103 results on '"Ahmed H. Kissebah"'
Search Results
2. Genetic determinants of obesity-related lipid traits
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Gabriele E. Sonnenberg, Glenn R. Krakower, Lisa J. Martin, Michael Olivier, Anne E. Kwitek, Anthony G. Comuzzie, John Blangero, and Ahmed H. Kissebah
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linkage analysis ,triglycerides ,obesity ,lipid profiles ,high density lipoprotein cholesterol ,Biochemistry ,QD415-436 - Abstract
In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol.These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.
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- 2004
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3. Correction: Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
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M. Geoffrey Hayes, Margrit Urbanek, David A. Ehrmann, Loren L. Armstrong, Ji Young Lee, Ryan Sisk, Tugce Karaderi, Thomas M. Barber, Mark I. McCarthy, Stephen Franks, Cecilia M. Lindgren, Corrine K. Welt, Evanthia Diamanti-Kandarakis, Dimitrios Panidis, Mark O. Goodarzi, Ricardo Azziz, Yi Zhang, Roland G. James, Michael Olivier, Ahmed H. Kissebah, Reproductive Medicine Network, Elisabet Stener-Victorin, Richard S. Legro, and Andrea Dunaif
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Science - Abstract
Nature Communications 6: Article number: 7502 (2015); Published: 18 August 2015; Updated: 12 February 2016 In the original version of this Article the genetic locus 8p23.1 was incorrectly referred to as 8p32.1 throughout. For example, in the Abstract, the sentence beginning ‘Three loci reach genome-wide significance in the case-control meta-analysis…' originally read ‘Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.
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- 2016
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4. Publisher Correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
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Ryan Sisk, Margrit Urbanek, Roland James, M G Hayes, Corrine K. Welt, Richard S. Legro, Thomas M. Barber, Cecilia M. Lindgren, Mark O. Goodarzi, Yi Zhang, Elisabet Stener-Victorin, Joongoo Lee, David A. Ehrmann, Andrea Dunaif, Michael Olivier, Ahmed H. Kissebah, Mark I. McCarthy, Evanthia Diamanti-Kandarakis, Ricardo Azziz, Tugce Karaderi, Loren L. Armstrong, Dimitrios Panidis, Stephen Franks, and MRC
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Adult ,medicine.medical_specialty ,Adolescent ,Science ,Quantitative Trait Loci ,General Physics and Astronomy ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,White People ,Article ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,Internal medicine ,medicine ,Humans ,lcsh:Science ,Reproductive Medicine Network ,Multidisciplinary ,General Chemistry ,Middle Aged ,Publisher Correction ,Polycystic ovary ,Gonadotropin secretion ,Endocrinology ,Gene Expression Regulation ,Case-Control Studies ,lcsh:Q ,Female ,Genome-Wide Association Study ,Polycystic Ovary Syndrome - Abstract
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case–control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis., Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.
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- 2020
5. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
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Xiuqing Guo, Jack W. Kent, Xinggang Liu, Wolfram Goessling, Alexander W. Drong, Lawrence F. Bielak, Jerome I. Rotter, René Laqua, Kurt Lohman, Juan M. Peralta, Nancy L. Heard-Costa, Henry Völzke, Matthias Nauck, Tamara B. Harris, Matthew A. Allison, Carl D. Langefeld, Braxton D. Mitchell, Audrey Y. Chu, Jie Yao, John D. Eicher, J. Jeffrey Carr, V. Gudnason, Georg Homuth, Henri Wallaschofski, Bradford Towne, Thomas H. Mosley, Anubha Mahajan, Ahmed H. Kissebah, Andrew P. Morris, Sharon L.R. Kardia, Lenore J. Launer, Patricia A. Peyser, Virginia Fisher, Nele Friedrich, Mary F. Feitosa, Stefan A. Czerwinski, Joel Kullberg, Erik Ingelsson, Thomas D. Dyer, Yi Zhang, Olivia Weeks, Jeffrey R. O'Connell, James G. Terry, James G. Wilson, Ingrid B. Borecki, Cecilia M. Lindgren, Matthew L. Steinhauser, Lars Lind, Yang Zhang, Albert V. Smith, Yongmei Liu, Alan R. Shuldiner, John Blangero, Jingzhong Ding, L. Adrienne Cupples, Caroline S. Fox, Ankita Parihar, Xuan Deng, Lingyi Lu, Donald W. Bowden, Mary K. Wojczynski, Audrey C. Choh, Michael Olivier, Tim Kacprowski, Ching-Ti Liu, Andrew D. Johnson, Leslie A. Lange, and Qing Duan
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Male ,0301 basic medicine ,Adipose tissue ,Genome-wide association study ,Type 2 diabetes ,Inbred C57BL ,Medical and Health Sciences ,Cohort Studies ,Mice ,chemistry.chemical_compound ,Adipocyte ,Ethnicity ,Adipocytes ,Body Fat Distribution ,2.1 Biological and endogenous factors ,610 Medicine & health ,Genetics ,Cell Differentiation ,Single Nucleotide ,Biological Sciences ,Phenotype ,Adipogenesis ,Medical genetics ,Female ,Genetic Markers ,medicine.medical_specialty ,Ethnic Groups ,Biology ,Metabolic and Endocrine ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Obesity ,Polymorphism ,Nutrition ,Human Genome ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Genetic Loci ,Genome-Wide Association Study ,Developmental Biology - Abstract
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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- 2017
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6. A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions
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Lili Ding, Michael Olivier, Xue Zhang, D. Woodrow Benson, Ahmed H. Kissebah, and Lisa J. Martin
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Linkage (software) ,Genetics ,Models, Genetic ,Quantitative Trait Loci ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,symbols.namesake ,Genetic linkage ,False positive paradox ,Mendelian inheritance ,symbols ,Humans ,Computer Simulation ,Lod Score ,Association mapping ,Algorithms ,Genetics (clinical) ,Genome-Wide Association Study ,Genetic association - Abstract
The Human Genome Project was expected to individualize medicine by rapidly advancing knowledge of common complex disease through discovery of disease-causing genetic variants. However, this has proved challenging. Although linkage analysis has identified replicated chromosomal regions, subsequent detection of causal variants for complex traits has been limited. One explanation for this difficulty is that utilization of association to follow up linkage is problematic given that linkage and association are not required to co-occur. Indeed, co-occurrence is likely to occur only in special circumstances, such as Mendelian inheritance, but cannot be universally expected. To overcome this problem, we propose a novel method, the Variant Impact On Linkage Effect Test (VIOLET), which differs from other quantitative methods in that it is designed to follow up linkage by identifying variants that influence the variance explained by a quantitative trait locus. VIOLET's performance was compared with measured genotype and combined linkage association in two data sets with quantitative traits. Using simulated data, VIOLET had high power to detect the causal variant and reduced false positives compared with standard methods. Using real data, VIOLET identified a single variant, which explained 24% of linkage; this variant exhibited only nominal association (P=0.04) using measured genotype and was not identified by combined linkage association. These results demonstrate that VIOLET is highly specific while retaining low false-negative results. In summary, VIOLET overcomes a barrier to gene discovery and thus may be broadly applicable to identify underlying genetic etiology for traits exhibiting linkage.
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- 2013
7. QTL-based association analyses reveal novel genes influencing pleiotropy of metabolic syndrome (MetS)
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Omar Ali, Melanie A. Carless, Ulrich Broeckel, Joanne E. Curran, John Blangero, Ahmed H. Kissebah, Michael Olivier, R. M. Abdou, JW Kent, David L. Rainwater, Anthony G. Comuzzie, Yi Zhang, Harald H H Göring, and Thomas D. Dyer
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Genetics ,0303 health sciences ,Candidate gene ,Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Single-nucleotide polymorphism ,Quantitative trait locus ,Biology ,Phenotype ,3. Good health ,Gene expression profiling ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pleiotropy ,Genetic linkage ,SNP ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Objective: Metabolic Syndrome (MetS) is a phenotype cluster predisposing to type 2 diabetes and cardiovascular disease. We conducted a study to elucidate the genetic basis underlying linkage signals for multiple representative traits of MetS that we had previously identified at two significant QTLs on chromosomes 3q27 and 17p12. Design and Methods: We performed QTL-specific genomic and transcriptomic analyses in 1,137 individuals from 85 extended families that contributed to the original linkage. We tested in SOLAR association of MetS phenotypes with QTL-specific haplotype-tagging SNPs as well as transcriptional profiles of peripheral blood mononuclear cells (PBMCs). Results: SNPs significantly associated with MetS phenotypes under the prior hypothesis of linkage mapped to seven genes at 3q27 and seven at 17p12. Prioritization based on biologic relevance, SNP association, and expression analyses identified two genes: insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at 3q27 and tumor necrosis factor receptor 13B (TNFRSF13B) at 17p12. Prioritized genes could influence cell-cell adhesion and adipocyte differentiation, insulin/glucose responsiveness, cytokine effectiveness, plasma lipid levels, and lipoprotein densities. Conclusions: Using an approach combining genomic, transcriptomic, and bioinformatic data we identified novel candidate genes for MetS.
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- 2013
8. Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
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M. Geoffrey Hayes, Margrit Urbanek, David A. Ehrmann, Loren L. Armstrong, Ji Young Lee, Ryan Sisk, Tugce Karaderi, Thomas M. Barber, Mark I. McCarthy, Stephen Franks, Cecilia M. Lindgren, Corrine K. Welt, Evanthia Diamanti-Kandarakis, Dimitrios Panidis, Mark O. Goodarzi, Ricardo Azziz, Yi Zhang, Roland G. James, Michael Olivier, Ahmed H. Kissebah, Reproductive Medicine Network, Elisabet Stener-Victorin, Richard S. Legro, and Andrea Dunaif
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Multidisciplinary ,Science ,General Physics and Astronomy ,General Chemistry ,Corrigenda ,General Biochemistry, Genetics and Molecular Biology - Abstract
Nature Communications 6: Article number: 7502 (2015); Published: 18 August 2015; Updated: 12 February 2016 In the original version of this Article the genetic locus 8p23.1 was incorrectly referred to as 8p32.1 throughout. For example, in the Abstract, the sentence beginning ‘Three loci reach genome-wide significance in the case-control meta-analysis…' originally read ‘Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.
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- 2016
9. Genetic Variation in the Peroxisome Proliferator Activated Receptor-Gamma Gene Is Associated with Histologically Advanced NAFLD
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Ahmed H. Kissebah, James R. Wallace, Samer Gawrieh, Michael Charlton, Carl D. Langefeld, Miranda C. Marion, Michael Olivier, and Richard A. Komorowski
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Adult ,Male ,Candidate gene ,Peroxisome proliferator-activated receptor gamma ,Genotype ,Physiology ,Peroxisome proliferator-activated receptor ,Biology ,Polymorphism, Single Nucleotide ,chemistry.chemical_compound ,Gene Frequency ,Non-alcoholic Fatty Liver Disease ,Adipocyte ,medicine ,Humans ,chemistry.chemical_classification ,Fatty liver ,Gastroenterology ,nutritional and metabolic diseases ,Lipid metabolism ,Middle Aged ,medicine.disease ,Fatty Liver ,PPAR gamma ,Haplotypes ,Liver ,chemistry ,Nuclear receptor ,Biochemistry ,Cancer research ,Female ,Peroxisome proliferator-activated receptor alpha - Abstract
The peroxisome proliferator activated receptor-gamma (PPARG) is a nuclear receptor that regulates adipocyte differentiation, insulin sensitivity and lipid metabolism, thus, it represents a good candidate gene for non-alcoholic fatty liver disease (NAFLD).We investigated the association of two PPARG variants (Pro12Ala and C1431T) with NAFLD and its histological features. DNA was extracted from 274 archived, formalin-fixed liver biopsy specimens from 212 patients with NAFLD and 62 controls with normal liver histology.Individual SNPs did not show significant association with NAFLD or its histological features. A haplotype comprised of both minor alleles (GT) was less enriched whereas a haplotype comprised of the two major alleles (CC) was more enriched in subjects with NAFLD compared to controls [9.3% vs. 28.1% for GT (P = 0.001, OR 0.26 (range 0.14-0.48) and 80.4% vs. 64.8% for CC (P = 0.037, OR 2.23 (range 1.30-3.81)]. Both haplotypes were significantly associated with steatosis and fibrosis. The GT haplotype was also associated with lobular inflammation.Genetic variation in PPARG is associated with NAFLD, and the GT haplotype is associated with inflammatory and fibrotic changes that denote histologically advanced NAFLD.
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- 2011
10. Hepatic Gene Networks in Morbidly Obese Patients With Nonalcoholic Fatty Liver Disease
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Samer Gawrieh, Joanne E. Curran, Bassem Makladi, Deborah A. Andris, John Blangero, Ahmed H. Kissebah, Richard A. Komorowski, Regina Cole, James R. Wallace, Tesfaye M. Baye, Thomas D. Dyer, David E. Kleiner, Jac Charlesworth, Michael Charlton, Michael Olivier, Russell A. Wilke, and Melanie A. Carless
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Comorbidity ,Bioinformatics ,digestive system ,Article ,White People ,Pathogenesis ,Diabetes mellitus genetics ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,Diabetes Mellitus ,medicine ,Humans ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Endoplasmic Reticulum Chaperone BiP ,Gene ,Nutrition and Dietetics ,business.industry ,Gene Expression Profiling ,Fatty liver ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Obesity ,digestive system diseases ,Obesity, Morbid ,Fatty Liver ,Gene expression profiling ,Liver ,Hypertension ,Female ,Surgery ,business - Abstract
BACKGROUND: Genetic factors alter the risk for nonalcoholic fatty liver disease (NAFLD). We sought to identify NAFLD-associated genes and elucidate gene networks and pathways involved in the pathogenesis of NAFLD. METHODS: Quantitative global hepatic gene expression analysis was performed on 53 morbidly obese Caucasian subjects undergoing bariatric surgery (27 with NAFLD and 26 controls). After standardization of data, gene expression profiles were compared between patients with NAFLD and controls. The set of genes that significantly correlated with NAFLD was further analyzed by hierarchical clustering and ingenuity pathways analyses. RESULTS: There were 25,643 quantitative transcripts, of which 108 were significantly associated with NAFLD (p
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- 2010
11. Integrated approach for the comprehensive characterization of lipoproteins from human plasma using FPLC and nano-HPLC-tandem mass spectrometry
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Michael Olivier, Ahmed H. Kissebah, Lisamarie A. Collins, and Shama P. Mirza
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Physiology ,Lipoproteins ,Fast protein liquid chromatography ,Biology ,Tandem mass spectrometry ,Mass spectrometry ,Proteomics ,High-performance liquid chromatography ,chemistry.chemical_compound ,High-density lipoprotein ,chemistry ,Biochemistry ,Tandem Mass Spectrometry ,Proteome ,Innovative Methodology ,Genetics ,Humans ,lipids (amino acids, peptides, and proteins) ,Chromatography, High Pressure Liquid ,Lipoprotein - Abstract
The implication of the various lipoprotein classes in the development of atherosclerotic cardiovascular disease has served to focus a great deal of attention on these particles over the past half-century. Using knowledge gained by the sequencing of the human genome, recent research efforts have been directed toward the elucidation of the proteomes of several lipoprotein subclasses. One of the challenges of such proteomic experimentation is the ability to initially isolate plasma lipoproteins subsequent to their analysis by mass spectrometry. Although several methods for the isolation of plasma lipoproteins are available, the most commonly utilized techniques require large sample volumes and may cause destruction and dissociation of lipoprotein particle-associated proteins. Fast protein liquid chromatography (FPLC) is a nondenaturing technique that has been validated for the isolation of plasma lipoproteins from relatively small sample volumes. In this study, we present the use of FPLC in conjunction with nano-HPLC-ESI-tandem mass spectrometry as a new integrated methodology suitable for the proteomic analysis of human lipoprotein fractions. Results from our analysis show that only 200 μl of human plasma suffices for the isolation of whole high density lipoprotein (HDL) and the identification of the majority of all known HDL-associated proteins using mass spectrometry of the resulting fractions.
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- 2010
12. Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent
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Yi Zhang, Ann DeLaForest, Gabriele E. Sonnenberg, Erin MacKinney, Russell A. Wilke, Jennifer Gunnell, Jack Littrell, Cecilia J. Hillard, Ahmed H. Kissebah, Tesfaye M. Baye, and Michael Olivier
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Male ,Candidate gene ,medicine.medical_specialty ,Genotype ,Quantitative Trait Loci ,Biology ,Polymorphism, Single Nucleotide ,White People ,Article ,Amidohydrolases ,Wisconsin ,Insulin resistance ,Fatty acid amide hydrolase ,Internal medicine ,Genetics ,medicine ,Humans ,Insulin ,Body Weights and Measures ,Obesity ,Genetic variability ,Dyslipidemias ,Pharmacology ,Lipid metabolism ,Glucose Tolerance Test ,Middle Aged ,Lipid Metabolism ,medicine.disease ,Endocannabinoid system ,Pedigree ,Europe ,Phenotype ,Endocrinology ,Molecular Medicine ,Female ,lipids (amino acids, peptides, and proteins) ,Metabolic syndrome ,Dyslipidemia - Abstract
A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. Aims: N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. Materials & methods: Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained for the FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). Results: A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. Conclusion: Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.
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- 2009
13. Relationship of Anthropometric Measurements of Body Fat Distribution to Metabolic Profile in Premenopausal Women
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Martha B. Lee, Charles R. Wilson, Magda M.I. Hennes, Alan N. Peiris, David J. Evans, and Ahmed H. Kissebah
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Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Insulin resistance ,Metabolic Diseases ,Classification of obesity ,Internal medicine ,Hyperlipidemia ,Internal Medicine ,medicine ,Hyperinsulinemia ,Humans ,Anthropometry ,business.industry ,Insulin ,nutritional and metabolic diseases ,medicine.disease ,Obesity ,Skinfold Thickness ,Blood pressure ,Endocrinology ,Adipose Tissue ,Regression Analysis ,Female ,Menopause ,business ,Forecasting - Abstract
Regional fat distribution has emerged as an independent predictor of metabolic aberrations including glucose intolerance, hyperinsulinemia, insulin resistance, hyperlipidemia and hypertension. We investigated the comparative efficacy of various body fat distribution indices in predicting these aberrations. The relationship of circumferential ratios, skinfold measurements, and computerized tomography (CT)-derived indices of intra- and extra-abdominal fat distribution to the metabolic variables and blood pressure was examined in a cohort of healthy premenopausal women. All indices denoting preponderance of fat in the central, upper body or abdominal region were predictive of the metabolic profile. The subscapular skinfold, subscapular-triceps ratio, waist-hip ratio (WHR), and the CT derived intra-abdominal fat area (CT-IFA) were closely related to alterations in glucose and insulin concentrations independent of age and obesity. The WHR and CT-IFA were better predictors of plasma triglyceride levels and blood pressure profile and thus the overall aberrations than skinfold measurements. Despite a high degree of intercorrelation between the anthropometric indices measured, only the relationship of WHR to CT-IFA remained significant after adjusting for the effects of age and degree of adiposity, suggesting that WHR indexes not only the relative distribution of truncal to gluteofemoral subcutaneous fat but also the abundance of intra-abdominal or visceral fat depots. The greater reproducibility of CT-IFA and WHR also suggests that these measurements are the most useful in predicting the regional obesity-associated metabolic abnormalities with their morbidity and mortality risks.
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- 2009
14. Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index
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Michael Olivier, Yi Zhang, Roland James, Cecilia J. Hillard, Ahmed H. Kissebah, Russell A. Wilke, Edward M. Smith, Joel B. Myklebust, Jennifer Gunnell, and Tes M. Baye
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Adult ,Adolescent ,Population ,Single-nucleotide polymorphism ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,Body Mass Index ,Nuclear Family ,Cohort Studies ,Young Adult ,Quantitative Trait, Heritable ,Receptor, Cannabinoid, CB1 ,Genetic variation ,Genetics ,Homeostasis ,Humans ,SNP ,Obesity ,International HapMap Project ,education ,Aged ,Dyslipidemias ,Genetic association ,Aged, 80 and over ,Pharmacology ,education.field_of_study ,Haplotype ,Middle Aged ,Lipids ,Haplotypes ,Molecular Medicine ,Insulin Resistance - Abstract
Aims: In humans, genetic variation in endocannabinergic signaling has been associated with anthropometric measures of obesity. In randomized trials, pharmacological blockade at the level of the cannabinoid receptor 1 (CNR1) receptor not only facilitates weight reduction, but also improves insulin sensitivity and clinical measures of lipid homeostasis. We therefore tested the hypothesis that genetic variation in CNR1 is associated with common obesity-related metabolic disorders. Materials & methods: A total of six haplotype tagging SNPs were selected for CNR1, using data available within the Human HapMap (Centre d’Etude du Polymorphisme Humain population) these included: two promoter SNPs, three exonic SNPs, and a single SNP within the 3’-untranslated region. These tags were then genotyped in a rigorously phenotyped family-based collection of obese study subjects of Northern European origin. Results & conclusions: A common CNR1 haplotype (H4; prevalence 0.132) is associated with abnormal lipid homeostasis. Additional statistical tests using single tagging SNPs revealed that these associations are partly independent of body mass index.
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- 2008
15. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes
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Eric K. Moses, Thomas D. Dyer, David L. Rainwater, Jeremy B. M. Jowett, Joanne E. Curran, Harald H H Göring, Matthew P. Johnson, Jean W. MacCluer, Michael C. Mahaney, Anthony G. Comuzzie, Lawrence J. Abraham, John Blangero, Gregory Collier, Jac Charlesworth, Shelley A. Cole, Laura Almasy, and Ahmed H. Kissebah
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Genetics ,Gene expression profiling ,Genetic linkage ,Genetic marker ,Expression quantitative trait loci ,Gene expression ,Quantitative trait locus ,Biology ,Gene ,Phenotype - Abstract
Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.
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- 2007
16. Meta-analysis of genome-wide linkage studies in BMI and obesity
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Mariza de Andrade, Philippe Froguel, Steven Stone, Adebowale Adeyemo, Michael P. Stern, David A. Collier, Cathryn M. Lewis, Rector Arya, Catherine L. Saunders, Susan Redline, Miina Öhman, Anthony G. Comuzzie, Robert L. Hanson, Gerald S. Berenson, John Blangero, Benedetta D. Chiodini, Wei Chen, Lisa J. Martin, Lyle J. Palmer, Leena Peltonen, Amy Luke, Ingrid B. Borecki, Hong-Wen Deng, Pak C. Sham, Yvon C. Chagnon, M W Nash, R. Arlen Price, Heather M. Stringham, Mary F. Feitosa, Stephen T. Turner, Cisca Wijmenga, Sathanur R. Srinivasan, Michael Boehnke, Markus Perola, Ravindranath Duggirala, Patricia Huezo-Dias, Victor Abkevich, Ahmed H. Kissebah, Weidong Li, Johannes Hebebrand, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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SCAN METAANALYSIS ,hypertension ,Genetic Linkage ,Endocrinology, Diabetes and Metabolism ,Medizin ,Medicine (miscellaneous) ,Locus (genetics) ,Quantitative trait locus ,FTO gene ,Childhood obesity ,Body Mass Index ,03 medical and health sciences ,Diabetes mellitus genetics ,Endocrinology ,Genetic linkage ,OBSTRUCTIVE SLEEP-APNEA ,medicine ,Diabetes Mellitus ,Humans ,genetics ,Obesity ,SUSCEPTIBILITY LOCUS ,030304 developmental biology ,METABOLIC SYNDROME ,Genetics ,0303 health sciences ,adiposity ,Nutrition and Dietetics ,diabetes ,business.industry ,Genetic heterogeneity ,Genome, Human ,030305 genetics & heredity ,DIABETES-MELLITUS ,BIPOLAR DISORDER ,SEARCH METAANALYSIS ,medicine.disease ,meta-analysis ,BODY-MASS INDEX ,Meta-analysis ,CHILDHOOD OBESITY ,business ,QUANTITATIVE-TRAIT LOCI - Abstract
Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values
- Published
- 2007
17. Comparison of linkage disequilibrium patterns between the HapMap CEPH samples and a family-based cohort of Northern European descent
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Jack Littrell, J. Eckert, Michael Olivier, Regina Cole, Xujing Wang, Edward M. Smith, and Ahmed H. Kissebah
- Subjects
haplotype ,Linkage disequilibrium ,Quantitative Trait Loci ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,Article ,Cohort Studies ,HapMap ,CEPH ,tagSNP ,Databases, Genetic ,Genetic variation ,Genetics ,Chromosomes, Human ,Humans ,Family ,Obesity ,International HapMap Project ,Expressed Sequence Tags ,Metabolic Syndrome ,Linkage (software) ,Models, Genetic ,Haplotype ,Genetic Variation ,Genetics, Population ,Haplotypes ,Cohort ,Cohort study - Abstract
The International HapMap Consortium has determined the linkage disequilibrium (LD) patterns of four major human populations. The aim of our investigation was to compare the LD patterns of the HapMap CEPH (Centre d'Etude du Polymorphisme Humain) samples with a family-based cohort of similar ancestry to determine its usefulness as a reference population for disease association studies. We examined four genomic regions on chromosomes 7q, 12p, and 14q totaling 14.3 Mb, initially identified in our linkage study of obesity and the metabolic syndrome. Near identical patterns of LD were detected in both populations. Furthermore, tagSNPs selected based on the HapMap CEPH cohort data capture over 98% of the variants at an r2 > 0.8 in the disease cohort. This confirms the usefulness of the CEPH cohort of the HapMap as a reference sample for further investigations into the genomic variation of populations of Northern European descent.
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- 2006
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18. Genetic variation in selenoprotein S influences inflammatory response
- Author
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Jeremy B. M. Jowett, Guowen Cai, Yuan Gao, Kate S. Elliott, Greg R. Collier, Ahmed H. Kissebah, Ken Walder, Jianmin Wang, Jean W. MacCluer, Dalia M Abel Azim, John Blangero, P. Z. Zimmet, Thomas D. Dyer, Michael C. Mahaney, Joanne E. Curran, Anthony G. Comuzzie, and Kristi Gluschenko
- Subjects
Adult ,Male ,Genotype ,medicine.medical_treatment ,Single-nucleotide polymorphism ,Inflammation ,Polymorphism, Single Nucleotide ,Proinflammatory cytokine ,Genetic variation ,Genetics ,medicine ,Humans ,RNA, Small Interfering ,Promoter Regions, Genetic ,Selenoproteins ,Aged ,Aged, 80 and over ,biology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Macrophages ,Endoplasmic reticulum ,Selenoprotein S ,Genetic Variation ,Membrane Proteins ,Middle Aged ,Cytokine ,Immunology ,Female ,Tumor necrosis factor alpha ,Inflammation Mediators ,medicine.symptom ,biology.gene ,Interleukin-1 - Abstract
Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.
- Published
- 2005
19. The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes
- Author
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Katherine S. Elliott, Eric Ravussin, P. Z. Zimmet, Anthony E. Civitarese, James L. Trevaskis, Natalie Bishara, Lawrence J. Mandarino, Jeremy B. M. Jowett, Gregory Collier, Ahmed H. Kissebah, Joanne E. Curran, Ken Walder, John Blangero, and Lyndal Kerr-Bayles
- Subjects
Male ,Candidate gene ,Endocrinology, Diabetes and Metabolism ,Omptin ,Molecular Sequence Data ,Type 2 diabetes ,Biology ,Mitochondrion ,Mitochondrial Proteins ,Gene expression ,Internal Medicine ,medicine ,Animals ,Humans ,Family ,Amino Acid Sequence ,Gene ,Conserved Sequence ,Genetics ,Sequence Homology, Amino Acid ,Siblings ,Rhomboid protease ,Skeletal muscle ,medicine.disease ,Mitochondria ,Disease Models, Animal ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Metalloproteases ,Female ,Gerbillinae ,Sequence Alignment - Abstract
This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes.We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions.We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects.Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.
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- 2005
20. Genetic determinants of obesity-related lipid traits
- Author
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Glenn R. Krakower, Gabriele E. Sonnenberg, Anne E. Kwitek, Michael Olivier, John Blangero, Lisa J. Martin, Ahmed H. Kissebah, and Anthony G. Comuzzie
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,lipid profiles ,Waist ,medicine.medical_treatment ,Quantitative Trait Loci ,QD415-436 ,Quantitative trait locus ,Biology ,Biochemistry ,Article ,Endocrinology ,high density lipoprotein cholesterol ,Genetic linkage ,Internal medicine ,medicine ,Humans ,Insulin ,linkage analysis ,Body Weights and Measures ,Obesity ,Triglycerides ,Family Health ,Linkage (software) ,Genetics ,Genome, Human ,Chromosome Mapping ,Chromosome ,Cell Biology ,medicine.disease ,Lipids ,Cholesterol ,Female ,lipids (amino acids, peptides, and proteins) ,Body mass index ,Chromosomes, Human, Pair 7 - Abstract
In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol. These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.
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- 2004
21. A Novel Pathway to the Manifestations of Metabolic Syndrome
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Gabriele E. Sonnenberg, Glenn R. Krakower, and Ahmed H. Kissebah
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Medicine (miscellaneous) ,Adipokine ,Proinflammatory cytokine ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,Humans ,Obesity ,Endothelial dysfunction ,Metabolic Syndrome ,Adiponectin ,Tumor Necrosis Factor-alpha ,business.industry ,Insulin ,NF-kappa B ,Public Health, Environmental and Occupational Health ,Proteins ,medicine.disease ,Oxidative Stress ,Adipose Tissue ,Intercellular Signaling Peptides and Proteins ,Tumor necrosis factor alpha ,Metabolic syndrome ,business ,Cell Adhesion Molecules ,Food Science - Abstract
Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappa B activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome.
- Published
- 2004
22. The Genetic Basis of Plasma Variation in Adiponectin, a Global Endophenotype for Obesity and the Metabolic Syndrome
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Diana Maas, Masahiko Takahashi, Tohru Funahashi, Ahmed H. Kissebah, Anthony G. Comuzzie, Shinji Kihara, Daniel A. Cohen, Gabriele E. Sonnenberg, Howard J. Jacob, Sachiyo Tanaka, Yuji Matsuzawa, Anne E. Kwitek Black, John Blangero, and Lisa J. Martin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,Genetic Linkage ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Quantitative trait locus ,Biology ,Biochemistry ,Genetic analysis ,Genetic determinism ,Endocrinology ,Metabolic Diseases ,Genetic linkage ,Internal medicine ,medicine ,Humans ,Obesity ,Child ,Aged ,Aged, 80 and over ,Genetics ,Adiponectin ,Biochemistry (medical) ,Proteins ,Chromosome ,Middle Aged ,Heritability ,Phenotype ,Adipose Tissue ,Intercellular Signaling Peptides and Proteins ,Female ,Chromosomes, Human, Pair 17 - Abstract
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 × 10−6), 35 cM from pter on chromosome 5. The second largest LOD score (LOD = 3.2; P = 6.2 × 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.
- Published
- 2001
23. Plasma leptin and insulin levels in weight-reduced obese women with normal body mass index: relationships with body composition and insulin
- Author
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Gabriele E. Sonnenberg, Glenn R. Krakower, S Guven, A El-Bershawi, Ahmed H. Kissebah, Charles R. Wilson, and Raymond G. Hoffmann
- Subjects
Adult ,Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Body Mass Index ,Cohort Studies ,Absorptiometry, Photon ,Reference Values ,Internal medicine ,Weight Loss ,Internal Medicine ,medicine ,Humans ,Insulin ,Obesity ,Pancreatic hormone ,business.industry ,Proteins ,Insulin sensitivity ,Middle Aged ,medicine.disease ,Pathophysiology ,Endocrinology ,Normal body mass index ,Cohort ,Body Composition ,Female ,business - Abstract
Obesity is a complex disease with multiple features that has confounded efforts to unravel its pathophysiology. As a means of distinguishing primary from secondary characteristics, we compared levels of fasting plasma leptin and insulin in a cohort of weight-reduced obese women who have attained and maintained a normal BMI for more than 1 year with the levels in cohorts of never-obese and currently obese women. Weight-reduced obese women showed decreased plasma concentrations of leptin and insulin compared with obese women, but these levels remained significantly higher than those of never-obese women. Plasma leptin levels were highly correlated with plasma insulin levels (r = 0.60, P < 0.001). To further explore relationships with body composition, total body fat was determined by dual-energy X-ray absorptiometry and body fat distribution by computed tomography in subsets of these groups. Weight-reduced obese women had a significantly greater percent body fat and subcutaneous abdominal fat mass than did the never-obese women, and these were highly correlated with plasma leptin (r = 0.90, P < 0.001, and r = 0.52, P < 0.001, respectively). In these weight-reduced obese women, visceral fat mass was similar to that of the never-obese. The insulin sensitivity index and first-phase insulin response were also comparable. These results demonstrate that higher leptin levels in weight-reduced obese women are related to the higher total fat and particularly the subcutaneous fat masses. Normalization of visceral fat mass in the weight-reduced obese was accompanied by normalization of insulin sensitivity index and first-phase insulin response. This study suggests that increases in plasma leptin and insulin in obesity are secondary features of the obese state.
- Published
- 1999
24. Glucose Utilization in Muscle Fiber Types: Use of the Partial Pancreatectomized Rat Model to Distinguish Effects of Glucose and Insulin on Insulin Resistance
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Glenn R. Krakower, Ahmed H. Kissebah, Daniel A. Meier, Nasser Rizk, and Debra Pastorek
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Muscle Fibers, Skeletal ,Biology ,Carbohydrate metabolism ,Models, Biological ,Biochemistry ,Rats, Sprague-Dawley ,Pancreatectomy ,Endocrinology ,Insulin resistance ,Internal medicine ,Genetics ,medicine ,Hyperinsulinemia ,Animals ,Insulin ,Glycolysis ,Molecular Biology ,Soleus muscle ,Skeletal muscle ,Glucose Tolerance Test ,medicine.disease ,Rats ,Glucose ,medicine.anatomical_structure ,Basal (medicine) ,Insulin Resistance - Abstract
We have used the partially pancreatectomized infusion model in order to examine individual and combined effects of glucose and insulin on insulin resistance in rat skeletal muscles. Infusing glucose or insulin can produce animals which are hyperglycemic, hyperinsulinemic, or both. Individual and combined effects of chronic hyperglycemia and hyperinsulinemia on basal and insulin-mediated glucose utilization indices in glycolytic and oxidative muscle fibers were examined by 2-deoxyglucose uptake. Hyperglycemia reduced the basal glucose utilization index by 49% and hyperinsulinemia by 55%, while combined hyperglycemia + hyperinsulinemia diminished 2-deoxyglucose uptake by 69%. Maximally insulin-stimulated utilization was diminished only 28% under hyperglycemia but by 81% in the hyperinsulinemic state. In order to assess utilization in individual muscle fibers, uptake was examined in three tissues of differing fiber composition. The slow-twitch oxidative soleus muscle demonstrated greater basal uptake than the fast-twitch gastrocnemius (glycolytic) and quadriceps (oxidative) muscles. In addition basal (though not maximally insulin-stimulated) glucose utilization in the fast-twitch fibers was affected by chronic glucose and insulin to a greater extent than the slow-twitch soleus muscle, indicating that chronic hyperglycemia is more likely to precipitate insulin resistance in fast-twitch muscles. Significant differences in glucose metabolism among muscle fiber types suggests that results from insulin resistance studies in mixed muscles may be skewed according to their fiber composition.
- Published
- 1998
25. Mechanisms of Insulin-Resistant Glucose Utilization in Rat Skeletal Muscle
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Daniel A. Meier, Nasser Rizk, Ahmed H. Kissebah, and Glenn R. Krakower
- Subjects
Blood Glucose ,Male ,endocrine system ,medicine.medical_specialty ,Monosaccharide Transport Proteins ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Muscle Proteins ,Biology ,Biochemistry ,Streptozocin ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Endocrinology ,Insulin resistance ,Hyperinsulinism ,Internal medicine ,Genetics ,medicine ,Hyperinsulinemia ,Animals ,RNA, Messenger ,Muscle, Skeletal ,Molecular Biology ,Glucose Transporter Type 4 ,Insulin ,Glucose transporter ,nutritional and metabolic diseases ,Skeletal muscle ,medicine.disease ,Rats ,medicine.anatomical_structure ,Basal (medicine) ,Hyperglycemia ,Solution hybridization ,Insulin Resistance ,hormones, hormone substitutes, and hormone antagonists - Abstract
Defects in glucose uptake are among the primary defects associated with peripheral insulin resistance, but fundamental mechanisms leading to this state are poorly understood. In order to elucidate mechanisms leading toward defects in glucose transport, we have used a partially pancreatectomized infusion (PxI) animal model with infusions of saline, glucose, or insulin to examine individual and combined effects of hyperglycemia and hyperinsulinemia on skeletal muscle glucose utilization. Moderate hyperglycemia induced by pancreatectomy reduced basal hindlimb muscle glucose utilization by 57% without affecting maximal insulin-stimulated glucose utilization; insulin administered in an amount sufficient to correct this hyperglycemia did not alter basal glucose utilization, but maximal insulin-stimulated glucose utilization was sharply diminished (75%); hyperglycemia with hyperinsulinemia similarly reduced basal and maximal insulin-stimulated glucose utilization. In order to establish the role of the glucose transporter protein in these insulin-resistant states, we quantified GLUT 4 content by immunoblotting and GLUT 4 mRNA by solution hybridization/RNAse protection assays. Hyperglycemia (2 weeks) reduced total muscle GLUT 4 protein content (53%) and mRNA (46%), while subsequent hyperinsulinemia (72 h) with either normo- or hyperglycemia partially restored both total GLUT 4 protein and mRNA levels. As insulin-stimulated GLUT 4 content in plasma membranes was not diminished by combined hyperglycemia/hyperinsulinemia, these results indicate functional GLUT 4 translocation in this model and suggest suppression of GLUT 4 transporter activity.
- Published
- 1998
26. A comprehensive analysis of adiponectin QTLs using SNP association, SNP cis-effects on peripheral blood gene expression and gene expression correlation identified novel metabolic syndrome (MetS) genes with potential role in carcinogenesis and systemic inflammation
- Author
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Ulrich Broeckel, Diana Cerjak, Yi Zhang, Anthony G. Comuzzie, Omar Ali, Reham M Abdou, Ahmed H. Kissebah, David L. Rainwater, Harald H H Göring, John Blangero, Thomas D. Dyer, Michael Olivier, Joanne E. Curran, Jack W. Kent, and Melanie A. Carless
- Subjects
Genotype ,Quantitative Trait Loci ,A Kinase Anchor Proteins ,Adipokine ,Nerve Tissue Proteins ,Single-nucleotide polymorphism ,Myosins ,Quantitative trait locus ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Cancer risk ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Basic Helix-Loop-Helix Transcription Factors ,Leukocytes ,Genetics ,medicine ,Humans ,SNP ,Genetics(clinical) ,RNA, Messenger ,Gene ,Genetics (clinical) ,030304 developmental biology ,Inflammation ,Chromosomes, Human, Pair 14 ,Metabolic Syndrome ,2. Zero hunger ,0303 health sciences ,Adiponectin ,Cadherins ,3. Good health ,Cell Transformation, Neoplastic ,Phenotype ,Haplotypes ,030220 oncology & carcinogenesis ,Chromosomes, Human, Pair 5 ,Carcinogenesis ,Research Article ,Transcription Factors - Abstract
Background Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13). Methods Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS. Results Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi-organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene’s transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p= 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be associated with insulin resistance, inflammatory markers or adiposity studies using genome-wide approaches whereas associations of CDH18 and MYO10 with MetS traits have not been reported before. Conclusions Adiponectin QTLs-based SNP association and mRNA expression identified genes that could mediate the association between MetS and cancer or inflammation.
- Published
- 2013
27. Influence of Androgenicity on Adipocytes and Precursor Cells in Female Rats
- Author
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Ahmed H. Kissebah, Glenn R. Krakower, and Roland James
- Subjects
medicine.medical_specialty ,Ovariectomy ,Endocrinology, Diabetes and Metabolism ,Fluorescent Antibody Technique ,Medicine (miscellaneous) ,Adipose tissue ,Cell Count ,Cell morphology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Endocrinology ,Precursor cell ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,Testosterone ,Cell Size ,Lipoprotein lipase ,Chemistry ,Cell growth ,Stem Cells ,Public Health, Environmental and Occupational Health ,Cell Differentiation ,Flow Cytometry ,Rats ,Lipoprotein Lipase ,Ovariectomized rat ,Female ,Food Science - Abstract
We examined the effects of overexposure of testosterone (T) on fat cell morphology and adipocyte precursor pools in inguinal and retroperitoneal fat depots of ovariectomized rats. In both tissues peripubertal T decreased weights without affecting adipocyte mean cell size or the size distribution profiles, but adipocyte number was decreased by 65% in the inguinal and by 38% in the retroperitoneal depots. Immunofluorescent flow cytometry utilizing a specific antibody to rat adipose tissue lipoprotein lipase was used to quantify regional precursor cell populations. T sharply reduced the percentages of differentiated and undifferentiated preadipocytes in the inguinal depot, from 43.2 +/- 5.3 to 23.5 +/- 2.1% and from 57.7 +/- 4.0 to 43.6 +/- 5.3%, respectively, with a concomitant increase in fibroblasts from 1.6 to 32.9%. On the other hand, T had no effect on retroperitoneal preadipocyte pools. Perinatal androgenization exacerbated the decline in the inguinal weight (1.4 +/- 0.1 vs. 2.2 +/- 0.1g) but otherwise did not influence the actions of peripubertal T. Androgens may thus act in a tissue-specific manner to regulate fat cell growth potential in the femoral region in the female.
- Published
- 1996
28. Dietary fish oil decreases low-density-lipoprotein clearance in nonhuman primates
- Author
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Lawrence E. Boerboom, Barbara V. Howard, Robert A. Mueller, Ahmed H. Kissebah, Judy Hannah, and Gordon Schectman
- Subjects
Male ,medicine.medical_specialty ,Apolipoprotein B ,Metabolic Clearance Rate ,Medicine (miscellaneous) ,CHO Cells ,Iodine Radioisotopes ,chemistry.chemical_compound ,Fish Oils ,Dietary Fats, Unsaturated ,Cricetinae ,Internal medicine ,medicine ,Animals ,Plant Oils ,Olive Oil ,Triglycerides ,Unsaturated fatty acid ,Nutrition and Dietetics ,biology ,Metabolism ,Fish oil ,Lipoproteins, LDL ,Kinetics ,Macaca fascicularis ,Cholesterol ,Endocrinology ,Receptors, LDL ,chemistry ,Low-density lipoprotein ,LDL receptor ,Cholesteryl ester ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Composition (visual arts) ,Cholesterol Esters - Abstract
To assess whether fish oil-induced alterations in low-density-lipoprotein (LDL) composition have distinct and important effects on LDL metabolism, we evaluated LDL kinetic behavior in cynomolgus macaques fed an atherogenic diet supple- mented with either fish oil ( 1.6 g n-3 fatty acids; n = 10) or olive oil (n = 9) for � 6 mo. LDL from monkeys supplemented with fish oil or olive oil was isolated, labeled with either 1251 or and simultaneously reinjected so that each monkey received its own (autologous injection) and donor (homologous injection) LDL. For LDL injected autologously (monkeys that received their own LDL), the LDL fractional clearance rate (FCR) was reduced in fish oil-supplemented monkeys compared with the olive oil- supplemented controls (0.42 ± 0.03 compared with 0.56 ± 0.05 pools/d, P = 0.04). The cholesteryl ester content of fish oil LDL increased compared with olive oil LDL (43 ± 2% and 36 ± 3%, respectively, P = 0.03), and the LDL cholesteryl ester content was strongly correlated with autologous LDL clearance (r = -0.76, P = 0.0001). Compared with olive oil LDL, fish oil LDL had a reduced dissociation constant (KD) for binding to the LDL receptor in vitro (KD for fish oil LDL compared with olive oil LDL: 13.9 ± 1.8 and 7.4 ± 1.0 mg LDL proteinlL, P = 0.03). When both fish oil LDL and olive oil LDL were simultaneously injected into fish oil-supplemented monkeys, the FCR of fish oil LDL was de- creased compared with olive oil LDL (0.42 ± 0.03 and 0.52 ± 0.04 pools/d, P = 0.006). These data suggest that dietary supple- mentation with fish oil decreases LDL clearance, and that this effect is mediated, at least in part, by altering LDL structure and reducing the affinity of LDL for its receptor. Am J C/in Nutr 1996;64:2l5-2l.
- Published
- 1996
29. Insulin-Resistant Lipolysis in Abdominally Obese Hypertensive Individuals
- Author
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Magda M.I. Hennes, Patrice LaBelle, Ahmed H. Kissebah, Irene M. O’Shaughnessy, Brent M. Egan, and Thomas M. Kelly
- Subjects
Adult ,Male ,medicine.medical_specialty ,Lipolysis ,medicine.medical_treatment ,Adipose tissue ,Angiotensin-Converting Enzyme Inhibitors ,Fatty Acids, Nonesterified ,Body Mass Index ,Placebos ,Renin-Angiotensin System ,Insulin resistance ,Enalapril ,Lipid oxidation ,Internal medicine ,Internal Medicine ,Humans ,Insulin ,Medicine ,Obesity ,Antihypertensive Agents ,Abdominal obesity ,business.industry ,Hemodynamics ,Calorimetry, Indirect ,medicine.disease ,Endocrinology ,Blood pressure ,Data Interpretation, Statistical ,Hypertension ,Body Constitution ,Female ,Insulin Resistance ,medicine.symptom ,business ,medicine.drug - Abstract
Resistance to the capacity of insulin to suppress lipolysis may be an important link in the association between abdominal obesity and hypertension. Furthermore, a more active renin-angiotensin system in adipose tissue may contribute to insulin-resistant lipolysis in abdominally obese hypertensive subjects. We determined nonesterified fatty acid concentrations and turnover as well as lipid oxidation under basal conditions and during steady-state euglycemia with two levels of insulinemia (72 and 287 pmol/L) in lean normotensive, abdominally obese normotensive, and abdominally obese hypertensive subjects. To assess the role of the renin-angiotensin system in determining nonesterified fatty acid turnover, we repeated studies in the abdominally obese hypertensive subjects after double-blind random assignment to placebo or enalapril for 1 month each. The main findings were the following: (1) Nonesterified fatty acid flux was significantly higher in abdominally obese hypertensive subjects at both levels of insulinemia than in either abdominally obese normotensive or lean normotensive subjects and correlated significantly with both mean blood pressure and total systemic resistance during the higher level of insulinemia. (2) Enalapril significantly improved insulin-resistant lipolysis in the abdominally obese hypertensive subjects. The improvement in insulin suppressibility of nonesterified fatty acid flux at the high hormonal concentrations correlated positively with the magnitude of reduction in blood pressure. (3) Basal lipid oxidation and suppression in response to insulin were similarly impaired in both obese groups. Resistance to the antilipolytic actions of insulin is thus a characteristic feature in abdominally obese hypertensive subjects and may be linked to the elevated blood pressure in these individuals. A more active renin-angiotensin system may partly explain the insulin-resistant lipolysis in this form of hypertension.
- Published
- 1996
30. Obesity Hypertension Is Related More to Insulin’s Fatty Acid Than Glucose Action
- Author
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Irene M. O’Shaughnessy, Magda M.I. Hennes, Brent M. Egan, Ahmed H. Kissebah, Theodore L. Goodfriend, and Konrad T. Stepniakowski
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Blood Pressure ,chemistry.chemical_compound ,Internal medicine ,Internal Medicine ,medicine ,Hyperinsulinemia ,Humans ,Insulin ,Obesity ,Abdominal obesity ,chemistry.chemical_classification ,Fatty acid metabolism ,business.industry ,Fatty Acids ,Insulin tolerance test ,Area under the curve ,Fatty acid ,medicine.disease ,Glucose ,Endocrinology ,Blood pressure ,chemistry ,Hypertension ,medicine.symptom ,business - Abstract
Abstract Although resistance to insulin-mediated glucose disposal has emerged as a link between abdominal obesity and hypertension, abnormalities of nonesterified fatty acid metabolism may play a greater role. Analyses were performed on existing data from 17 abdominally obese subjects (11 hypertensive, 6 normotensive) to determine whether fatty acid concentration and turnover were related to blood pressure independently of hyperinsulinemia and resistance to insulin-mediated glucose disposal. Glucose utilization, fatty acid concentration, and fatty acid turnover were obtained fasting and during euglycemic hyperinsulinemia at 10 and 40 mU·m −2 ·min −1 . Analyses were also performed on another group of 30 subjects with a wide range of risk factors who had blood pressure data as well as glucose and fatty acid measurements during an insulin tolerance test. Fatty acid concentration and turnover were markedly more resistant to suppression by insulin in obese hypertensive than in lean or obese normotensive individuals. In the 17 obese subjects, blood pressure measured at screening, in the laboratory, and over a period of 24 hours correlated significantly with fatty acid concentration and turnover but not with glucose disposal measured during the hyperinsulinemic clamp. These correlations remained significant after fasting insulin, the insulin area under the curve during an oral glucose tolerance test, and glucose disposal during the clamp were controlled for. In the second group of subjects, plasma fatty acids 15 minutes after intravenous insulin also correlated with blood pressure. These correlations remained significant after insulin and an index of sensitivity to insulin-mediated glucose disposal were statistically controlled for. The data indicate that blood pressure is related to the effects of insulin on fatty acid metabolism. The findings raise the possibility that resistance of hormone-sensitive lipase to insulin participates in elevating the blood pressure of abdominally obese hypertensive subjects by increasing fatty acid concentration and turnover.
- Published
- 1996
31. Glucose Metabolism in Abdominally Obese Hypertensive and Normotensive Subjects
- Author
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Raymond G. Hoffmann, Thomas J. Myers, Irene M. O’Shaughnessy, Brent M. Egan, Konrad T. Stepniakowski, Thomas M. Kelly, Pietro Nazzaro, and Ahmed H. Kissebah
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Radioimmunoassay ,Hemodynamics ,Blood Pressure ,Calorimetry ,Carbohydrate metabolism ,Insulin resistance ,Internal medicine ,Abdomen ,Internal Medicine ,medicine ,Humans ,Insulin ,Obesity ,Abdominal obesity ,Analysis of Variance ,Leg ,business.industry ,Metabolism ,Middle Aged ,Glucose clamp technique ,medicine.disease ,Plethysmography ,Forearm ,Glucose ,Endocrinology ,Regional Blood Flow ,Hypertension ,Glucose Clamp Technique ,Female ,Vascular Resistance ,medicine.symptom ,business ,Perfusion - Abstract
Abstract To determine whether the combination of obesity and hypertension results in additive defects in oxidative and nonoxidative glucose metabolism and the association of these changes with altered hemodynamic actions of insulin, we studied 11 abdominally obese hypertensive, 6 abdominally obese normotensive, and 7 lean normotensive nondiabetic subjects. Endogenous glucose production and glucose metabolized were calculated from a euglycemic clamp at 72 and 287 pmol insulin/m 2 per minute. Glucose metabolized divided by insulin was lower at 72 pmol/m 2 per minute in both obese groups than in lean normotensive subjects, at 148±14, 144±33, and 373±69 (μmol/m 2 per minute)/(pmol/L), respectively ( P P
- Published
- 1995
32. Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome
- Author
-
Magda M.I. Hennes, Dimitris Platanissiotis, Asimina Mitrakou, Elli Georgiadou, Nicholas Kaklas, Evanthia Diamanti-Kandarakis, Ahmed H. Kissebah, Raymond G. Hoffmann, Jovanna Spina, and Sotos Raptis
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biology ,Antiandrogen ,Flutamide ,chemistry.chemical_compound ,Endocrinology ,Insulin resistance ,Dehydroepiandrosterone sulfate ,Internal medicine ,medicine ,Humans ,Obesity ,Pancreatic hormone ,Insulin ,Androgen Antagonists ,medicine.disease ,Polycystic ovary ,chemistry ,Androgens ,Female ,Insulin Resistance ,Polycystic Ovary Syndrome - Abstract
Polycystic ovary (PCO) syndrome is strongly associated with insulin resistance and the accompanying adverse metabolic profile. To distinguish the mechanisms of this association, we determined the interactions of PCO with obesity and the influence of ameliorating direct androgenic actions via short-term treatment with the antiandrogen flutamide. Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp in groups of lean and obese PCO women and weight-matched controls. Compared with control values, insulin-mediated glucose utilization in PCO women was significantly lower in lean (1.96 +/- 0.17 v 1.24 +/- 0.10, P.01) and obese (1.23 +/- 0.18 v 1.03 +/- 0.09 mmol/m2/min, P.01) subjects. ANOVA indicated that the effects of obesity and androgenicity are independent and additive. In both lean and obese PCO women, treatment with flutamide for 1 or 3 months markedly improved the clinical and biochemical androgenic features, but did not significantly influence the overall insulin sensitivity. A large disparity between individuals in the response to treatment correlated significantly with a simultaneous reduction in plasma levels of dehydroepiandrosterone sulfate (DHEA-S). Thus in women, PCO and obesity exert synergistic effects on insulin resistance. The decreased insulin sensitivity is mediated via indirect androgenic actions or nonandrogenic mechanisms. In some individuals, a direct effect of androgens might have been masked by a decrease in DHEA-S levels.
- Published
- 1995
33. Elevated Blood Pressures in Obese Young Men With Mild Hypertension Are Sustained During the Day and Night
- Author
-
Pietro Nazzaro, Konrad T. Stepniakowski, Irene M. O’Shaughnessy, Brent M. Egan, and Ahmed H. Kissebah
- Subjects
Adult ,Male ,medicine.medical_specialty ,Ambulatory blood pressure ,Office Visits ,medicine.medical_treatment ,Monitoring, Ambulatory ,Blood Pressure ,Heart Rate ,Internal medicine ,Heart rate ,Internal Medicine ,medicine ,Hyperinsulinemia ,Humans ,Insulin ,Obesity ,Systole ,Pancreatic hormone ,Glucose tolerance test ,Anthropometry ,medicine.diagnostic_test ,business.industry ,Blood Pressure Determination ,medicine.disease ,Circadian Rhythm ,Blood pressure ,Endocrinology ,Hypertension ,business - Abstract
The major goal of this study was to determine if the elevated blood pressures in obese men < 45 years old with mild hypertension persist outside the clinic. A secondary aim was to determine if hyperinsulinemia is associated with accentuated diurnal changes of blood pressure. To address these objectives, the clinic and ambulatory blood pressures as well as a 75-g, 2-h oral glucose tolerance test measurements were obtained from 9 lean normotensive, 9 lean hypertensive, and 22 obese hypertensive men < 45 years old. The week before study, volunteers ate an isocaloric diet with 220 mEq of NaCl/day. Obese hypertensives, subdivided by high (n = 11) and low (n = 11) insulin areas-under-the-curve (AUCs) in response to oral glucose, and lean hypertensives maintained higher ambulatory blood pressure than lean normotensives (130 +/- 3/74 +/- 1, 136 +/- 4/78 +/- 2, 132 +/- 5/77 +/- 3 v 118 +/- 4/65 +/- 2 mm Hg, respectively, P < .05). As expected, the insulin AUC during the glucose tolerance test was higher in obese hypertensives with higher insulin AUCs than in obese hypertensives with lower insulin AUCs, lean hypertensives, or lean normotensives (13.9 +/- 1.2 v 7.9 +/- 0.3, 7.2 +/- 0.7, 5.7 +/- 0.7 mU-min/dL, P < .05). Insulin AUCs were not significantly different in obese hypertensives with lower insulin levels, lean hypertensives, or lean normotensives. The diurnal increases of systolic and diastolic blood pressure as well as heart rate and pressure-rate product were similar in all four groups.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
34. Splanchnic Insulin Dynamics and Secretion Pulsatilities in Abdominal Obesity
- Author
-
Robert A. Mueller, Raymond G Hoffman, Ahmed H. Kissebah, and Gabriele E. Sonnenberg
- Subjects
Adult ,Blood Glucose ,Periodicity ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biology ,Enteral administration ,Enteral Nutrition ,Insulin resistance ,Internal medicine ,Abdomen ,Insulin Secretion ,Internal Medicine ,medicine ,Hyperinsulinemia ,Humans ,Insulin ,Obesity ,Pancreatic hormone ,Abdominal obesity ,Ultradian rhythm ,medicine.disease ,Insulin oscillation ,Endocrinology ,Adipose Tissue ,Body Constitution ,Female ,medicine.symptom - Abstract
Insulin secretion, clearance dynamics, and their relationship to peripheral plasma insulin and glucose levels were monitored during three 12-h periods of overnight rest, intake of three meals, and continuous enteral feeding of mixed nutrients. The low-frequency ultradian and the high-frequency insulin secretion pulsatility characteristics during the steady-states of overnight rest and continuous enteral feeding were also examined. In abdominally obese subjects, the insulin secretion rate was consistently higher than normal by 2.3-fold. Peripheral plasma insulin levels were increased by 3.4-fold during the overnight period and by 4- to 5-fold during the two fed states. Endogenous insulin clearance was significantly reduced during feeding. Both low- and high-frequency insulin secretory pulsatilities were detected in the abdominally obese subjects. Pulse periods were within the normal range. Pulse maxima, nadirs, and absolute amplitudes were increased concomitant with the increase in insulin secretion. Ultradian relative pulse amplitudes, however, were blunted. A significantly higher pulse-to-pulse variability was observed in the abdominally obese subjects compared with normal subjects. Furthermore, a significantly higher level of interindividual variability in the nutrient-stimulated insulin secretion and in the ultradian pulse characteristics was observed. Thus in abdominal obesity, the increase in pancreatic insulin output is limited and the secretory pulsatilities are aberrant, suggesting a defect in the insulin secretory process. Diminished insulin clearance contributes to the degree of peripheral hyperinsulinemia compensating for the insulin resistance characteristic of this form of obesity.
- Published
- 1994
35. Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels
- Author
-
Edward M. Smith, Michael Olivier, Lawrence J. Abraham, Ahmed H. Kissebah, Yi Zhang, Jeff V. Eckert, Eric K. Moses, Lisa J. Martin, and Tes M. Baye
- Subjects
Genetics ,Genotype ,Physiology ,Leptin ,Genetic Variation ,Single-nucleotide polymorphism ,Biology ,Regulatory Sequences, Nucleic Acid ,Polymorphism, Single Nucleotide ,Cohort Studies ,Phenotype ,Receptors, Serotonin ,SNP ,Humans ,Electrophoretic mobility shift assay ,Serotonin ,Allele ,Receptor ,5-HT receptor ,Triglycerides ,Research Articles - Abstract
Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent ( n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels ( P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability ( P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.
- Published
- 2010
36. The effect of interferon on the metabolism of LDLs
- Author
-
Ernest C. Borden, Ahmed H. Kissebah, Robert A. Mueller, Sushma Kaul, and Gordon Schectman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Apolipoprotein B ,chemistry.chemical_compound ,Interferon ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Humans ,Apolipoproteins B ,Glycoproteins ,biology ,Cholesterol ,Interferon beta-1b ,Interferon beta-1a ,Cholesterol, LDL ,Interferon-beta ,Metabolism ,Middle Aged ,Cholesterol Ester Transfer Proteins ,Lipoproteins, LDL ,Endocrinology ,chemistry ,Low-density lipoprotein ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Carrier Proteins ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Interferons have been shown to lower low density lipoprotein (LDL) cholesterol concentrations by 20-50%. To evaluate the effect of interferons on LDL metabolic behavior in individuals with normal and mildly elevated LDL cholesterol levels, autologous LDL labeled with 125I was administered to subjects at baseline and during interferon treatment. Interferon beta serine (IFN-beta serine) was administered intravenously at 4.5 x 10(6) units daily for at least 3 weeks before the start of kinetic study and continued for an additional 2 weeks. Results were analyzed by using a multicompartmental model that allows for two intravascular LDL compartments. In normal subjects, IFN-beta serine reduced LDL cholesterol and apolipoprotein (apo) B levels by 25% and 27%, respectively (p less than 0.05); LDL apo B synthesis was decreased by 59% (p less than 0.05). In hypercholesterolemic subjects, IFN-beta serine reduced LDL cholesterol levels by 38% (p less than 0.05); however, apo B concentrations and production rates were not significantly decreased. Clearance of LDL from the first intravascular apo B pool was markedly reduced in these subjects, resulting in a shift in the distribution of LDL apo B from the second to the first intravascular LDL apo B pool. We conclude that interferon's actions on LDL metabolism differ in normocholesterolemic and hypercholesterolemic subjects. In normal subjects, interferon decreased LDL cholesterol and apo B levels through a reduction in the LDL apo B production rate. However, in hypercholesterolemic subjects, interferon reduced LDL cholesterol by altering the distribution of apo B mass between LDL subspecies.
- Published
- 1992
37. INSIG1 influences obesity-related hypertriglyceridemia in humans
- Author
-
Edward M. Smith, Tesfaye M. Baye, Melanie A. Carless, Yi Zhang, Regina Cole, Lawrence J. Abraham, Joanne E. Curran, Michael Olivier, Ahmed H. Kissebah, Samer Gawrieh, Eric K. Moses, Thomas D. Dyer, John Blangero, and Lisa J. Martin
- Subjects
Adult ,Male ,Candidate gene ,Adolescent ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,QD415-436 ,Biology ,Quantitative trait locus ,EMSA ,Biochemistry ,Polymorphism, Single Nucleotide ,White People ,Cohort Studies ,Young Adult ,Endocrinology ,INSIG2 ,Polymorphism (computer science) ,medicine ,Humans ,Family ,triglyceride ,Obesity ,SNP association ,Allele ,Promoter Regions, Genetic ,QH426 ,Gene ,Genetic Association Studies ,Triglycerides ,Aged ,Genetics ,Aged, 80 and over ,Hypertriglyceridemia ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Cell Biology ,Hep G2 Cells ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Liver ,gene expression ,Female ,Chromosomes, Human, Pair 7 ,RC ,Research Article - Abstract
In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans.
- Published
- 2009
38. Genetic Variation in PARL Influences Mitochondrial Content
- Author
-
John Blangero, Ken Walder, Lyndal Kerr-Bayles, Eric K. Moses, Joanne E. Curran, Thomas D. Dyer, Jeremy B. M. Jowett, Luke A. Diepeveen, Anthony G. Comuzzie, Lawrence J. Abraham, Gregory Collier, Ahmed H. Kissebah, Matthew P. Johnson, and Katherine S. Elliott
- Subjects
Male ,Genotype ,Single-nucleotide polymorphism ,Biology ,Mitochondrion ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Article ,Linkage Disequilibrium ,White People ,Mitochondrial Proteins ,Gene Frequency ,Genetic variation ,Genetics ,Humans ,Genetic variability ,Allele ,Promoter Regions, Genetic ,Gene ,Genetics (clinical) ,Family Health ,PARL ,Genetic Variation ,Sequence Analysis, DNA ,Middle Aged ,Human genetics ,Metalloproteases ,Female - Abstract
Given their involvement in processes necessary for life, mitochondrial damage and subsequent dysfunction can lead to a wide range of human diseases. Previous studies of both animal models and humans have suggested that PARL, presenilins-associated rhomboid-like protein, is a key regulator of mitochondrial integrity and function, and plays a role in cellular apoptosis. As a surrogate measure of mitochondrial integrity, we previously measured mitochondrial content in a Caucasian population consisting of large extended pedigrees, with results highlighting a substantial genetic component to this trait. To assess the influence of variation in the PARL gene on mitochondrial content, we re-sequenced 6.5kb of the gene, identifying 16 SNPs and genotyped these in 1,031 of these Caucasian individuals, distributed across 162 families. Statistical genetic analysis revealed that one promoter variant, T-191C, exhibited significant effects (after correction for multiple testing) on mitochondrial content levels. Comparison of the transcription factor binding characteristics of the T-191C promoter SNP by EMSA indicates preferential binding of nuclear factors to the T allele, suggesting functional variation in PARL expression. These results suggest that genetic variation within PARL influences mitochondrial abundance and integrity.
- Published
- 2009
39. Relationship of Regional Fat Distribution and Obesity to Electrocardiographic Parameters in Healthy Premenopausal Women
- Author
-
Anthony B. Gustafson, R. K. Thakur, Alan N. Peiris, Charles R. Wilson, Magda M.I. Hennes, Mark S. Sothmann, and Ahmed H. Kissebah
- Subjects
Adult ,medicine.medical_specialty ,Diet, Reducing ,Blood Pressure ,Sudden death ,QT interval ,Electrocardiography ,QRS complex ,Risk Factors ,Weight loss ,Internal medicine ,Abdomen ,medicine ,Humans ,Obesity ,cardiovascular diseases ,Risk factor ,Triglycerides ,Abdominal obesity ,business.industry ,General Medicine ,medicine.disease ,Cholesterol ,Blood pressure ,Endocrinology ,Adipose Tissue ,Cardiovascular Diseases ,Body Composition ,cardiovascular system ,Cardiology ,Female ,medicine.symptom ,Tomography, X-Ray Computed ,business ,circulatory and respiratory physiology - Abstract
Abdominal obesity is an independent cardiovascular risk factor. The coexistence of abdominal obesity and electrocardiographic abnormalities may facilitate the development of cardiac arrhythmias and sudden death. We determined the relationship of body fat distribution and obesity to ECG indices in 27 obese premenopausal women on an isocaloric diet. Intra-abdominal fat distribution was assessed by computerized tomography, and obesity was assessed by hydrostatic weighing. The PR, QRS, and QTc intervals, the P and QRS axes, and the P-QRS angle were determined from a resting electrocardiogram. Cardiovascular risk profile was assessed by systolic and diastolic blood pressure and plasma cholesterol and triglyceride levels. Increased deposition of intra-abdominal fat was significantly associated with prolongation of the QTc interval independent of obesity and other cardiovascular risk factors. The prolongation of the QTc interval seen with increasing intra-abdominal fat distribution may enhance susceptibility to cardiac arrhythmias. These subjects should have electrocardiographic monitoring during periods of weight loss achieved by intensive regimens.
- Published
- 1991
40. Body fat distribution and male/female differences in lipids and lipoproteins
- Author
-
Steven J. Jacobsen, E A Sasse, Kathleen A. Sobocinski, Harvey W. Gruchow, Ahmed H. Kissebah, David S. Freedman, Joseph J. Barboriak, and Alfred J. Anderson
- Subjects
Adult ,Male ,medicine.medical_specialty ,Alcohol Drinking ,Apolipoprotein B ,Lipoproteins ,Overweight ,chemistry.chemical_compound ,High-density lipoprotein ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Exercise ,Apolipoproteins A ,Triglycerides ,Aged ,Apolipoproteins B ,Body fat distribution ,Sex Characteristics ,Anthropometry ,Apolipoprotein A-I ,biology ,Cholesterol ,business.industry ,Cholesterol, HDL ,Smoking ,Male female ,Middle Aged ,Generalized obesity ,Lipids ,Endocrinology ,Adipose Tissue ,chemistry ,Body Composition ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
The role of body fat distribution, as assessed by the ratio of waist-to-hip circumferences (WHR), in statistically explaining differences in levels of lipoproteins between men and women was studied using data collected in 1985-1986 from employed adults (mean age, 40 years). As compared with the 415 women, the 709 men had higher mean levels of triglycerides (+38 mg/dl) and apolipoprotein B (+11 mg/dl) as well as lower mean levels of high density lipoprotein (HDL) cholesterol (-15 mg/dl) and apolipoprotein A-I (-19 mg/dl). Additionally, men were more overweight, consumed more alcohol, and exercised more frequently than women but were less likely to smoke cigarettes. Controlling for these characteristics, however, did not alter the differences in lipoprotein levels between men and women. In contrast, adjustment for WHR (which was greater among men) reduced the sex differences in levels of apolipoprotein B (by 98%), triglycerides (by 94%), HDL cholesterol (by 33%), and apolipoprotein A-I (by 21%). Similar results were obtained using analysis of covariance, stratification, or matching; at comparable levels of WHR, differences in lipid and lipoprotein levels between men and women were greatly reduced. Although these results are based on cross-sectional analyses of employed adults and need to be replicated in other populations, the findings emphasize the relative importance of body fat distribution. Whereas generalized obesity and body fat distribution are associated with lipid levels, fat distribution (or a characteristic influencing fat patterning) can be an important determinant of sex differences in levels of triglycerides, HDL cholesterol, and apolipoproteins B and A-I.
- Published
- 1990
41. The genes influencing adiponectin levels also influence risk factors for metabolic syndrome and type 2 diabetes
- Author
-
Ahmed H. Kissebah, Anthony G. Comuzzie, John Blangero, Lisa J. Martin, Shinji Kihara, Masahiko Takahashi, Tohru Funahashi, David L. Rainwater, M. Elizabeth Tejero, Jean W. MacCluer, Sachiyo Tanaka, and Yūji Matsuzawa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Disease ,Type 2 diabetes ,Coronary Artery Disease ,Biology ,Risk Assessment ,Risk Factors ,Internal medicine ,Genetics ,medicine ,Humans ,Risk factor ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Aged ,Aged, 80 and over ,Metabolic Syndrome ,Adiponectin ,Leptin ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Middle Aged ,medicine.disease ,Obesity ,Texas ,Endocrinology ,Genetics, Population ,Phenotype ,Diabetes Mellitus, Type 2 ,Body Composition ,Female ,Metabolic syndrome - Abstract
1 Abstract Results from previous studies suggest that adiponectin levels are associated with risk factors for cardiovascular disease and type 2 diabetes mel- litus; however, the genetic and/or environmental components of this relation- ship have not been characterized. The aims of this study were (1) to assess the presence of pleiotropy between adiponectin levels and risk factors for cardio- vascular disease and (2) to study the association of circulating levels of adiponectin with risk factors for cardiovascular disease in the absence and presence of obesity in Mexican American adults from the San Antonio Family Heart Study. Body composition and circulating levels of adiponectin, leptin, and lipid subfractions and measurements of glucose metabolism were meas- ured in 898 subjects. The mean and standard error of the circulating levels of adiponectin was 8.7 ± 3.2 μg/ml. Bivariate quantitative analyses between adiponectin levels and phenotypes related to cardiovascular disease and type 2 diabetes mellitus were conducted using the variance decomposition approach implemented in SOLAR. A second analysis in unrelated subjects compared these risk factors between sex- and age-matched lean and obese subjects with high and low adiponectin levels. We found significant evidence of pleiotropy (i.e., shared genetic effects) between plasma levels of adiponectin and well- established risk factors for cardiovascular disease and type 2 diabetes melli- tus. Individuals with low adiponectin levels per body weight had more adverse risk profiles. These findings offer new insights into the genetic connection be- tween increasing adiposity and risk for cardiovascular disease and type 2 di- abetes mellitus, and they suggest that adiponectin may be an important risk factor for the development of these conditions.
- Published
- 2007
42. Genetic determinants of mitochondrial content
- Author
-
Shelley A. Cole, Jac Charlesworth, John Blangero, Eric K. Moses, Harald H H Göring, Ahmed H. Kissebah, Jack W. Kent, Thomas D. Dyer, Matthew P. Johnson, Joanne E. Curran, Jeremy B. M. Jowett, Jean W. MacCluer, and Anthony J. Borg
- Subjects
Genetic Markers ,Male ,Mitochondrial DNA ,Transcription, Genetic ,Genetic Linkage ,Quantitative Trait Loci ,Genome Scan ,Mitochondrion ,Biology ,Quantitative trait locus ,Genome ,DNA, Mitochondrial ,Ion binding ,Mexican Americans ,Genetics ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Genetics (clinical) ,Chromosome ,Genetic Variation ,General Medicine ,Mitochondria ,Regression Analysis ,Female - Abstract
The mitochondria are the major cellular site of energy production and respiration. Recent research has focused on investigating the role of mitochondria in disease development and it has become increasingly evident that mitochondrial dysfunction contributes to a variety of human diseases. Mitochondrial DNA (mtDNA) quantity is very important for maintaining mitochondrial function and meeting the energy needs of the body. We have measured mitochondrial content in 1259 Mexican American individuals (from 42 extended families) and have shown that mtDNA quantity (a surrogate measure of mitochondrial integrity) has a large genetic component. We performed a genome scan and a genome-wide quantitative transcriptomic scan to identify QTLs influencing mitochondrial content. A variance components linkage-based genome scan utilizing 439 STR markers was used to localize a QTL for mitochondrial content on chromosome 10q (LOD = 3.83). Significant linkage to the mitochondrial genome was also detected for mitochondrial transmission (LOD = 3.39). For replication, we measured mitochondrial content in an independent Caucasian population (1088 individuals) finding evidence for linkage in these same regions. As part of the San Antonio Family Heart Study, we obtained genome-wide quantitative transcriptional profiles from 1240 individuals. Using lymphocyte samples, we quantitated 20 413 transcripts and examined correlations between the expression levels of these transcripts and mitochondrial content using the variance components method. Using regression analysis allowing for residual genetic components, we identified 829 transcripts (including many novel genes) influencing mitochondrial content that vary in their general biological actions, from cell signaling to cell trafficking and ion binding.
- Published
- 2007
43. Susceptibility genes for end-organ damage. New strategies to understand diabetic and hypertensive nephropathy
- Author
-
Howard J. Jacob, Ulrich Broeckel, Masahide Shiozawa, Abraham P. Provoost, and Ahmed H. Kissebah
- Subjects
Transplantation ,business.industry ,End organ damage ,Susceptibility gene ,Bioinformatics ,medicine.disease ,Disease Models, Animal ,Nephrology ,Hypertensive Nephropathy ,Diabetes mellitus ,Hypertension ,Animals ,Humans ,Kidney Failure, Chronic ,Medicine ,Diabetic Nephropathies ,Genetic Predisposition to Disease ,business - Published
- 1998
44. SEPS1 protects RAW264.7 cells from pharmacological ER stress agent-induced apoptosis
- Author
-
Kee-Hong Kim, Ken Walder, Yuan Gao, Ahmed H. Kissebah, Gregory Collier, and Joseph A. Skelton
- Subjects
Cell type ,Programmed cell death ,Cell Survival ,Biophysics ,Apoptosis ,Endoplasmic Reticulum ,Biochemistry ,Article ,Proinflammatory cytokine ,Cell Line ,Mice ,Macrophage ,Animals ,Selenoproteins ,Molecular Biology ,biology ,Chemistry ,Endoplasmic reticulum ,Macrophages ,Tunicamycin ,Selenoprotein S ,Membrane Proteins ,Cell Biology ,Cell biology ,Oxidative Stress ,Unfolded protein response ,Thapsigargin ,biology.gene - Abstract
Selenoprotein S (SEPS1) is a novel endoplasmic reticulum (ER) resident protein and it is known to play an important role in production of inflammatory cytokines. Here, we show evidence that SEPS1 is stimulated by pharmacological ER stress agents in RAW264.7 macrophages as well as other cell types. Overexpression studies reveal a protective action of SEPS1 in macrophages against ER stress-induced cytotoxicity and apoptosis, resulting in promoting cell survival during ER stress. The protective action of SEPS1 is largely dependent on ER stress-mediated cell death signal with less effect on non-ER stress component cell death signals. Conversely, suppression of SEPS1 in macrophages results in sensitization of cells to ER stress-induced cell death. These findings suggest that SEPS1 could be a new ER stress-dependent survival factor that protects macrophage against ER stress-induced cellular dysfunction.
- Published
- 2006
45. A protective role of selenoprotein S (SEPS1) against endoplasmic reticulum stress‐induced cytotoxicity and apoptosis in macrophages
- Author
-
Yuan Gao, Greg R. Collier, Joseph A. Skelton, Ahmed H. Kissebah, Ken Walder, and Kee-Hong Kim
- Subjects
biology ,Apoptosis ,Chemistry ,Endoplasmic reticulum ,Selenoprotein S ,Stress induced ,Genetics ,biology.gene ,Cytotoxicity ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2006
46. Genetic linkage and association of the growth hormone secretagogue receptor (Ghrelin receptor) gene in human obesity
- Author
-
A. Baessler, Anthony G. Comuzzie, Gabriele E. Sonnenberg, Michael Hasinoff, Angela Doering, Jeanette Erdmann, Heribert Schunkert, Wibke Reinhard, Michael Olivier, Marcus Fischer, Ahmed H. Kissebah, Anne E. Kwitek, and Howard J. Jacob
- Subjects
Male ,medicine.medical_specialty ,Linkage disequilibrium ,Candidate gene ,Endocrinology, Diabetes and Metabolism ,Growth hormone secretagogue receptor ,Population ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Body Mass Index ,Receptors, G-Protein-Coupled ,Gene Frequency ,Genetic linkage ,Internal medicine ,Internal Medicine ,medicine ,Body Size ,Humans ,Obesity ,Allele ,Receptors, Ghrelin ,education ,Genetics ,education.field_of_study ,Haplotype ,digestive, oral, and skin physiology ,Chromosome Mapping ,Middle Aged ,Endocrinology ,Female ,Energy Intake ,Energy Metabolism - Abstract
The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.
- Published
- 2005
47. Leptin: A Significant Indicator of Total Body Fat but Not of Visceral Fat and Insulin Insensitivity in African-American Women
- Author
-
Ahmed H. Kissebah, Glenn R. Krakower, Arnavaz Dua, Magda M.I. Hennes, Raymond G. Hoffmann, Diana Maas, and Gabriele E. Sonnenberg
- Subjects
Adult ,Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adipose tissue ,Biology ,White People ,Body Mass Index ,Wisconsin ,Classification of obesity ,Internal medicine ,Insulin Secretion ,Internal Medicine ,medicine ,Humans ,Insulin ,Pancreatic hormone ,Anthropometry ,Proteins ,medicine.disease ,Obesity ,Recombinant Proteins ,Black or African American ,Endocrinology ,Adipose Tissue ,Premenopause ,Body Constitution ,Regression Analysis ,Female ,Body mass index ,Biomarkers ,Hormone - Abstract
The recently cloned adipose tissue hormone leptin has been proposed to be involved in the neuroendocrine regulation of adiposity and its metabolic sequelae. Visceral fat is known to predict reduced insulin sensitivity and associated adverse metabolic profiles. In this study, we report the first evaluation of the relationships between leptin levels and total body fat, visceral fat, and insulin sensitivity in a cohort of premenopausal African-American women. Thirty-four subjects were analyzed for total fat mass and visceral fat by dual-energy X-ray absorptiometry and computerized axial tomography, respectively. Insulin sensitivity (SI) was assessed using Bergman's minimal model. Results showed that fasting leptin levels strongly correlated with total body fat mass (r = 0.797, P < 0.001). Correlations of leptin with visceral fat (r = 0.54, P < 0.001) and SI (r = −0.419, P = 0.02) were dependent on total body fat. In conclusion, leptin levels reflect total body fat mass, and although visceral fat is known to predict reduced insulin sensitivity independently, leptin did not. Our data thus suggest that diverse mechanisms are responsible for the regulation of total body versus visceral fat distribution, with its metabolic and health risks.
- Published
- 1996
48. Central obesity and free fatty acid metabolism
- Author
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Magda M.I. Hennes and Ahmed H. Kissebah
- Subjects
medicine.medical_specialty ,biology ,Fatty acid metabolism ,Chemistry ,Clinical Biochemistry ,Cell Biology ,Metabolism ,Fatty Acids, Nonesterified ,medicine.disease ,Obesity ,chemistry.chemical_compound ,Glucose ,Endocrinology ,Biochemistry ,Internal medicine ,medicine ,biology.protein ,Body Constitution ,Humans ,Insulin ,Female ,Insulin Resistance ,adipocyte protein 2 ,Peptides - Published
- 1995
49. Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes project
- Author
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Ahmed H. Kissebah, Anthony G. Comuzzie, John Blangero, Gabriele E. Sonnenberg, and Lisa J. Martin
- Subjects
Leptin ,Male ,medicine.medical_specialty ,Genotype ,Genetic Linkage ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Quantitative trait locus ,Genetic determinism ,Quantitative Trait, Heritable ,Genetic linkage ,Internal medicine ,Medicine ,Humans ,Genetic Predisposition to Disease ,Obesity ,Gene–environment interaction ,Analysis of Variance ,Nutrition and Dietetics ,business.industry ,Smoking ,medicine.disease ,Endocrinology ,Phenotype ,Female ,Analysis of variance ,Lod Score ,business ,Chromosomes, Human, Pair 8 - Abstract
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.
- Published
- 2003
50. Gallstones: genetics versus environment
- Author
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Ahmed H. Kissebah, Attila Nakeeb, Anthony G. Comuzzie, Lisa J. Martin, Debra Swartz-Basile, Gabriele E. Sonnenberg, and Henry A. Pitt
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,medicine.medical_treatment ,Population ,Gallbladder disease ,Cholelithiasis ,Risk Factors ,Epidemiology ,medicine ,Scientific Papers ,Humans ,Genetic Predisposition to Disease ,Family history ,Risk factor ,education ,Aged ,Genetics ,Aged, 80 and over ,education.field_of_study ,business.industry ,Gallstones ,Middle Aged ,medicine.disease ,Relative risk ,Surgery ,Cholecystectomy ,Female ,business - Abstract
Objective The aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. Background Data Gallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. Methods A gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. Results In the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P 30, relative risk 3.7, P 50 (relative risk 2.5, P
- Published
- 2002
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