, especially among smokers. With appropriate tools, such as genome screening, it should be possible to localize genes that regulate redox homeostasis and, ultimately, identify the DNA sequence variants predisposing subjects to oxidative damage.

Adolescent↗
PubMed2001

A quantitative trait locus influencing activin-to-estrogen ratio in pedigreed baboons maps to a region homologous to human chromosome 19.

Activin is a multifunctional hormone playing a major role in the regulation of reproduction and growth and development. We performed a genomewide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in the activin-to-estrogen ratio in baboons. A microsatellite polymorphism, D19S714, which maps to human chromosome 19p13.2, showed marginal evidence of linkage with a lod (log10 of the odds in favor of genetic linkage) score of 1.95 (0.014). This region contains several potential candidate genes including PKA (protein kinase, cAMP-dependent, catalytic alpha) and the gene pair JUN-B and JUN-D. This is the first evidence of a quantitative trait locus with a significant effect on the activin-to-estrogen ratio.

Activins↗
PubMed2000

A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms.

A first-generation genetic linkage map of the baboon (Papio hamadryas) genome was developed for use in biomedical and evolutionary genetics. Pedigreed baboons (n = 694) were selected from the breeding colony maintained by the Southwest Foundation for Biomedical Research. To facilitate comparison with the human genome, the baboon linkage map consists primarily of human microsatellite loci amplified using published human PCR primers. Genotypes for 325 human microsatellites and 6 novel baboon microsatellites were used in linkage analyses performed with the MultiMap expert system. The resulting sex-averaged meiotic recombination map covers all 20 baboon autosomes, with average spacing among loci of 7.2 cM. Direct comparison among homologous (orthologous) loci reveals that, for 7 human autosomes, locus order is conserved between humans and baboons. For the other 15 autosomes, one or more rearrangements distinguish the two genomes. The total centimorgan distances among homologous markers are 28.0% longer in the human genome than in the baboon, suggesting that rates of recombination may be higher in humans. This baboon linkage map is the first reported for any nonhuman primate species and creates opportunities for mapping quantitative trait loci in baboons, as well as for comparative evolutionary analyses of genome structure.

Animals↗