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Biomedical subjects

A G Comuzzie

Publications and source records attributed to A G Comuzzie.

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

The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with measures of obesity in Mexican Americans.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.

Adult↗
PubMed2000

Linkage exclusion analysis of the chromosome 11 region containing UCP2 and UCP3 with obesity-related phenotypes in Mexican Americans.

OBJECTIVE: To investigate whether the region of chromosome 11 (11q13) containing the genes UCP2 and UCP3 could be excluded for linkage with a variety of obesity-related phenotypes in humans. DESIGN: Exclusion mapping using a variance component approach in extended pedigrees. SUBJECTS: Four-hundred and fifty eight individuals (195 females, 263 males) distributed in 10 Mexican American families of probands randomly ascertained with respect to any disease state and who are participating in the San Antonio Family Heart Study. Ages range from 18 to 87 (mean age 35 y). MEASUREMENTS: Serum leptin levels, fat mass (FM), body mass index (BMI), and waist circumference. RESULTS: We were able to exclude the chromosomal region containing UCP2/UCP3 as having an effect on this set of obesity-related phenotypes at relative effect sizes of 10% or greater (P-values<0.05). CONCLUSIONS: These results suggest that variation in these genes is unlikely to have a substantial effect on the expression of obesity-related phenotypes in the Mexican American population.

Adolescent↗
PubMed2000

Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans.

Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genome-wide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p approximately 109 cM from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from pter. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include GBE1 and ACOX2, which encode enzymes involved in glycogen and fatty acid metabolism, respectively.

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

Correcting for ascertainment bias in the COGA data set.

The effects of several corrections for ascertainment bias on a linkage result in the COGA data are examined. A correction that models the complete ascertainment protocol markedly reduces the evidence for linkage. Different partial corrections increase the linkage signal and recover good estimates of the population trait prevalence, but do not represent adequately the complexity of the COGA ascertainment scheme. Evidently the present size of the COGA data set cannot support a complete correction for ascertainment bias, but an effective partial correction can and should be implemented.

Alcoholism↗
PubMed1999

Relationship of low-density lipoprotein particle size and measures of adiposity.

OBJECTIVE: To determine if obesity measures are related to measures of low-density lipoprotein (LDL) size and LDL subfractions in a population of Mexican-Americans with high prevalence of obesity. METHODS: LDL size phenotypes, based on nondenaturing gradient gel electrophoresis and staining for cholesterol (using Sudan black B), were determined for 313 unrelated Mexican-American participants in the San Antonio Family Heart Study. LDL size measures included predominant particle diameter, median diameter (particle diameter, where half the LDL absorbance is on larger and half on smaller LDLs) and cholesterol level in various LDL subfractions. Adiposity traits included two measures of general body fatness (body-mass index (BMI) and fat mass determined with bioimpedance) and three measures of regional fat deposition (waist-to-hip ratio (WHR), waist circumference and subscapular-triceps skinfold ratio (STR)). RESULTS: Gender and diabetes were significantly associated with most LDL size measures. In addition, BMI, WHR, waist circumference and STR were significantly (P<0.05) associated with several LDL size measures. Stepwise regression analysis (including adjustment for age, gender and diabetes status) showed that in every case, the strongest adiposity correlate of LDL size, was WHR, which reflects deposition of visceral fat. If triglyceride (TG) concentration was also included in the models, no fat measure was independently correlated with LDL size, suggesting that elevation of TG, associated with increased adiposity, was more directly correlated with LDL size. Supporting this interpretation, we found that WHR was also the strongest correlate of TG among adiposity measures. Regression analysis of the LDL particle size cholesterol profile expressed in 0.1 nm increments revealed a positive correlation of WHR and LDLs in the interval 25.9-26.3 nm (P < 0.05) and a negative correlation of BMI with LDLs in the interval 27.3-28.1 nm (P < 0.05). CONCLUSION: These results suggest that different adiposity measures, reflecting different aspects of fat deposition, are related to specific LDL size intervals. We speculate that increased deposition of fat, particularly visceral fat, is associated with increased TG, which in turn is associated with decreases in LDL particle size.

Adipose Tissue↗
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

A quantitative trait locus influencing BMI maps to the region of the beta-3 adrenergic receptor.

The beta-3 adrenergic receptor (ADRB3) has been implicated as a regulator of energy expenditure, and a polymorphism in codon 64 of this gene (Trp64Arg) has been associated in some studies with obesity and insulin resistance. However, many studies have failed to detect an effect of this variant, and the importance of the Trp64Arg variant in human obesity remains controversial. We performed a quantitative linkage analysis of the ADRB3 and obesity, using 12 markers (including the intragenic Trp64Arg polymorphism) spanning a 57-cM region of chromosome 8. The study population consisted of 470 individuals from 10 large multigenerational families of Mexican-American ancestry residing in San Antonio, TX. In two-point analysis, logarithm of odds (LOD) scores >1.0 were observed for six markers surrounding ADRB3 in a 33-cM region spanned by markers D8S1477 and D8S1136. The multipoint LOD score was 3.21, occurring between markers D8S1121 and ADRB3, approximately 2-3 cM from ADRB3. Adjusting for the presence of the Arg64 allele or excluding from the analysis the 11 individuals homozygous for the Arg64 allele did not reduce the evidence for linkage. A genome scan was conducted at 10 cM map density to detect other loci influencing variation in BMI. Multipoint LOD scores >1.0 were observed in four other regions, including two on chromosome 17, one on chromosome 6q, and one on chromosome 2p. These data suggest that the ADRB3 should continue to be regarded as a strong candidate gene for obesity even though evidence for an effect of the Trp64Arg polymorphism could not be established. It is also possible that a gene closely linked to ADRB3 may influence susceptibility to obesity.

Adult↗
PubMed1998

Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic "passenger leukocytes" harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.

Adult↗
PubMed1998

The search for human obesity genes.

Understanding of the genetic influences on obesity has increased at a tremendous rate in recent years. By some estimates, 40 to 70 percent of the variation in obesity-related phenotypes in humans is heritable. Although several single-gene mutations have been shown to cause obesity in animal models, the situation in humans is considerably more complex. The most common forms of human obesity arise from the interactions of multiple genes, environmental factors, and behavior, and this complex etiology makes the search for obesity genes especially challenging. This article discusses the strategies currently being used to search for human obesity genes and recent promising results from these efforts.

Animals↗
PubMed1998

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Adult↗
PubMed1997

Characterization of new simian foamy viruses from African nonhuman primates.

Simian foamy viruses (SFV) are exogenous retroviruses present in most if not all nonhuman primate species. Baboons and other African monkey species are known to harbor SFVs, yet there is presently no data in regard to their genetic relationship. Here we studied SFVs from baboons as compared to other SFVs isolated from a Hamlyn's guenon, a patas monkey, and a vervet. By Western blot analysis, the gag precursor proteins (p74/p70) were detected from all SFVs. In addition, the envelope glycoproteins from a vervet isolate (SFV-Agm2) were comparable in size to the env precursor gp130, the exterior glycoprotein (gp70), and the transmembrane protein (gp48) as detected by lentil lectin binding and radioimmunoprecipitation (RIPA). Molecular comparison of PCR amplified products from pol and LTR regions of each SFV demonstrated a close relationship among baboon SFVs while SFVs from patas, Hamlyn's guenon, and vervet clustered together. The baboon viruses only varied by 4% among each other in the LTR region; however, as much as 26% variation was noted when compared to the other African monkey SFVs. To determine the prevalence rate of SFV-Bab in our baboon colony, we employed both Western blotting and PCR analysis. Antibodies to SFV gag precursor proteins were seen in 7 of 10 infants; however, none were positive by PCR, suggesting that these infants were virus negative and that their antibodies were maternal in origin. Only one juvenile (1/10) and all adults (38/38) were infected with SFV. Taken together these results suggest that SFVs have arisen and diverged along with the evolution of their natural hosts. Furthermore, the high prevalence rates to SFV seen in adult baboons strongly suggest a sexual or oral routes of transmission.

Africa↗
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↗