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Wang S, Lenzini P, Thyagarajan B, Lee JH, Vardarajan BN, Yashin A, Miljkovic I, Daw EW, Lin SJ, Patti GJ, Brent MR, Zmuda JM, Perls TT, Christensen K, Province MA, An P. Evidence of a novel gene locus ARHGAP44 for longitudinal change in hemoglobin A1c levels among subjects without diabetes from the Long Life Family Study. Physiol Genomics 2025; 57:293-298. [PMID: 40019798 DOI: 10.1152/physiolgenomics.00137.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/24/2024] [Accepted: 02/24/2025] [Indexed: 04/01/2025] Open
Abstract
Glycated hemoglobin A1c (HbA1c) indicates average glucose levels over 3 mo and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal change in circulating HbA1c (ΔHbA1c) is also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 nondiabetic Europeans from the Long Life Family Study (LLFS) to uncover gene loci influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis revealed a gene locus ARHGAP44 (rs56340929, explaining 27% of the linkage peak) that was significantly associated with ΔHbA1c. Interestingly, RNA transcription of ARHGAP44 was also significantly associated with ΔHbA1c in the LLFS, and this discovery was replicable on the gene locus level in the Framingham Offspring Study (FOS). Taking together, we successfully identified a novel gene locus ARHGAP44 for ΔHbA1c in family members without T2D. Further follow-up studies using longitudinal omics data in large independent cohorts are warranted.NEW & NOTEWORTHY HbA1c is clinically used in T2D diagnosis and monitoring. Its longitudinal change (ΔHbA1c) is associated with T2D-related aging processes and mortality. Targeted association tests under significant linkage peaks in extended families permit identification of unique gene loci. We uncovered a novel gene locus ARHGAP44 for ΔHbA1c with gene-level validations from the FOS and RNAseq data in the LLFS. The finding provides genetically informed biological insight into mechanistic inference of glycemia/HbA1c homeostasis and potential T2D pathophysiology.
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Affiliation(s)
- Siyu Wang
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Petra Lenzini
- Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Joseph H Lee
- Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University Medical Center, New York City, New York, United States
| | - Badri N Vardarajan
- Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University Medical Center, New York City, New York, United States
| | - Anatoli Yashin
- Social Science Research Institute, Duke University, Durham, North Carolina, United States
| | - Iva Miljkovic
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - E Warwick Daw
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Shiow J Lin
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Gary J Patti
- Department of Chemistry, Washington University School of Arts & Sciences, St. Louis, Missouri, United States
| | - Michael R Brent
- Department of Computer Science & Engineering, McKelvey School of Engineering, Washington University, St. Louis, Missouri, United States
| | - Joseph M Zmuda
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Thomas T Perls
- Department of Medicine, Section of Geriatrics, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, United States
| | - Kaare Christensen
- Unit of Epidemiology, Biostatistics, and Biodemography, Department of Public Health, Southern Denmark University, Odense, Denmark
| | - Michael A Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Ping An
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
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Wang S, Lenzini P, Thygarajan B, Lee JH, Vardarajan BN, Yashin A, Miljkovic I, Warwick Daw E, Lin SJ, Patti G, Brent M, Zmuda JM, Perls TT, Christensen K, Province MA, An P. A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.16.594575. [PMID: 38826208 PMCID: PMC11142083 DOI: 10.1101/2024.05.16.594575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c (ΔHbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with ΔHbA1c. RNA transcription of ARHGAP44 was associated with ΔHbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for ΔHbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.
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Affiliation(s)
- Siyu Wang
- Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA
| | - Petra Lenzini
- Department of Radiology, Washington University School of Medicine. St. Louis, MO, USA
| | - Bharat Thygarajan
- Departments of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Joseph H. Lee
- Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University, New York City, NY, USA
| | - Badri N. Vardarajan
- Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University, New York City, NY, USA
| | - Anatoli Yashin
- Social Science Research Institute, Duke University, Durham, NC, USA
| | - Iva Miljkovic
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - E. Warwick Daw
- Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA
| | - Shiow J. Lin
- Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA
| | - Gary Patti
- Department of Chemistry, Washington University School of Art and Sciences, St. Louis, MO, USA
| | - Michael Brent
- Deptartment of Computer Science and Center for Genome Sciences, Washington University, St. Louis, MO, USA
| | - Joseph M. Zmuda
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thomas T. Perls
- Departments of Medicine and Geriatrics, Boston University School of Medicine, Boston, MA, USA
| | - Kaare Christensen
- Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark
| | - Michael A. Province
- Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA
| | - Ping An
- Department of Genetics Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA
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3
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Calamita G, Delporte C. Insights into the Function of Aquaporins in Gastrointestinal Fluid Absorption and Secretion in Health and Disease. Cells 2023; 12:2170. [PMID: 37681902 PMCID: PMC10486417 DOI: 10.3390/cells12172170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
Aquaporins (AQPs), transmembrane proteins permeable to water, are involved in gastrointestinal secretion. The secretory products of the glands are delivered either to some organ cavities for exocrine glands or to the bloodstream for endocrine glands. The main secretory glands being part of the gastrointestinal system are salivary glands, gastric glands, duodenal Brunner's gland, liver, bile ducts, gallbladder, intestinal goblet cells, exocrine and endocrine pancreas. Due to their expression in gastrointestinal exocrine and endocrine glands, AQPs fulfill important roles in the secretion of various fluids involved in food handling. This review summarizes the contribution of AQPs in physiological and pathophysiological stages related to gastrointestinal secretion.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy;
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium
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da Silva IV, Soveral G. Aquaporins in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:289-302. [PMID: 36717502 DOI: 10.1007/978-981-19-7415-1_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Obesity is one of the most important metabolic disorders of this century and is associated with a cluster of the most dangerous cardiovascular disease risk factors, such as insulin resistance and diabetes, dyslipidemia, and hypertension, collectively named Metabolic Syndrome. The role of aquaporins (AQP) in glycerol metabolism facilitating glycerol release from the adipose tissue and distribution to various tissues and organs unveils these membrane channels as important players in lipid balance and energy homeostasis and points to their involvement in a variety of pathophysiological mechanisms including insulin resistance, obesity, and diabetes. This review summarizes the physiologic role of aquaglyceroporins in glycerol metabolism and lipid homeostasis, describing their specific tissue distribution, involvement in glycerol balance, and implication in obesity and fat-related metabolic complications. The development of specify pharmacologic modulators able to regulate aquaglyceroporins expression and function, in particular AQP7 in adipose tissue, might constitute a novel approach for controlling obesity and other metabolic disorders.
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Affiliation(s)
- Inês V da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- Department Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
- Department Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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Dutta A, Das M. Deciphering the Role of Aquaporins in Metabolic Diseases: A Mini Review. Am J Med Sci 2022; 364:148-162. [DOI: 10.1016/j.amjms.2021.10.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 06/16/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022]
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Wawrzkiewicz-Jałowiecka A, Lalik A, Soveral G. Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue. Int J Mol Sci 2021; 22:5226. [PMID: 34069293 PMCID: PMC8157194 DOI: 10.3390/ijms22105226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023] Open
Abstract
The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient's hormonal status.
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Affiliation(s)
- Agata Wawrzkiewicz-Jałowiecka
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Anna Lalik
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland;
- Biotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Graça Soveral
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisboa, Portugal;
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Calamita G, Delporte C. Involvement of aquaglyceroporins in energy metabolism in health and disease. Biochimie 2021; 188:20-34. [PMID: 33689852 DOI: 10.1016/j.biochi.2021.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/23/2021] [Accepted: 03/01/2021] [Indexed: 11/27/2022]
Abstract
Aquaglyceroporins are a group of the aquaporin (AQP) family of transmembrane water channels. While AQPs facilitate the passage of water, small solutes, and gases across biological membranes, aquaglyceroporins allow passage of water, glycerol, urea and some other solutes. Thanks to their glycerol permeability, aquaglyceroporins are involved in energy homeostasis. This review provides an overview of what is currently known concerning the functional implication and control of aquaglyceroporins in tissues involved in energy metabolism, i.e. liver, adipose tissue and endocrine pancreas. The expression, role and (dys)regulation of aquaglyceroporins in disorders affecting energy metabolism, and the potential relevance of aquaglyceroporins as drug targets to treat the alterations of the energy balance is also addressed.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Bari, Italy
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, Brussels, Belgium.
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Oikonomou E, Kostopoulou E, Rojas-Gil AP, Georgiou G, Spiliotis BE. The metabolic implications of aquaporin 7 (AQP7) promoter variants in lean children and children with obesity. Hormones (Athens) 2020; 19:187-195. [PMID: 32146590 DOI: 10.1007/s42000-020-00184-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 02/13/2020] [Indexed: 01/27/2023]
Abstract
PURPOSE AQP7, a water/glycerol transporting protein, regulates adipocyte glycerol efflux and influences lipid and glucose homeostasis. Altered AQP7 expression in adults leads to impaired glycerol dynamics, adipocyte hypertrophy, and a predisposition to obesity and diabetes. AQP7 gene promoter variants lead to impaired AQP7-mediated adipocyte glycerol efflux and adipocyte hypertrophy. To assess its possible involvement in childhood obesity and metabolic abnormalities, the AQP7 promoter was studied in order to identify possible mutations and/or polymorphisms in children. METHODS Genomic DNA was extracted from the blood of 61 lean children (BMI < 85%) (46 prepubertal and 15 pubertal) and 41 children with obesity (BMI > 95%) (22 prepubertal and 19 pubertal). The samples were sequenced for AQP7 promoter region - 2580 (2421) to - 1161 (3840) using Automated Sanger sequence analysis. RESULTS One novel mutation -2185 (T2816A) was found in an obese prepubertal child with low AQP7 mRNA expression, high levels of serum glycerol, and low serum insulin levels. The novel single nucleotide polymorphisms (SNPs) - 2291 (A2710G), - 2219 (C2782A), - 2091 (C2910A), and - 1932 (G3069A) were identified, together with the previously described SNP - 1884 (C3117T), rs3758268. The heterozygous state and the recessive allele of all four SNPs were related to a positive family history of diabetes mellitus type 2 (p = 0.001). CONCLUSIONS The novel mutation - 2185 (T2816A) might be associated with the lower gene expression of AQP7 and high levels of serum glycerol that possibly contribute to the obese phenotype. The heterozygous genotype of the four SNPs - 2291 (A2710G), - 2219 (C2782A), - 2091 (C2910A), and - 1884 (C3117T) in children may be related to a familial predisposition to diabetes mellitus type 2.
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Affiliation(s)
- Eleni Oikonomou
- Department of Paediatrics, Research Laboratory of the Division of Paediatric Endocrinology and Diabetes, University of Patras School of Medicine, 26504, Patras, Greece
| | - Eirini Kostopoulou
- Department of Paediatrics, Research Laboratory of the Division of Paediatric Endocrinology and Diabetes, University of Patras School of Medicine, 26504, Patras, Greece
| | - Andrea Paola Rojas-Gil
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Tripoli, Lakonias, Greece
| | - George Georgiou
- Department of Paediatric Surgery, Karamandaneio Children's Hospital, Patras, Greece
| | - Bessie E Spiliotis
- Department of Paediatrics, Research Laboratory of the Division of Paediatric Endocrinology and Diabetes, University of Patras School of Medicine, 26504, Patras, Greece.
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González-Dávalos L, Álvarez-Pérez M, Quesada-López T, Cereijo R, Campderrós L, Piña E, Shimada A, Villarroya F, Varela-Echavarria A, Mora O. Glucocorticoid gene regulation of aquaporin-7. VITAMINS AND HORMONES 2020; 112:179-207. [PMID: 32061341 DOI: 10.1016/bs.vh.2019.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
AQP7 is the primary glycerol transporter in white (WAT) and brown (BAT) adipose tissues. There are immediate and quantitatively important actions of cortisone over the expression of AQP7 in murine and human adipocytes. Short-term response (minutes) of cortisone treatment result in an mRNA overexpression in white and brown differentiated adipocytes (between 1.5 and 6 folds). Conversely, long-term response (hours or days) result in decreased mRNA expression. The effects observed on AQP7 mRNA expression upon cortisone treatment in brown and white differentiated adipocytes are concordant with those observed for GK and HSD1B11.
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Affiliation(s)
- Laura González-Dávalos
- Laboratorio de Rumiología y Metabolismo Nutricional (RuMeN), Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlán, Mexico
| | - Mariana Álvarez-Pérez
- Laboratorio de Rumiología y Metabolismo Nutricional (RuMeN), Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlán, Mexico
| | - Tania Quesada-López
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Rubén Cereijo
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Laura Campderrós
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Enrique Piña
- Departamento de Bioquímica, Facultad de Medicina, UNAM, Ciudad de México, Mexico
| | - Armando Shimada
- Laboratorio de Rumiología y Metabolismo Nutricional (RuMeN), Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlán, Mexico
| | - Francesc Villarroya
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Alfredo Varela-Echavarria
- Laboratorio de Diferenciación Neural y Axogénesis, Instituto de Neurobiología, UNAM, Querétaro, Mexico
| | - Ofelia Mora
- Laboratorio de Rumiología y Metabolismo Nutricional (RuMeN), Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlán, Mexico.
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Arsenijevic T, Perret J, Van Laethem JL, Delporte C. Aquaporins Involvement in Pancreas Physiology and in Pancreatic Diseases. Int J Mol Sci 2019; 20:E5052. [PMID: 31614661 PMCID: PMC6834120 DOI: 10.3390/ijms20205052] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/10/2019] [Accepted: 10/11/2019] [Indexed: 12/14/2022] Open
Abstract
Aquaporins are a family of transmembrane proteins permeable to water. In mammals, they are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H2O2 through cell membranes; and so called unorthodox aquaporins. Aquaporins ensure important physiological functions in both exocrine and endocrine pancreas. Indeed, they are involved in pancreatic fluid secretion and insulin secretion. Modification of aquaporin expression and/or subcellular localization may be involved in the pathogenesis of pancreatic insufficiencies, diabetes and pancreatic cancer. Aquaporins may represent useful drug targets for the treatment of pathophysiological conditions affecting pancreatic function, and/or diagnostic/predictive biomarker for pancreatic cancer. This review summarizes the current knowledge related to the involvement of aquaporins in the pancreas physiology and physiopathology.
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Affiliation(s)
- Tatjana Arsenijevic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium.
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hôpital Erasme, Université Libre de Bruxelles, 808, Route de Lennik, 1070 Brussels, Belgium.
| | - Jason Perret
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium.
| | - Jean-Luc Van Laethem
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium.
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hôpital Erasme, Université Libre de Bruxelles, 808, Route de Lennik, 1070 Brussels, Belgium.
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium.
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11
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Associations between Aquaglyceroporin Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8167538. [PMID: 30598999 PMCID: PMC6288565 DOI: 10.1155/2018/8167538] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 09/24/2018] [Indexed: 12/11/2022]
Abstract
Objectives AQP7 and AQP9 represent glycerol channel in adipose tissue and liver and have been associated with metabolic diseases. We aimed to investigate the associations between genetic variants in AQP7 and AQP9 genes and the risk of type 2 diabetes (T2DM) in Chinese population. Methods Blood samples were drawn from 400 T2DM patients and 400 age- and gender-matched controls. Genomic DNA was extracted by proteinase K digestion and phenol–chloroform extraction. Genotyping of 5 single nucleotide polymorphisms (SNPs) in AQP7 (rs2989924, rs3758269, and rs62542743) and AQP9 (rs57139208, rs16939881) was performed by the polymerase chain reaction assay with TaqMan probes. Results The subjects with rs2989924 GA+AA genotypes had 1.47-fold increased risk of T2DM (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.06-2.04), compared to those with GG genotype, and this association remained significant after adjustment for covariates (OR 1.66, 95% CI 1.07-2.57). When compared with rs3758269 CC genotype, the subjects with CT+TT genotypes had 45% decreased T2DM risk after multivariate adjustment (OR 0.55, 95% CI 0.35-0.85). The associations were evident in elder and overweight subjects and those with central obesity. No association was observed between AQP9 SNPs and T2DM risk. Conclusions AQP7 SNP rs2989924 and rs3758269 were associated with T2DM risk in Chinese Han population.
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12
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The role of insulin receptor substrate 1 gene polymorphism Gly972Arg as a risk factor for ischemic stroke among Indonesian subjects. BMC Res Notes 2018; 11:718. [PMID: 30305144 PMCID: PMC6180639 DOI: 10.1186/s13104-018-3823-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 10/04/2018] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE The identification of new genetic-associated risk factor of ischemic stroke could improves strategies for stroke prevention. This study aims to identify insulin receptor substrate 1 (IRS-1) gene polymorphism Gly972Arg as the risk factor for ischemic stroke among Indonesian subjects. The case-control study was conducted by matching the gender and race on 85 cases of patients with ischemic stroke and 86 healthy non-stroke control subjects. Ischemic stroke was established by the complete neurology examination and brain computed tomography scan or magnetic resonance imaging. Polymerase chain reaction-Restriction Fragment Length Polymorphism was performed to analyze IRS-1 gene Gly972Arg genotype. RESULTS There were 85 ischemic stroke cases and 86 control subjects. The distribution of nucleotide IRS-1 gene polymorphism Gly972Arg in the ischemic stroke vs health controls for GG were 32.2% vs 41.5%, for GR were 16% vs 7.6%, and for RR were 0.5% vs 1.9%. IRS-1 gene polymorphism Gly972Arg was found as significant risk factor for ischemic stroke [odds ratio of 2.6 (1.27-5.27); CI 95%, p = 0.008]. Conclusively, the IRS-1 gene polymorphism Gly972Arg should be considered as an important factor in the prevention and treatment of ischemic stroke.
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Calamita G, Perret J, Delporte C. Aquaglyceroporins: Drug Targets for Metabolic Diseases? Front Physiol 2018; 9:851. [PMID: 30042691 PMCID: PMC6048697 DOI: 10.3389/fphys.2018.00851] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 06/15/2018] [Indexed: 12/29/2022] Open
Abstract
Aquaporins (AQPs) are a family of transmembrane channel proteins facilitating the transport of water, small solutes, and gasses across biological membranes. AQPs are expressed in all tissues and ensure multiple roles under normal and pathophysiological conditions. Aquaglyceroporins are a subfamily of AQPs permeable to glycerol in addition to water and participate thereby to energy metabolism. This review focalizes on the present knowledge of the expression, regulation and physiological roles of AQPs in adipose tissue, liver and endocrine pancreas, that are involved in energy metabolism. In addition, the review aims at summarizing the involvement of AQPs in metabolic disorders, such as obesity, diabetes and liver diseases. Finally, challenges and recent advances related to pharmacological modulation of AQPs expression and function to control and treat metabolic diseases are discussed.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy
| | - Jason Perret
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, Brussels, Belgium
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, Brussels, Belgium
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da Silva IV, Rodrigues JS, Rebelo I, Miranda JPG, Soveral G. Revisiting the metabolic syndrome: the emerging role of aquaglyceroporins. Cell Mol Life Sci 2018; 75:1973-1988. [PMID: 29464285 PMCID: PMC11105723 DOI: 10.1007/s00018-018-2781-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/05/2018] [Accepted: 02/15/2018] [Indexed: 02/07/2023]
Abstract
The metabolic syndrome (MetS) includes a group of medical conditions such as insulin resistance (IR), dyslipidemia and hypertension, all associated with an increased risk for cardiovascular disease. Increased visceral and ectopic fat deposition are also key features in the development of IR and MetS, with pathophysiological sequels on adipose tissue, liver and muscle. The recent recognition of aquaporins (AQPs) involvement in adipose tissue homeostasis has opened new perspectives for research in this field. The members of the aquaglyceroporin subfamily are specific glycerol channels implicated in energy metabolism by facilitating glycerol outflow from adipose tissue and its systemic distribution and uptake by liver and muscle, unveiling these membrane channels as key players in lipid balance and energy homeostasis. Being involved in a variety of pathophysiological mechanisms including IR and obesity, AQPs are considered promising drug targets that may prompt novel therapeutic approaches for metabolic disorders such as MetS. This review addresses the interplay between adipose tissue, liver and muscle, which is the basis of the metabolic syndrome, and highlights the involvement of aquaglyceroporins in obesity and related pathologies and how their regulation in different organs contributes to the features of the metabolic syndrome.
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Affiliation(s)
- Inês Vieira da Silva
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003, Lisbon, Portugal
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal
| | - Joana S Rodrigues
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003, Lisbon, Portugal
- Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal
| | - Irene Rebelo
- UCIBIO, REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, Universidade do Porto, Porto, Portugal
| | - Joana P G Miranda
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003, Lisbon, Portugal
- Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal
| | - Graça Soveral
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003, Lisbon, Portugal.
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal.
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15
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Fex M, Nicholas LM, Vishnu N, Medina A, Sharoyko VV, Nicholls DG, Spégel P, Mulder H. The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol 2018; 236:R145-R159. [PMID: 29431147 DOI: 10.1530/joe-17-0367] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Affiliation(s)
- Malin Fex
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Lisa M Nicholas
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Neelanjan Vishnu
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Anya Medina
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Vladimir V Sharoyko
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - David G Nicholls
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Peter Spégel
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
- Department of ChemistryCenter for Analysis and Synthesis, Lund University, Sweden
| | - Hindrik Mulder
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
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16
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Iena FM, Lebeck J. Implications of Aquaglyceroporin 7 in Energy Metabolism. Int J Mol Sci 2018; 19:ijms19010154. [PMID: 29300344 PMCID: PMC5796103 DOI: 10.3390/ijms19010154] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 12/29/2017] [Accepted: 12/31/2017] [Indexed: 12/14/2022] Open
Abstract
The aquaglyceroporin AQP7 is a pore-forming transmembrane protein that facilitates the transport of glycerol across cell membranes. Glycerol is utilized both in carbohydrate and lipid metabolism. It is primarily stored in white adipose tissue as part of the triglyceride molecules. During states with increased lipolysis, such as fasting and diabetes, glycerol is released from adipose tissue and metabolized in other tissues. AQP7 is expressed in adipose tissue where it facilitates the efflux of glycerol, and AQP7 deficiency has been linked to increased glycerol kinase activity and triglyceride accumulation in adipose tissue, leading to obesity and secondary development of insulin resistance. However, AQP7 is also expressed in a wide range of other tissues, including kidney, muscle, pancreatic β-cells and liver, where AQP7 also holds the potential to influence whole body energy metabolism. The aim of the review is to summarize the current knowledge on AQP7 in adipose tissue, as well as AQP7 expressed in other tissues where AQP7 might play a significant role in modulating whole body energy metabolism.
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Affiliation(s)
- Francesco Maria Iena
- Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
| | - Janne Lebeck
- Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
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17
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Abstract
Obesity is one of the most important metabolic disorders of this century and is associated with a cluster of the most dangerous cardiovascular disease risk factors, such as insulin resistance and diabetes , dyslipidemia and hypertension , collectively named Metabolic Syndrome. The role of aquaporins in glycerol metabolism facilitating glycerol release from the adipose tissue and distribution to various tissues and organs, unveils these membrane channels as important players in lipid balance and energy homeostasis and points to their involvement in a variety of pathophysiological mechanisms including insulin resistance, obesity and diabetes.This review summarizes the physiologic role of aquaglyceroporins in glycerol metabolism and lipid homeostasis, describing their specific tissue distribution, their involvement in glycerol balance and their implication in obesity and fat-related metabolic complications. The development of specify pharmacologic modulators able to regulate aquaglyceroporins expression and function , in particular AQP7 in adipose tissue, might constitute a novel approach for controlling obesity and other metabolic disorders.
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Affiliation(s)
- Inês Vieira da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, 1649-003, Portugal
- Department of Bioquimica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, 1649-003, Portugal.
- Department of Bioquimica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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18
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López-Barradas A, González-Cid T, Vázquez N, Gavi-Maza M, Reyes-Camacho A, Velázquez-Villegas LA, Ramírez V, Zandi-Nejad K, Mount DB, Torres N, Tovar AR, Romero MF, Gamba G, Plata C. Insulin and SGK1 reduce the function of Na+/monocarboxylate transporter 1 (SMCT1/SLC5A8). Am J Physiol Cell Physiol 2016; 311:C720-C734. [PMID: 27488665 DOI: 10.1152/ajpcell.00104.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/27/2016] [Indexed: 11/22/2022]
Abstract
SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.
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Affiliation(s)
- Adriana López-Barradas
- Department of Physiology of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Tania González-Cid
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Norma Vázquez
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico.,Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM, Tlalpan, Mexico City, Mexico
| | - Marisol Gavi-Maza
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Adriana Reyes-Camacho
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Laura A Velázquez-Villegas
- Department of Physiology of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Victoria Ramírez
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | | | - David B Mount
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.,Veterans Affairs Boston Healthcare System, Boston, Massachusetts; and
| | - Nimbe Torres
- Department of Physiology of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Armando R Tovar
- Department of Physiology of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico
| | - Michael F Romero
- Physiology & Biomedical Engineering, Nephrology & Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Gerardo Gamba
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico.,Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM, Tlalpan, Mexico City, Mexico
| | - Consuelo Plata
- Department of Nephrology & Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico;
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19
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Cigliola V, Populaire C, Pierri CL, Deutsch S, Haefliger JA, Fadista J, Lyssenko V, Groop L, Rueedi R, Thorel F, Herrera PL, Meda P. A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells. PLoS One 2016; 11:e0150880. [PMID: 26959991 PMCID: PMC4784816 DOI: 10.1371/journal.pone.0150880] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/20/2016] [Indexed: 01/16/2023] Open
Abstract
Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis.
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Affiliation(s)
- Valentina Cigliola
- Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
| | - Celine Populaire
- Centre Hospitalier Régional Universitaire Besançon, Besançon, France
| | - Ciro L. Pierri
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | - Samuel Deutsch
- Joint Genome Institute, Walnut Creek, California, United States of America
| | | | - João Fadista
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden
| | - Valeriya Lyssenko
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- Steno Diabetes Center A/S, Gentofte, Denmark
| | - Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden
| | - Rico Rueedi
- Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland
| | - Fabrizio Thorel
- Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
| | - Pedro Luis Herrera
- Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
| | - Paolo Meda
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneva, Switzerland
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20
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Abstract
Adhesion G protein-coupled receptors (aGPCRs) have a long evolutionary history dating back to very basal unicellular eukaryotes. Almost every vertebrate is equipped with a set of different aGPCRs. Genomic sequence data of several hundred extinct and extant species allows for reconstruction of aGPCR phylogeny in vertebrates and non-vertebrates in general but also provides a detailed view into the recent evolutionary history of human aGPCRs. Mining these sequence sources with bioinformatic tools can unveil many facets of formerly unappreciated aGPCR functions. In this review, we extracted such information from the literature and open public sources and provide insights into the history of aGPCR in humans. This includes comprehensive analyses of signatures of selection, variability of human aGPCR genes, and quantitative traits at human aGPCR loci. As indicated by a large number of genome-wide genotype-phenotype association studies, variations in aGPCR contribute to specific human phenotypes. Our survey demonstrates that aGPCRs are significantly involved in adaptation processes, phenotype variations, and diseases in humans.
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Affiliation(s)
- Peter Kovacs
- Integrated Research and Treatment Center (IFB) AdiposityDiseases, Medical Faculty, University of Leipzig, Liebigstr. 21, Leipzig, 04103, Germany.
| | - Torsten Schöneberg
- Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig, 04103, Germany.
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21
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Tekola-Ayele F, Doumatey AP, Shriner D, Bentley AR, Chen G, Zhou J, Fasanmade O, Johnson T, Oli J, Okafor G, Eghan BA, Agyenim-Boateng K, Adebamowo C, Amoah A, Acheampong J, Adeyemo A, Rotimi CN. Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome. Mol Genet Metab 2015; 116:305-13. [PMID: 26507551 PMCID: PMC5292212 DOI: 10.1016/j.ymgme.2015.10.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 10/21/2015] [Accepted: 10/21/2015] [Indexed: 12/21/2022]
Abstract
The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 × 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 × 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 × 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 × 10(-8), Pmeta=7.82 × 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.
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Affiliation(s)
- Fasil Tekola-Ayele
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Ayo P Doumatey
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Daniel Shriner
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Amy R Bentley
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Guanjie Chen
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jie Zhou
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - Johnnie Oli
- University of Nigeria Teaching Hospital, Enugu, Nigeria
| | | | - Benjami A Eghan
- University of Science and Technology, Department of Medicine, Kumasi, Ghana
| | | | - Clement Adebamowo
- Department of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Albert Amoah
- University of Ghana Medical School, Department of Medicine, Accra, Ghana
| | - Joseph Acheampong
- University of Science and Technology, Department of Medicine, Kumasi, Ghana
| | - Adebowale Adeyemo
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Charles N Rotimi
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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22
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Madeira A, Moura TF, Soveral G. Aquaglyceroporins: implications in adipose biology and obesity. Cell Mol Life Sci 2015; 72:759-71. [PMID: 25359234 PMCID: PMC11113391 DOI: 10.1007/s00018-014-1773-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/07/2014] [Accepted: 10/27/2014] [Indexed: 01/19/2023]
Abstract
Aquaporins (AQPs) are membrane water/glycerol channels that are involved in many physiological processes. Their primary function is to facilitate the bidirectional transfer of water and small solutes across biological membranes in response to osmotic gradients. Aquaglyceroporins, a subset of the AQP family, are the only mammalian proteins with the ability to permeate glycerol. For a long time, AQP7 has been the only aquaglyceroporin associated with the adipose tissue, which is the major source of circulating glycerol in response to the energy demand. AQP7 dysregulation was positively correlated with obesity onset and adipocyte glycerol permeation through AQP7 was appointed as a novel regulator of adipocyte metabolism and whole-body fat mass. Recently, AQP3, AQP9, AQP10 and AQP11 were additionally identified in human adipocytes and proposed as additional glycerol pathways in these cells. This review contextualizes the importance of aquaglyceroporins in adipose tissue biology and highlights aquaglyceroporins' unique structural features which are relevant for the design of effective therapeutic compounds. We also refer to the latest advances in the identification and characterization of novel aquaporin isoforms in adipose tissue. Finally, considerations on the actual progress of aquaporin research and its implications on obesity therapy are suggested.
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Affiliation(s)
- Ana Madeira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon, 1649-003 Portugal
- Department of Bioquimica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Teresa F. Moura
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon, 1649-003 Portugal
- FCT-UNL, 2829-516 Caparica, Portugal
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon, 1649-003 Portugal
- Department of Bioquimica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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23
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Olsson AH, Volkov P, Bacos K, Dayeh T, Hall E, Nilsson EA, Ladenvall C, Rönn T, Ling C. Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets. PLoS Genet 2014; 10:e1004735. [PMID: 25375650 PMCID: PMC4222689 DOI: 10.1371/journal.pgen.1004735] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 09/05/2014] [Indexed: 12/29/2022] Open
Abstract
Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic variation interacts to influence gene expression, islet function and potential diabetes risk in humans. Inter-individual variation in genetics and epigenetics affects biological processes and disease susceptibility. However, most studies have investigated genetic and epigenetic mechanisms independently and to uncover novel mechanisms affecting disease susceptibility there is a highlighted need to study interactions between these factors on a genome-wide scale. To identify novel loci affecting islet function and potentially diabetes, we performed the first genome-wide methylation quantitative trait locus (mQTL) analysis in human pancreatic islets including DNA methylation of 468,787 CpG sites located throughout the genome. Our results showed that DNA methylation of 11,735 CpGs in 4,504 unique genes is regulated by genetic factors located in cis (67,438 SNP-CpG pairs). Furthermore, significant mQTLs cover previously reported diabetes loci including KCNJ11, INS, HLA, PDX1 and GRB10. We also found mQTLs associated with gene expression and insulin secretion in human islets. By performing causality inference tests (CIT), we identified CpGs where DNA methylation potentially mediates the genetic impact on gene expression and insulin secretion. Our functional follow-up experiments further demonstrated that identified mQTLs/genes (GPX7, GSTT1 and SNX19) directly affect pancreatic β-cell function. Together, our study provides a detailed map of genome-wide associations between genetic and epigenetic variation, which affect gene expression and insulin secretion in human pancreatic islets.
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Affiliation(s)
- Anders H. Olsson
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Petr Volkov
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Karl Bacos
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Tasnim Dayeh
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Elin Hall
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Emma A. Nilsson
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Claes Ladenvall
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Tina Rönn
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
| | - Charlotte Ling
- Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden
- * E-mail:
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Abstract
Obesity and secondary development of type 2 diabetes (T2D) are major health care problems throughout the developed world. Accumulating evidence suggest that glycerol metabolism contributes to the pathophysiology of obesity and T2D. Glycerol is a small molecule that serves as an important intermediate between carbohydrate and lipid metabolism. It is stored primarily in adipose tissue as the backbone of triglyceride (TG) and during states of metabolic stress, such as fasting and diabetes, it is released for metabolism in other tissues. In the liver, glycerol serves as a gluconeogenic precursor and it is used for the esterification of free fatty acid into TGs. Aquaporin 7 (AQP7) in adipose tissue and AQP9 in the liver are transmembrane proteins that belong to the subset of AQPs called aquaglyceroporins. AQP7 facilitates the efflux of glycerol from adipose tissue and AQP7 deficiency has been linked to TG accumulation in adipose tissue and adult onset obesity. On the other hand, AQP9 expressed in liver facilitates the hepatic uptake of glycerol and thereby the availability of glycerol for de novo synthesis of glucose and TG that both are involved in the pathophysiology of diabetes. The aim of this review was to summarize the current knowledge on the role of the two glycerol channels in controlling glycerol metabolism in adipose tissue and liver.
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Affiliation(s)
- Janne Lebeck
- The Danish Diabetes Academy, Odense, Denmark Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, DK-8000 Aarhus, Denmark
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25
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Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 2014; 10:e1004160. [PMID: 24603685 PMCID: PMC3945174 DOI: 10.1371/journal.pgen.1004160] [Citation(s) in RCA: 350] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 12/20/2013] [Indexed: 01/09/2023] Open
Abstract
Impaired insulin secretion is a hallmark of type 2 diabetes (T2D). Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea) were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼ 7%) and overrepresented in the open sea (∼ 60%). 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These results highlight the importance of epigenetics in the pathogenesis of T2D.
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26
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Aslibekyan S, An P, Frazier-Wood AC, Kabagambe EK, Irvin MR, Straka RJ, Tiwari HK, Tsai MY, Hopkins PN, Borecki IB, Ordovas JM, Arnett DK. Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. Nutr Metab Cardiovasc Dis 2013; 23:987-994. [PMID: 23149075 PMCID: PMC3578131 DOI: 10.1016/j.numecd.2012.07.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Revised: 07/27/2012] [Accepted: 07/27/2012] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIMS Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. METHODS AND RESULTS Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10⁻⁸) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. CONCLUSIONS We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.
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Affiliation(s)
- S Aslibekyan
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, RPHB 217G, Birmingham, AL 35294, USA.
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27
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Suh YJ, Kim S, Kim SH, Park J, Lim HA, Park HJ, Choi H, Ng D, Lee MK, Nam M. Combined genome-wide linkage and association analyses of fasting glucose level in healthy twins and families of Korea. J Korean Med Sci 2013; 28:415-23. [PMID: 23487342 PMCID: PMC3594606 DOI: 10.3346/jkms.2013.28.3.415] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 01/04/2013] [Indexed: 11/20/2022] Open
Abstract
This study was undertaken to identify genetic polymorphisms that are associated with the risk of an elevated fasting glucose (FG) level using genome-wide analyses. We explored a quantitative trait locus (QTL) for FG level in a genome-wide study from a Korean twin-family cohort (the Healthy Twin Study) using a combined linkage and family-based association analysis approach. We investigated 1,754 individuals, which included 432 families and 219 pairs of monozygotic twins. Regions of chromosomes 2q23.3-2q31.1, 15q26.1-15q26.3, 16p12.1, and 20p13-20p12.2, were found to show evidence of linkage with FG level, and several markers in these regions were found to be significantly associated with FG level using family-based or general association tests. In particular, a single-nucleotide polymorphism (rs6138953) on the PTPRA gene in the 20p13 region (combined P = 1.8 × 10(-6)) was found to be associated with FG level, and the PRKCB1 gene (in 16p12.1) to be possibly associated with FG level. In conclusion, multiple regions of chromosomes 2q23.3-2q31.1, 15q26.1-15q26.3, 16p12.1, and 20p13-20p12.2 are associated with FG level in our Korean twin-family cohort. The combined approach of genome-wide linkage and family-based association analysis is useful to identify novel or known genetic regions concerning FG level in a family cohort study.
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MESH Headings
- Adult
- Aged
- Asian People/genetics
- Blood Glucose/genetics
- Chromosomes, Human, Pair 15/genetics
- Chromosomes, Human, Pair 16/genetics
- Chromosomes, Human, Pair 2/genetics
- Chromosomes, Human, Pair 20/genetics
- Cohort Studies
- Family
- Female
- Genetic Linkage
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Protein Kinase C/genetics
- Protein Kinase C beta
- Quantitative Trait Loci
- Receptor-Like Protein Tyrosine Phosphatases, Class 4/genetics
- Republic of Korea
- Twins, Monozygotic/genetics
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Affiliation(s)
- Young Ju Suh
- Institute of Clinical Research, Inha University School of Medicine, Incheon, Korea
| | - SungHwan Kim
- Department of Biostatistics, University of Pittsburg, PA, USA
| | - So Hun Kim
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Jia Park
- Clinical Trial Center, Inha University Hospital, Incheon, Korea
| | - Hyun Ae Lim
- Clinical Trial Center, Inha University Hospital, Incheon, Korea
| | - Hyun Ju Park
- Clinical Trial Center, Inha University Hospital, Incheon, Korea
| | | | - Daniel Ng
- Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mi Kyeong Lee
- Department of Epidemiology and Institute of Environment and Health, Seoul National University School of Public Health, Seoul, Korea
| | - Moonsuk Nam
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
- Clinical Trial Center, Inha University Hospital, Incheon, Korea
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28
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Park MH, Kwak SH, Kim KJ, Go MJ, Lee HJ, Kim KS, Hwang JY, Kimm K, Cho YM, Lee HK, Park KS, Lee JY. Identification of a genetic locus on chromosome 4q34-35 for type 2 diabetes with overweight. Exp Mol Med 2013; 45:e7. [PMID: 23392254 PMCID: PMC3584667 DOI: 10.1038/emm.2013.5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The incidence of type 2 diabetes is rising rapidly because of an increase in the incidence of being overweight and obesity. Identification of genetic determinants for complex diseases, such as type 2 diabetes, may provide insight into disease pathogenesis. The aim of the study was to investigate the shared genetic factors that predispose individuals to being overweight and developing type 2 diabetes. We conducted genome-wide linkage analyses for type 2 diabetes in 386 affected individuals (269 sibpairs) from 171 Korean families and association analyses with single-nucleotide polymorphisms of candidate genes within linkage regions to identify genetic variants that predispose individuals to being overweight and developing type 2 diabetes. Through fine-mapping analysis of chromosome 4q34-35, we detected a locus potentially linked (nonparametric linkage 2.81, logarithm of odds 2.27, P=6 × 10−4) to type 2 diabetes in overweight or obese individuals (body mass index, BMI⩾23 kg m−2). Multiple regression analysis with type 2 diabetes-related phenotypes revealed a significant association (false discovery rate (FDR) P=0.006 for rs13144140; FDR P=0.002 for rs6830266) between GPM6A (rs13144140) and BMI and waist–hip ratio, and between NEIL3 (rs6830266) and insulin level from 1314 normal individuals. Our systematic search of genome-wide linkage and association studies, demonstrate that a linkage peak for type 2 diabetes on chromosome 4q34-35 contains two type 2 diabetes-related genes, GPM6A and NEIL3.
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Affiliation(s)
- Mi-Hyun Park
- Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Korea
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29
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Chen K, Jin X, Li Q, Wang W, Wang Y, Zhang J. Association of TRPC1 gene polymorphisms with type 2 diabetes and diabetic nephropathy in Han Chinese population. Endocr Res 2013; 38:59-68. [PMID: 23544998 PMCID: PMC3619450 DOI: 10.3109/07435800.2012.681824] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The recent genome-wide association studies reveal that chromosome 3q resides within the linkage region for diabetic nephropathy (DN) in type 1 and type 2 diabetes mellitus (T1D and T2D). The TRPC1 gene is on chromosome 3q22-24, and it has been demonstrated that TRPC1 expression is reduced in the kidney of diabetic animal models. Genetic association of TRPC1 polymorphism with T1D and DN has been reported in European Americans. However, there are no studies reporting the association of TRPC1 genetic polymorphism with T2D with and without DN in Chinese population. This study aimed to demonstrate the genetic role of TRPC1 in the development of T2D with and without DN in Chinese Han population. A genetic association study of TRPC1 was performed in T2D cases and in nondiabetic controls from Han population located in Northern Chinese areas. Six tag single nucleotide polymorphism (SNP) markers derived from HapMap data were genotyped. Among the six SNPs, only rs7638459 was suspected as risk factor of T2D without DN, fitting the log-additive model. The adjusted odds ratio (OR) for the CC genotyping was 2.39 (95% confidence interval (CI) = 1.00-5.68), compared with the TT genotyping. In addition, rs953239 was found to be a protective factor of getting DN in T2D, also fitting the log-additive model. When compared with the AA genotyping for SNP rs953239, the adjusted OR for CC genotyping was 0.63 (95% CI = 0.44-0.99). To summarize, this study shows that TRPC1 genetic polymorphisms are associated with T2D and DN in T2D in the Han Chinese population.
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Affiliation(s)
- Kelin Chen
- Departmentof Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuehua Jin
- Department of Endocrinology and Metabolism, Daqing Oil Field General Hospital, Daqing, China
| | - Qiang Li
- Departmentof Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Wang
- Departmentof Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yan Wang
- Department of Endocrinology and Metabolism, Daqing Oil Field General Hospital, Daqing, China
| | - Jinchao Zhang
- Departmentof Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Lebeck J, Østergård T, Rojek A, Füchtbauer EM, Lund S, Nielsen S, Praetorius J. Gender-specific effect of physical training on AQP7 protein expression in human adipose tissue. Acta Diabetol 2012; 49 Suppl 1:S215-26. [PMID: 23001483 DOI: 10.1007/s00592-012-0430-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 09/03/2012] [Indexed: 02/08/2023]
Abstract
AQP7 is a glycerol channel in adipose tissue with a suggested role in controlling the accumulation of triglycerides and secondly development of obesity and type-2 diabetes. In the present study, we aimed to test the hypotheses that (1) AQP7 is localized to the capillaries within human adipose tissue, (2) genetic predisposition to type-2 diabetes is associated with a low expression of AQP7 in abdominal subcutaneous adipose tissue (SAT) and (3) physical training increases AQP7 expression in SAT. The cellular localization of AQP7 in adipose tissue was investigated by immunohistochemistry. The relative expression of AQP7 protein in abdominal SAT was analysed before and after ending a 10-week exercise training programme in first-degree relatives to type-2 diabetic patients and control individuals. Non-obese first-degree relatives to type-2 diabetic patients (n = 20) and control (n = 11) men and women participated in this study. By this, we find that AQP7 is localized to the capillary endothelial cells within adipose tissue. We were unable to evidence a link between a low AQP7 abundance in SAT and genetic predisposition type-2 diabetes. Instead we demonstrate that physical training influences the expression of AQP7 in SAT in a gender-specific manner. Thus, women responds by increasing the abundance of AQP7 by 2.2-fold (p = 0.03) whereas in men a reduced expression is observed (p = 0.00009), resulting in a more than twofold higher abundance of AQP7 in women as compared with men. In conclusion, the adipose tissue glycerol channel, AQP7, is regulated in response to physical training in a gender-dependent manner in SAT.
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Affiliation(s)
- Janne Lebeck
- Department of Biomedicine, The Water and Salt Research Center, Health, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
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31
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Giguère Y, Charland M, Thériault S, Bujold E, Laroche M, Rousseau F, Lafond J, Forest JC. Linking preeclampsia and cardiovascular disease later in life. Clin Chem Lab Med 2012; 50:985-93. [PMID: 22107134 DOI: 10.1515/cclm.2011.764] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Preeclampsia (PE), which is defined as new onset hypertension after 20 weeks of pregnancy accompanied by proteinuria, is characterized by inadequate placentation, oxidative stress, inflammation and widespread endothelial dysfunction. A link between PE and long-term risk of cardiovascular disease (CVD) was suggested by retrospective studies, which found that PE was associated with a 2–3-fold risk of CVD later in life, with a 5–7-fold risk in the case of severe and/or early-onset PE. Recently, meta-analyses and prospective studies have confirmed the association between PE and the emergence of an unfavorable CVD risk profile, in particular a 3–5-fold increased prevalence of the metabolic syndrome only 8 years after the index pregnancy. PE and CVD share many risk factors, including obesity, hypertension, dyslipidemia, hypercoagulability, insulin resistance and both entities are characterized by endothelial dysfunction. PE and CVD are complex traits sharing common risk factors and pathophysiological processes, but the genetic link between both remains to be elucidated. However, recent evidence suggests that genetic determinants associated with the metabolic syndrome, inflammation and subsequent endothelial dysfunction are involved. As the evidence now supports that PE represents a risk factor for the emergence of the metabolic syndrome and CVD later in life, the importance of long-term follow-up assessment of CVD risk beginning early in women with a history of PE must be considered and translated into new preventive measures.
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Affiliation(s)
- Yves Giguère
- Centre Hospitalier Universitaire de Québec, Québec City, QC, Canada.
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32
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Kim KZ, Min JY, Kwon GY, Sung JH, Cho SI. Directed Causal Network Construction Using Linkage Analysis with Metabolic Syndrome-Related Expression Quantitative Traits. Genomics Inform 2011. [DOI: 10.5808/gi.2011.9.4.143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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33
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Juárez-Meavepeña M, Carreón-Torres E, López-Osorio C, García-Sánchez C, Gamboa R, Torres-Tamayo M, Fragoso JM, Rodríguez-Pérez JM, Vargas-Alarcón G, Pérez-Méndez O. The Srb1+1050T allele is associated with metabolic syndrome in children but not with cholesteryl ester plasma concentrations of high-density lipoprotein subclasses. Metab Syndr Relat Disord 2011; 10:110-6. [PMID: 22182283 DOI: 10.1089/met.2011.0071] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Low cholesterol and phospholipid plasma levels of some high-density lipoprotein (HDL) subclasses have been described in children with metabolic syndrome. Scavenger receptor class B type I (SR-BI) has been proposed to be at the origin of such HDL alterations because of its key role on cholesteryl esters-HDL metabolism. However, the possible contribution of SR-BI has not been specifically explored in this kind of patients. METHODS Plasma lipid concentrations of HDL subclasses, i.e., triglycerides (TG), phosphatidylcholine (Ph), free cholesterol (FC), and total cholesterol (TC), were determined by enzymatic staining on polyacrylamide gradient gels (PAGE) in 39 pediatric patients with metabolic syndrome and 65 children as controls. Cholesteryl esters were estimated by the difference between TC and FC. Proteins of HDL subclasses were also stained for the assessment of the relative size distribution of HDL. For statistical analysis, the study population was grouped by Srb1 +1050C-->T polymorphism (rs5888) as carriers or noncarriers of the T allele, and data were corrected by metabolic syndrome status. RESULTS The Srb1 +1050T allele was associated with metabolic syndrome [odds ratio (OR)=2.18 (1.12-4.22), P=0.02]. Plasma TG corresponding to HDL3a, as well as the relative proportion of this HDL subclass, were slightly higher in carriers of the T allele as compared to CC homozygous subjects. Cholesteryl esters plasma concentrations of all HDL subclasses were comparable between T allele carriers and noncarriers after correction by metabolic syndrome status. CONCLUSIONS Srb1 +1050T was associated with metabolic syndrome, but T carrier subjects did not show important differences concerning HDL subclasses as compared to noncarriers.
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Affiliation(s)
- Minerva Juárez-Meavepeña
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
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Revelli JP, Smith D, Allen J, Jeter-Jones S, Shadoan MK, Desai U, Schneider M, van Sligtenhorst I, Kirkpatrick L, Platt KA, Suwanichkul A, Savelieva K, Gerhardt B, Mitchell J, Syrewicz J, Zambrowicz B, Hamman BD, Vogel P, Powell DR. Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. Obesity (Silver Spring) 2011; 19:1010-8. [PMID: 21127480 DOI: 10.1038/oby.2010.282] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The kinase suppressor of ras 2 (KSR2) gene resides at human chromosome 12q24, a region linked to obesity and type 2 diabetes (T2D). While knocking out and phenotypically screening mouse orthologs of thousands of druggable human genes, we found KSR2 knockout (KSR2(-/-)) mice to be more obese and glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. The obesity and T2D of KSR2(-/-) mice resulted from hyperphagia which was unresponsive to leptin and did not originate downstream of MC4R. The kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in KSR2(-/-) mouse brain, and the ability of rapamycin to inhibit food intake in KSR2(-/-) mice further implicated mTOR in this process. The metabolic phenotype of KSR2 heterozygous (KSR2(+/minus;)) and KSR2(-/-) mice suggests that human KSR2 variants may contribute to a similar phenotype linked to human chromosome 12q24.
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35
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Cruz-Mariño T, González-Zaldivar Y, Laffita-Mesa JM, Almaguer-Mederos L, Aguilera-Rodríguez R, Almaguer-Gotay D, Rodríguez-Labrada R, Canales-Ochoa N, Macleod P, Velázquez-Pérez L. Uncommon features in Cuban families affected with Friedreich ataxia. Neurosci Lett 2010; 472:85-9. [PMID: 20109528 DOI: 10.1016/j.neulet.2010.01.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 12/23/2009] [Accepted: 01/21/2010] [Indexed: 01/19/2023]
Abstract
This report describes two families who presented with autosomal recessive ataxia. By means of Polymerase Chain Reaction (PCR) molecular testing we identified expansions in the gene encoding Frataxin (FTX) that is diagnostic of Friedreich ataxia. A history of reproductive loss in the two families, prominent scoliosis deformity preceding the onset of ataxic gait, the presence of a sensitive axonal neuropathy, as well as the common origin of ancestors are unusual features of these families. These cases illustrate the importance of molecular diagnosis in patients with a recessive ataxia. The origin of the expanded gene and the GAA repeat size in the normal population are issues to be further investigated. The molecular diagnosis of Friedreich ataxia is now established in Cuba.
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Solberg Woods LC, Holl K, Tschannen M, Valdar W. Fine-mapping a locus for glucose tolerance using heterogeneous stock rats. Physiol Genomics 2010; 41:102-8. [PMID: 20068026 DOI: 10.1152/physiolgenomics.00178.2009] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Heterogeneous stock (HS) animals provide the ability to map quantitative trait loci at high resolution [<5 Megabase (Mb)] in a relatively short time period. In the current study, we hypothesized that the HS rat colony would be useful for fine-mapping a region on rat chromosome 1 that has previously been implicated in glucose regulation. We administered a glucose tolerance test to 515 HS rats and genotyped these animals with 69 microsatellite markers, spaced an average distance of <1 Mb apart, on a 67 Mb region of rat chromosome 1. Using regression modeling of inferred haplotypes based on a hidden Markov model reconstruction and mixed model analysis in which we accounted for the complex family structure of the HS, we identified one sharp peak within this region. Using positional bootstrapping, we determined the most likely location of this locus is from 205.04 to 207.48 Mb. This work demonstrates the utility of HS rats for fine-mapping complex traits and emphasizes the importance of taking into account family structure when using highly recombinant populations.
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Affiliation(s)
- Leah C Solberg Woods
- Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
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Malhotra A, Igo RP, Thameem F, Kao WL, Abboud HE, Adler SG, Arar NH, Bowden DW, Duggirala R, Freedman BI, Goddard KA, Ipp E, Iyengar SK, Kimmel PL, Knowler WC, Kohn O, Leehey D, Meoni LA, Nelson RG, Nicholas SB, Parekh RS, Rich SS, Chen YDI, Saad MF, Scavini M, Schelling JR, Sedor JR, Shah VO, Taylor KD, Thornley-Brown D, Zager PG, Horvath A, Hanson RL. Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations-significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes Research Group. Diabetes Metab Res Rev 2009; 25:740-7. [PMID: 19795399 PMCID: PMC2783577 DOI: 10.1002/dmrr.1031] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. METHODS Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. RESULTS Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. CONCLUSIONS The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
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Affiliation(s)
- Alka Malhotra
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | | | - Farook Thameem
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | - Hanna E. Abboud
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Sharon G. Adler
- Harbor-University of California Los Angeles Medical Center, Torrance, California
| | - Nedal H. Arar
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | | | | | | | - Eli Ipp
- Harbor-University of California Los Angeles Medical Center, Torrance, California
| | | | - Paul L. Kimmel
- National Institute of Diabetes and Digestive and Kidney Diseases Program Office, Bethesda, Maryland
| | - William C. Knowler
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | - Orly Kohn
- University of Chicago, Chicago, Illinois
| | | | | | - Robert G. Nelson
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | | | | | | | - Yii-Der I. Chen
- University of California Los Angeles, Los Angeles, California
| | | | - Marina Scavini
- University of New Mexico, Albuquerque, New Mexico
- San Raffaele Scientific Institute, Milan (Italy)
| | | | | | | | - Kent D. Taylor
- University of California Los Angeles, Los Angeles, California
| | | | | | | | - Robert L. Hanson
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
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38
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Lillioja S, Wilton A. Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies. Diabetologia 2009; 52:1061-74. [PMID: 19296077 DOI: 10.1007/s00125-009-1324-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 02/13/2009] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. METHODS We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. RESULTS Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. CONCLUSIONS/INTERPRETATION Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.
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Affiliation(s)
- S Lillioja
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
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39
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Kofteridis D, Krasoudaki E, Kavousanaki M, Zervou MI, Panierakis C, Boumpas DT, Goulielmos GN. STAT4Is Not Associated with Type 2 Diabetes in the Genetically Homogeneous Population of Crete. Genet Test Mol Biomarkers 2009; 13:281-4. [DOI: 10.1089/gtmb.2008.0128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Diamantis Kofteridis
- Department of Internal Medicine, Section of Molecular Medicine and Human Genetics, Medical School, University of Crete, Heraklion, Greece
| | - Eleni Krasoudaki
- Department of Internal Medicine, Section of Molecular Medicine and Human Genetics, Medical School, University of Crete, Heraklion, Greece
| | - Melina Kavousanaki
- Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Crete, Greece
| | | | | | - Dimitrios T. Boumpas
- Department of Internal Medicine, Section of Molecular Medicine and Human Genetics, Medical School, University of Crete, Heraklion, Greece
- Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Crete, Greece
| | - George N. Goulielmos
- Department of Internal Medicine, Section of Molecular Medicine and Human Genetics, Medical School, University of Crete, Heraklion, Greece
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40
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Wu J, Pankow JS, Tracy RP, North KE, Myers RH, Feitosa ME, Province MA, Borecki IB. A QTL on 12q influencing an inflammation marker and obesity in white women: the NHLBI Family Heart Study. Obesity (Silver Spring) 2009; 17:525-31. [PMID: 19238141 PMCID: PMC4962615 DOI: 10.1038/oby.2008.556] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
It has been recognized that obese individuals are intrinsically in a state of chronic inflammation, as indicated by positive correlations between serum levels of C-reactive protein (CRP) and various anthropometric measures of obesity. To explore the hypothesis that a gene(s) may underlie this relationship, we conducted bivariate linkage analyses of BMI and CRP in white and African-American (AA) families of the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (FHS). Variance components linkage analysis as implemented in SOLAR was performed in 1,825 whites (840 men and 985 women) and 548 AAs (199 men and 351 women). CRP exhibited significant genetic correlations with BMI in women (0.54 +/- 0.10 for white and 0.53 +/- 0.14 for AA) and the combined samples (0.37 +/- 0.09 for white and 0.56 +/- 0.13 for AA), but not in men. We detected a maximum bivariate lod score of 3.86 on chromosome 12q24.2-24.3 at 139 cM and a suggestive linkage signal (lod = 2.19) on chromosome 19p13.1 (44 cM) in white women. Both bivariate peaks were substantially higher than their respective univariate lods at the same locus for each trait. No significant lod scores were detected in AAs. Our results indicate that chromosome 12q may harbor quantitative trait loci (QTLs) jointly regulating BMI and CRP in white women.
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Affiliation(s)
- Jun Wu
- Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - James S. Pankow
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Russell P. Tracy
- Department of Pathology, University of Vermont College of Medicine, Colchester, Vermont, USA
- Department of Biochemistry, University of Vermont College of Medicine, Colchester, Vermont, USA
| | - Kari E. North
- Department of Epidemiology, University of North Carolina at Chapel Hill, ChapelHill, North Carolina, USA
| | - Richard H. Myers
- Department of Neurology, Section of Preventive Medicine and Epidemiology, Boston University Medical Center, Boston, Massachusetts, USA
| | - Mary E. Feitosa
- Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Michael A. Province
- Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ingrid B. Borecki
- Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA
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41
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Schroeder KB, Jakobsson M, Crawford MH, Schurr TG, Boca SM, Conrad DF, Tito RY, Osipova LP, Tarskaia LA, Zhadanov SI, Wall JD, Pritchard JK, Malhi RS, Smith DG, Rosenberg NA. Haplotypic background of a private allele at high frequency in the Americas. Mol Biol Evol 2009; 26:995-1016. [PMID: 19221006 DOI: 10.1093/molbev/msp024] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across approximately 500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population that may have been isolated from other Asian populations prior to expanding into the Americas.
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Affiliation(s)
- Kari B Schroeder
- Department of Anthropology, University of California, Davis, CA, USA.
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Abstract
Preeclampsia is specific to pregnancy and is still a leading cause of maternal and perinatal mortality and morbidity, affecting about 3% of women, but the underlying pathogenetic mechanisms still remain unclear. Immune maladaptation, placental ischemia and increased oxidative stress represent the main components discussed to be of etiologic importance, and they all may have genetic implications. Since the familial nature of preeclampsia is known for many years, extensive research on the genetic contribution to the pathogenesis of this severe pregnancy disorder has been performed. In this review, we will overview the linkage and candidate gene studies carried out so far as well as summarize important historical notes on the genetic hypotheses generated in preeclampsia research. Moreover, the influence of maternal and fetal genes and their interaction as well as the role of genomic imprinting in preeclampsia will be discussed.
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Affiliation(s)
- Sabine Mütze
- Department of Obstetrics and Gynecology, Aachen University (RWTH), Aachen, Germany.
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43
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Ling C, Poulsen P, Simonsson S, Rönn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 2008; 117:3427-35. [PMID: 17948130 DOI: 10.1172/jci30938] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Accepted: 07/20/2007] [Indexed: 12/19/2022] Open
Abstract
Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance.
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Affiliation(s)
- Charlotte Ling
- Department of Clinical Sciences, Lund University, University Hospital MAS, Malmö, Sweden.
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44
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Palomer X, González-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab 2008; 10:185-97. [PMID: 18269634 DOI: 10.1111/j.1463-1326.2007.00710.x] [Citation(s) in RCA: 282] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Vitamin D deficiency has been shown to alter insulin synthesis and secretion in both humans and animal models. It has been reported that vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion and type 2 diabetes mellitus. Vitamin D replenishment improves glycaemia and insulin secretion in patients with type 2 diabetes with established hypovitaminosis D, thereby suggesting a role for vitamin D in the pathogenesis of type 2 diabetes mellitus. The presence of vitamin D receptors (VDR) and vitamin D-binding proteins (DBP) in pancreatic tissue and the relationship between certain allelic variations in the VDR and DBP genes with glucose tolerance and insulin secretion have further supported this hypothesis. The mechanism of action of vitamin D in type 2 diabetes is thought to be mediated not only through regulation of plasma calcium levels, which regulate insulin synthesis and secretion, but also through a direct action on pancreatic beta-cell function. Therefore, owing to its increasing relevance, this review focuses on the role of vitamin D in the pathogenesis of type 2 diabetes mellitus.
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Affiliation(s)
- X Palomer
- Institut de Recerca, Hospital de Santa Creu i Sant Pau, Barcelona, Spain
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45
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Marchetti P, Dotta F, Lauro D, Purrello F. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment. ACTA ACUST UNITED AC 2008; 146:4-11. [PMID: 17889380 DOI: 10.1016/j.regpep.2007.08.017] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2007] [Revised: 08/07/2007] [Accepted: 08/09/2007] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes is the most common form of diabetes in humans. It results from a combination of factors that impair beta-cell function and tissue insulin sensitivity. However, growing evidence is showing that the beta-cell is central to the development and progression of this form of diabetes. Reduced islet and/or insulin-containing cell mass or volume in Type 2 diabetes has been reported by several authors. Furthermore, studies with isolated Type 2 diabetic islets have consistently shown both quantitative and qualitative defects of glucose-stimulated insulin secretion. The impact of genotype in affecting beta-cell function and survival is a very fast growing field or research, and several gene polymorphisms have been associated with this form of diabetes. Among acquired factors, glucotoxicity, lipotoxicity and altered IAPP processing are likely to play an important role. Interestingly, however, pharmacological intervention can improve several defects of Type 2 diabetes islet cells in vitro, suggesting that progression of the disease might not be relentless.
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Affiliation(s)
- Piero Marchetti
- Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
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46
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Voruganti VS, Lopez-Alvarenga JC, Nath SD, Rainwater DL, Bauer R, Cole SA, Maccluer JW, Blangero J, Comuzzie AG. Genetics of variation in HOMA-IR and cardiovascular risk factors in Mexican-Americans. J Mol Med (Berl) 2008; 86:303-11. [PMID: 18204828 DOI: 10.1007/s00109-007-0273-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Revised: 08/31/2007] [Accepted: 09/24/2007] [Indexed: 12/15/2022]
Abstract
Insulin resistance is a major biochemical defect underlying the pathogenesis of cardiovascular disease (CVD). Mexican-Americans are known to have an unfavorable cardiovascular profile. Thus, the aim of this study was to investigate the genetic effect on variation in HOMA-IR and to evaluate its genetic correlations with other phenotypes related to risk of CVD in Mexican-Americans. The homeostatic model assessment method (HOMA-IR) is one of several approaches that are used to measure insulin resistance and was used here to generate a quantitative phenotype for genetic analysis. For 644 adults who had participated in the San Antonio Family Heart Study (SAFHS), estimates of genetic contribution were computed using a variance components method implemented in SOLAR. Traits that exhibited significant heritabilities were body mass index (BMI) (h (2) = 0.43), waist circumference (h (2) = 0.48), systolic blood pressure (h (2) = 0.30), diastolic blood pressure (h (2) = 0.21), pulse pressure (h (2) = 0.32), triglycerides (h (2) = 0.51), LDL cholesterol (h (2) = 0.31), HDL cholesterol (h (2) = 0.24), C-reactive protein (h (2) = 0.17), and HOMA-IR (h (2) = 0.33). A genome-wide scan for HOMA-IR revealed significant evidence of linkage on chromosome 12q24 (close to PAH (phenylalanine hydroxylase), LOD = 3.01, p < 0.001). Bivariate analyses demonstrated significant genetic correlations (p < 0.05) of HOMA-IR with BMI (rho (G) = 0.36), waist circumference (rho (G) = 0.47), pulse pressure (rho (G) = 0.39), and HDL cholesterol (rho (G) = -0.18). Identification of significant linkage for HOMA-IR on chromosome 12q replicates previous family-based studies reporting linkage of phenotypes associated with type 2 diabetes in the same chromosomal region. Significant genetic correlations between HOMA-IR and phenotypes related to CVD risk factors suggest that a common set of gene(s) influence the regulation of these phenotypes.
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Affiliation(s)
- V Saroja Voruganti
- Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
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47
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Eising S, Svensson J, Skogstrand K, Nilsson A, Lynch K, Andersen PS, Lernmark A, Hougaard DM, Pociot F, Nørgaard-Pedersen B, Nerup J. Type 1 diabetes risk analysis on dried blood spot samples from population-based newborns: design and feasibility of an unselected case-control study. Paediatr Perinat Epidemiol 2007; 21:507-17. [PMID: 17937736 DOI: 10.1111/j.1365-3016.2007.00846.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Development of type 1 diabetes mellitus (T1D) may be triggered pre- or perinatally by multiple factors. Identifying new predisposing T1D markers or combinations of markers in a large, well-characterised case-control collection may be important for future T1D prevention. The present work describes the design and feasibility of a large and unselected case-control study, which will define and evaluate prediction criteria for T1D at the time of birth. Danish registries (Biological Specimen Bank for Neonatal Screening, and the National Discharge Registry) made it possible to identify and collect dried blood spots (DBS) from newborns who later developed T1D (cases) born 1981-2002. DBS samples from 2086 cases and two matching control subjects per case were analysed for genetic and immune factors that are associated with T1D: (a) candidate genes (HLA, INS and CTLA4), (b) cytokines and inflammatory markers, (c) islet auto-antibodies (GAD65A, IA-2A). The objective of the study was to define reliable prediction tools for T1D using samples available at the time of birth. In a unique approach, the study linked a large unselected and population-based sample resource to well-ascertained clinical databases and advanced technology. It combined genetic, immunological and demographic data to develop prediction algorithms. It also provided a resource for future studies in which new genetic markers can be included as they are identified.
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Gragnoli C, Cronsell J. PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes. J Cell Physiol 2007; 212:568-71. [PMID: 17516568 DOI: 10.1002/jcp.21127] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n = 237) and controls subjects (n = 215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case-control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G > A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations.
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Affiliation(s)
- C Gragnoli
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
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49
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Prudente S, Flex E, Morini E, Turchi F, Capponi D, De Cosmo S, Tassi V, Guida V, Avogaro A, Folli F, Maiani F, Frittitta L, Dallapiccola B, Trischitta V. A functional variant of the adipocyte glycerol channel aquaporin 7 gene is associated with obesity and related metabolic abnormalities. Diabetes 2007; 56:1468-74. [PMID: 17351148 DOI: 10.2337/db06-1389] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 +/- 6.6 vs. 28.9 +/- 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)beta transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.
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Plata C, Sussman CR, Sindic A, Liang JO, Mount DB, Josephs ZM, Chang MH, Romero MF. Zebrafish Slc5a12 Encodes an Electroneutral Sodium Monocarboxylate Transporter (SMCTn). J Biol Chem 2007; 282:11996-2009. [PMID: 17255103 DOI: 10.1074/jbc.m609313200] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We have identified and characterized two different sodium-coupled monocarboxylate cotransporters (SMCT) from zebrafish (Danio rerio), electrogenic (zSMCTe) and electroneutral (zSMCTn). zSMCTn is the 12th member of the zebrafish Slc5 gene family (zSlc5a12). Both zSMCT sequences have approximately 50% homology to human SLC5A8 (hSMCT). Transport function and kinetics were measured in Xenopus oocytes injected with zSMCT cRNAs by measurement of intracellular Na(+) concentration ([Na(+)](i)) and membrane potential. Both zSMCTs oocytes increased [Na(+)](i) with addition of monocarboxylates (MC) such as lactate, pyruvate, nicotinate, and butyrate. By using two electrode voltage clamp experiments, we measured currents elicited from zSMCTe after MC addition. MC-elicited currents from zSMCTe were similar to hSMCT currents. In contrast, we found no significant MC-elicited current in either zSMCTn or control oocytes. Kinetic data show that zSMCTe has a higher affinity for lactate, nicotinate, and pyruvate (K(m)(L-lactate) = 0.17 +/- 0.02 mM, K(m)(nicotinate) = 0.54 +/- 0.12 mM at -150 mV) than zSMCTn (K(m)(L-lactate) = 1.81 +/- 0.19 mM, K(m)(nicotinate) = 23.68 +/- 4.88 mM). In situ hybridization showed that 1-, 3-, and 5-day-old zebrafish embryos abundantly express both zSMCTs in the brain, eyes, intestine, and kidney. Within the kidney, zSMCTn mRNA is expressed in pronephric tubules, whereas zSMCTe mRNA is more distal in pronephric ducts. zSMCTn is expressed in exocrine pancreas, but zSMCTe is not. Roles for Na(+)-coupled monocarboxylate cotransporters have not been described for the brain or eye. In summary, zSMCTe is the zebrafish SLC5A8 ortholog, and zSMCTn is a novel, electroneutral SMCT (zSlc5a12). Slc5a12 in higher vertebrates is likely responsible for the electroneutral Na(+)/lactate cotransport reported in mammalian and amphibian kidneys.
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Affiliation(s)
- Consuelo Plata
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA
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