Biomedical subjects

A G Comuzzie

Publications and source records attributed to A G Comuzzie.

At least 19 recordsLinked to original sources

PubMed2006

Linkage analysis of circulating levels of adiponectin in Hispanic children.

INTRODUCTION: Adiponectin, a hormone produced exclusively by adipose tissue, is inversely associated with insulin resistance and proinflammatory conditions. The aim of this study was to find quantitative trait loci (QTLs) that affect circulating levels of adiponectin in Hispanic children participating in the VIVA LA FAMILIA Study by use of a systematic genome scan. METHODS: The present study included extended families with at least one overweight child between 4 and 19 years old. Overweight was defined as body mass index (BMI) 95th percentile. Fasting blood was collected from 466 children from 127 families. Adiponectin was assayed by radioimmunoassay (RIA) technique in fasting serum. A genome-wide scan on circulating levels of adiponectin as a quantitative phenotype was conducted using the variance decomposition approach. RESULTS: The highest logarithm of odds (LOD) score (4.2) was found on chromosome 11q23.2-11q24.2, and a second significant signal (LOD score=3.0) was found on chromosome 8q12.1-8q21.3. In addition, a signal suggestive of linkage (LOD score=2.5) was found between 18q21.3 and 18q22.3. After adjustment for BMI-Z score, the LOD score on chromosome 11 remained unchanged, but the signals on chromosomes 8 and 18 dropped to 1.6 and 1.7, respectively. Two other signals suggestive of linkage were found on chromosome 3 (LOD score=2.1) and 10 (LOD score=2.5). Although the region on chromosome 11 has been associated with obesity and diabetes-related traits in adult populations, this is the first observation of linkage in this region for adiponectin levels. Our suggestive linkages on chromosomes 10 and 3 replicate results for adiponectin seen in other populations. The influence of loci on chromosomes 18 and 8 on circulating adiponectin seemed to be mediated by BMI in the present study. CONCLUSION: Our genome scan in children has identified a novel QTL and replicated QTLs in chromosomal regions previously shown to be linked with obesity and type 2 diabetes (T2D)-related phenotypes in adults. The genetic contribution of loci to adiponectin levels may vary across different populations and age groups. The strong linkage signal on chromosome 11 is most likely underlain by a gene(s) that may contribute to the high susceptibility of these Hispanic children to obesity and T2D.

Adiponectin↗

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↗

PubMed2005

Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p.

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).

Adult↗

PubMed2003

Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes project.

RATIONALE: Recently, we identified a genotype-by-smoking status interaction with serum leptin levels in a sample of Mexican Americans. However, it is unknown whether this phenomenon occurs in other populations as well. OBJECTIVE: The goal of this study was to examine the genetic architecture of the response to smoking in leptin levels using data from Midwestern Caucasian subjects participating in the Metabolic Risk Complications of Obesity Genes project. METHODS: We employed a variance decomposition analysis using maximum likelihood methods to model genotype-by-smoking interactions for leptin levels and examined the impact of the exclusion of smokers in a subsequent linkage analysis. RESULTS: We found significant evidence (p-value=0.027) for a genotype-by-smoking status interaction for serum leptin levels. In the subsequent linkage analysis with smokers excluded, we obtained a maximum LOD score of 3.4 (P=0.00004) near D8S1128. CONCLUSIONS: These results suggest that a QTL on chromosome 8 may have a differential effect on the expression of leptin in smokers vs nonsmokers, as first identified in Mexican Americans.

Analysis of Variance↗

PubMed2003

Genetics of leptin expression in baboons.

OBJECTIVE: Leptin gene expression is higher in females than in males, and is regulated by many factors including energy intake and insulin, but little is known about the inheritance of leptin gene expression. We have investigated leptin (LEP) gene express-ion, to determine whether it is heritable, and whether the difference in LEP expression between males and females has a genetic component. STUDY POPULATION: A total of 319 baboons (Papio hamadryas) (220 females, 99 males) from a captive, pedigreed colony. MEASUREMENTS AND METHODS: We cloned a baboon LEP cDNA, and quantified LEP mRNA expression in baboon omental adipose tissue using a ribonuclease protection assay. In addition, we assayed circulating leptin levels, adipocyte cell volume, and weight. We used maximum likelihood-based variance decomposition methods to determine the genetic architecture of LEP levels, including testing for genotype-by-sex interaction. RESULTS: Omental LEP mRNA expression was significantly and positively correlated with weight and adipocyte cell volume in baboons. Both mRNA and plasma levels of leptin were higher in females than in males, and both measures were heritable. The results of our genetic analysis show that there was a genotype-by-sex interaction in the levels of plasma leptin, but not in omental LEP mRNA. CONCLUSIONS: As in humans, baboon leptin mRNA and protein levels are expressed at a higher level in females than in males. We detected evidence that the plasma levels were affected by genes that are differentially expressed in males and females, while the omental mRNA levels were not. This finding suggests that the genes that differentially regulate plasma leptin levels between males and females may exert their effects on post-transcriptional processes.

Amino Acid Sequence↗

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

Genetic and environmental correlations between various anthropometric and blood pressure traits among adult Samoans.

Shared polygenic effects (i.e., pleiotropy) are assumed to exist for such obesity-related phenotypes as blood pressure and adiposity. It is possible to identify these shared genetic effects through bivariate genetic analyses. This analysis of 1,342 adult Samoans, across 801 pedigrees, indicates that significant heritable components (P < 0.05) ranging from 29-58% exist for weight, height, systolic blood pressure, diastolic blood pressure, triceps skinfold, subscapular skinfold, body mass index, and sum of skinfolds. In general, the anthropometric measurements share additive genetic effects, as do the anthropometric measures, with blood pressure. Heritabilities for central fat distribution are not significant in this population, which could be due to a lack of power. On the other hand, heritabilities have been found in Hispanics; hence the genes responsible for central fat distribution may not be evenly distributed among populations.

Adult↗

PubMed2001

The utility of Bayesian model averaging for detecting known oligogenic effects.

In this paper we examine the utility of the Bayesian model averaging approach proposed by Blangero et al. [Genet Epidemiol 17(Suppl. 1):S67-72, 1999] for the detection of known oligogenic effects on quantitative trait 1 (Q1) in the simulated Genetic Analysis Workshop 12 data. The results were consistent with the underlying genetic model: two major QTLs were identified on chromosomes 19 and 2, with heritabilities of 17% and 20%, respectively, located near the position of major genes 1 and 2.

Analysis of Variance↗

PubMed2001

Distribution of lod scores in oligogenic linkage analysis.

In variance component oligogenic linkage analysis it can happen that the residual additive genetic variance bounds to zero when estimating the effect of the ith quantitative trait locus. Using quantitative trait Q1 from the Genetic Analysis Workshop 12 simulated general population data, we compare the observed lod scores from oligogenic linkage analysis with the empirical lod score distribution under a null model of no linkage. We find that zero residual additive genetic variance in the null model alters the usual distribution of the likelihood-ratio statistic.

Chromosome Mapping↗

PubMed2001

Searching for genes underlying normal variation in human adiposity.

A primary challenge in biomedical research today is the elucidation of the underlying genetic architecture of complex conditions such as obesity. In contrast to simple Mendelian disorders that result from a mutation in a single gene, complex phenotypes are the product of the action (as well as interaction) of multiple genes and environmental factors. The genetic configuration of these genes can range from effectively polygenic (i.e., many genes each with a relatively small contribution) to oligogenic (i.e., a few genes with relatively large measurable effects often expressed on a residual additive genetic background). While the task at hand is complicated, it is not intractable; however, it does require consideration of the nature of the disease and definition of its associated phenotypes in selecting the most appropriate study design. Here we will discuss the characteristics of obesity and its related phenotypes, which must be considered in designing analyses to identify the genes involved as well as reviewing what these approaches have provided in the search for genes influencing adiposity in humans

Body Mass Index↗

PubMed2001

The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans.

OBJECTIVE: To examine the role of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and the beta 3-adrenergic receptor gene locus in obesity-related traits in African Americans. SUBJECTS: A total of 687 individuals representing 193 African American families who were residents of metropolitan Chicago. MEASUREMENTS: Genotyping of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and three microsatellite markers flanking the beta 3-adrenergic receptor gene (ADRB3) locus and measuring various obesity-related traits, including body mass index (BMI), fat-free mass, fat mass, percentage fat mass, waist circumference and serum lipid levels. RESULTS: The prevalence of obesity (defined as body mass index > or = 30 kg/m(2)) in the population was 27.3% and 51.2% in men and women, respectively. The frequency of the Arg64 allele was 10.0%. Multivariate regression analyses confirmed the existence of a significant contribution of familial variance to each of the five obesity-related traits noted above. Likelihood ratio statistics computed in a multivariate regression analysis failed to demonstrate a significant association between the Arg64 allele and any of the five obesity-related traits. Single and multipoint analyses using extended Haseman--Elston regression analyses failed to demonstrate suggestive evidence of linkage of three microsatellite markers that flank the beta 3-adrenergic receptor gene to BMI, percentage body fat, waist circumference or serum leptin levels. CONCLUSION: Given the contribution of familial variance to obesity-related traits in this population, neither the null finding for the Arg64 allele nor the lack of evidence of linkage of the ADRB3 locus to obesity-related traits could be attributed to lack of transmissibility of the traits suggesting that neither the Arg64 variant of the beta 3-adrenergic receptor gene nor another genetic variant in or near the ADRB3 locus contribute significantly to familial aggregation of obesity-related traits in African Americans. International Journal of Obesity (2001) 25, 54-60

Adipose Tissue↗

PubMed2001

Heritability of obesity-related traits among Nigerians, Jamaicans and US black people.

OBJECTIVE: The mean values for anthropometric traits vary across population groups and this variation is clearly determined for the most part by the environment. The familiarity of anthropometric traits also varies in reports from different populations, although this variation has not been shown to follow a consistent pattern. To examine whether heritability is influenced by socio-cultural factors, we conducted a cross-cultural study of populations of the African diaspora. PARTICIPANTS: Data were collected on 1868 family members from Nigeria, 623 from Jamaica and 2132 from metropolitan Chicago, IL, USA. MEASUREMENTS: Height and weight were measured and body mass index (kg/m(2)) calculated. Fat-free mass, fat mass and percentage body fat were estimated using bioelectrical impedance analysis. Plasma leptin concentrations were also measured. The proportion of variance attributable to additive genetic and non-shared environmental components was estimated with the maximum likelihood variance decomposition method. RESULTS: Mean values for all anthropometric traits increased along the socio-cultural gradient, and obesity increased from 5% in Nigeria to 23% in Jamaica and 39% in the USA. Within populations the relationships among traits both within individuals and within families were highly consistent. Heritability estimates for weight, body mass index, fat mass and percentage body fat were approximately 50% for all groups. Heritability for height was lower in Nigeria (62%) than in Jamaica (74%) or the US (87%). CONCLUSION: The familial patterns of body size and energy storage appear to be consistent in these genetically related populations across a wide range of environmental conditions.

Adult↗

PubMed2001

Familial resemblance of body composition in prepubertal girls and their biological parents.

BACKGROUND: Heritability estimates for body mass index (BMI; in kg/m(2)) in children generally have been derived from twin and adoption studies. However, BMI does not reflect total or regional body composition. OBJECTIVE: We evaluated the familial resemblance of body composition between prepubertal girls of normal weight and body fatness and their parents by using state-of-the-art technology. DESIGN: The subjects were 101 girls [mean age: 8.5 +/- 0.4 y; percentage body fat (%BF): 12-30%] and their biological parents. Weight, height, and body composition [fat mass (FM), fat-free mass (FFM), and %BF] were measured with dual-energy X-ray absorptiometry (DXA) and total body potassium (TBK). RESULTS: Weight, height, and BMI showed low-to-moderate similarity between the girls and both their parents (r = 0.29-0.44, P < 0.01). The girls' FM, FFM, and %BF were significantly related to both parents' body composition. Cross-generational equations were developed for DXA, eg, child's %BF = 12.4 + (0.158 paternal %BF) + (0.145 maternal %BF) (adjusted r(2) = 0.16, P < 0.001). Regional analysis with DXA showed that the adjusted r(2) values for the arm, trunk, and leg regions, respectively, were 0.17, 0.33, and 0.31 for lean tissue mass and 0.11, 0.14, and 0.09 for FM. TBK showed a similar relation between parents and girls (r = 0.28-0.47, P < 0.01). Significant heritability (h(2) +/- SE) was detected for BMI (0.35 +/- 0.17, P = 0.03) and %BF measured with DXA (0.50 +/- 0.12, P = 0.0001). CONCLUSION: The body composition of prepubertal girls of normal weight and body fatness is significantly related to the body composition of both biological parents.

Absorptiometry, Photon↗

PubMed2001

Genetic control of coordinated changes in HDL and LDL size phenotypes.

We investigated the correlation of high density lipoprotein (HDL) and low density lipoprotein (LDL) particle size distributions in samples from >1100 participants in the San Antonio Family Heart Study. By use of analyses of individual correlations of each HDL fraction with each LDL fraction, we devised new metrics for particle size phenotype, termed DeltaHDL and DeltaLDL, to optimally reflect the size correlations. Confirming previous studies, we found that the 2 size phenotype variables were positively correlated (r=0.51). Quantitative genetic analysis indicated that nearly half (44%) of the variance in DeltaHDL and in DeltaLDL was explained by the additive effects of genes. Bivariate genetic analyses indicated that a positive genetic correlation (rho(G)=0.56) exists between them and suggested that the pleiotropic effects of a gene or group of genes account for approximately 31% [ie, rho(G)(2) =(0.56)(2)=0.31] of the genetic variance in the 2 traits. Triglyceride (TG) levels were negatively related to DeltaHDL and DeltaLDL, with phenotypic correlations of -0.48 and -0.58, respectively, and genetic correlations of -0.45 and -0.76, respectively, suggesting that genes exert significant pleiotropic effects on the covariation of TGs with each of the size variables. Finally, we evaluated a bivariate model for DeltaHDL and DeltaLDL in which TG level was included as a covariate. This analysis indicated that a small but significant genetic correlation remains for DeltaHDL and DeltaLDL, even after accounting for the effects of TGs. Thus, our study demonstrates that the phenotypic correlation of HDL and LDL sizes results in part from the pleiotropic actions of a set of genes, some of which also influence TG levels and some of which do not.

Coronary Disease↗

PubMed2001

The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome.

Here we present the first genetic analysis of adiponectin levels, a newly identified adipocyte-derived protein. Recent work has suggested that adiponectin may play a role in mediating the effects of body weight as a risk factor for coronary artery disease. For this analysis we assayed serum levels of adiponectin in 1100 adults of predominantly northern European ancestry distributed across 170 families. Quantitative genetic analysis of adiponectin levels detected an additive genetic heritability of 46%. The maximum LOD score detected in a genome wide scan for adiponectin levels was 4.06 (P = 7.7 x 10(-6)), 35 cM from pter on chromosome 5. The second largest LOD score (LOD = 3.2; P = 6.2 x 10(-5)) was detected on chromosome 14, 29 cM from pter. The detection of a significant linkage with a quantitative trait locus on chromosome 5 provides strong evidence for a replication of a previously reported quantitative trait locus for obesity-related phenotypes. In addition, several secondary signals offer potential evidence of replications for additional previously reported obesity-related quantitative trait loci on chromosomes 2 and 10. Not only do these results identify quantitative trait loci with significant effects on a newly described, and potentially very important, adipocyte-derived protein, they also reveal the emergence of a consistent pattern of linkage results for obesity-related traits across a number of human populations.

Adiponectin↗

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

Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.

Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod = 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome.

Blood Glucose↗

PubMed2000

Association among 5-year changes in weight, physical activity, and cardiovascular disease risk factors in Mexican Americans.

Recent changes in lifestyle have led to a global epidemic of obesity. To determine the associations of these changes with cardiovascular disease (CVD) risk, the authors correlated changes in CVD risk factors with changes in weight and physical activity in a population-based sample of 539 Mexican Americans in the San Antonio Heart Study in 1992-1999 who were examined twice approximately 5 years apart. Average weight change during that interval was 2.7 kg. While change in physical activity (expressed as percent change) was associated modestly only with change in low density lipoprotein cholesterol median diameter (p = 0.017), weight change was strongly and positively associated with unfavorable changes in lipid and lipoprotein traits, insulin levels, and blood pressure, explaining 2-10% of the variation in the risk factor changes during the interval. The unfavorable associations with weight gain tended to be more pronounced in lean compared with obese individuals and in men compared with women. However, the associations were significant for most CVD risk factors in all groups. In Mexican Americans, a population at high risk for obesity, weight change was positively correlated with metabolic variables associated with risk of CVD. Therefore, increasing adiposity in this population may tend to slow, or even reverse, the decline in CVD morbidity and mortality.

Adult↗