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1. Are IL18RAP gene polymorphisms associated with body mass regulation? A cross-sectional study.

Author

Martínez-Barquero V, Marco G, Martínez-Hervas S, Adam-Felici V, Pérez-Soriano C, Gonzalez-Albert V, Rojo G, Ascaso JF, Real JT, Garcia-Garcia AB, Martín-Escudero JC, Cortes R, and Chaves FJ

Subjects
Adult, Aged, Alleles, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Spain, White People genetics, Body Mass Index, Interleukin-18 Receptor beta Subunit genetics, MicroRNAs genetics, Obesity genetics
Abstract

Objectives: To investigate the association between IL18RAP and body mass index (BMI) and obesity and to verify the effect of a polymorphism in the microRNA136 (MIR136) IL18RAP binding region., Design: We analysed samples from two Spanish cross-sectional studies, VALCAR (Spanish Mediterranean coast) and Hortega (Spanish centre). These studies aimed at analysing cardiovascular risk and development of cardiovascular disease in the general population. Both populations correspond to regions with different characteristics., Setting: Five IL18RAP single nucleotide polymorphisms were selected using the SYSNPs web tool and analysed by oligonucleotide ligation assay (SNPlex). For the MIR136 functional study, cells were transfected with plasmids containing different rs7559479 polymorphism alleles and analysed by luciferase reporter assays., Participants: 1970 individuals (Caucasian, both genders): VALCAR (468) and Hortega (1502)., Results: rs2293225, rs2272127 and rs7559479 showed the following associations: rs7559479 G allele correlated with a higher obesity risk (P=0.01; OR=1.82; 95% CI 1.15 to 2.87 for the VALCAR group; P=0.033; OR=1.35; 95% CI 1.03 to 1.79 for the Hortega population) and higher body mass index (BMI) values (P=0.0045; P=0.1 for VALCAR and Hortega, respectively); a significant association with obesity (P=0.0024, OR=1.44, 95% CI 1.14 to 1.82) and increased BMI values (P=0.008) was found when considering both populations together. rs2293225 T allele was associated with lower obesity risk (P=0.036; OR=0.60; 95% CI 0.35 to 0.96) and lower BMI values (P=0.0038; OR=1.41) while the rs2272127 G allele was associated with lower obesity risk (P=0.028; OR=0.66; 95% CI 0.44 to 0.97) only in the VALCAR population. A reporter assay showed that the presence of the A allele in rs7559479 was associated with increased MIR136 binding to IL18RAP ., Conclusions: Our results suggest that polymorphisms in IL18RAP influence susceptibility to obesity. We demonstrated that the A allele in rs7559479 increases MIR136 binding, which regulates IL-18 system activity., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Published
2017
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2. Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

Author

Martínez-Barquero V, de Marco G, Martínez-Hervas S, Rentero P, Galan-Chilet I, Blesa S, Morchon D, Morcillo S, Rojo G, Ascaso JF, Real JT, Martín-Escudero JC, and Chaves FJ

Subjects
Female, Follow-Up Studies, Genotype, Haplotypes genetics, Humans, Male, Middle Aged, Obesity blood, Prognosis, Risk Factors, Spain epidemiology, Arsenic blood, Endothelins genetics, Genetic Predisposition to Disease, Obesity epidemiology, Obesity genetics, Polymorphism, Single Nucleotide genetics, Receptor, Endothelin A genetics
Abstract

Background/objectives: Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity., Subjects/methods: We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex., Results: We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53)., Conclusions: Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.

Published
2015
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3. Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population

Author

Chaves, F.J. (F.Javier.), Redon, J. (Josep), Serrano-Rios, M. (M.), Martin-Escudero, J.C. (J.C.), Soriguer, F. (Federico), Morcillo, S. (Sonsoles), Rojo, G. (G.), Zabena, C. (C.), Martinez-Larrad, M.T. (M.T.), Martinez, F. (Fernando), and Mansego-Talavera, M.L. (María Luisa)

Subjects
Genotyping, Cholesterol, Haplotypes, Type 2 diabetes, Insulin resistance, Obesity, Alleles
Abstract

Summary: The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. Methods: 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1- 4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. Results:One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. Conclusions: The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians.

Published
2012

5. Polymorphisms in endothelin system genes, arsenic levels and obesity risk

Author

Inmaculada Galan-Chilet, David Morchon, Sonsoles Morcillo, Sergio Martínez-Hervás, Juan F. Ascaso, Felipe J. Chaves, Juan Carlos Martín-Escudero, Griselda de Marco, José T. Real, Vanesa Martínez-Barquero, Gemma Rojo, Pilar Rentero, Sebastian Blesa, [Martínez-Barquero,V, Martínez-Hervas,S, Ascaso,JF, Real,JT] Department of Medicine, University of Valencia, Valencia, Spain. [Martínez-Barquero,V, de Marco,G, Rentero,P, Galan-Chilet,I, Blesa,S, Chaves,FJ] Genotyping and Genetic Diagnosis Unit, Hospital Clínico Research Foundation (INCLIVA), Valencia, Spain. [Martínez-Hervas,S, Morcillo,S, Rojo,G, Real,JT, Chaves,FJ] CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain. [Morcillo,S, Rojo G] Service of Endocrinology and Nutrition, Hospital Regional Universitario, Málaga, Spain, Instituto de Biomedicina de Málaga (IBIMA), Málaga, Spain. [Martínez-Hervas,S, Real, JT] Service of Endocrinology and Nutrition, Hospital Clínico Universitario de Valencia, Valencia, Spain. [Morchon,D, Martín-Escudero,JC] Internal Medicine, Rio Hortega Hospital, University of Valladolid, Valladolid, Spain., This work was supported by the funds for research in health sciences from Carlos III Health Institute (PI07/0497 and PI11/00726), by CIBER de Diabetes y Enfermedades Metabólicas Relacionadas (CIBERDEM), and CIBERDEM is an initiative by Carlos III Health Institute in Madrid and the Spanish Health Ministry, by PROMETEO/2009/029, AP-091/11, and ACOMP/2013/039 from the Valencian Government, and by GRS 279/a/08 research project from JUNTA DE CASTILLA Y LEON Government.

Subjects
Male, España, Obesidad, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Fat Distribution::Adiposity [Medical Subject Headings], Endothelins, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Endothelins [Medical Subject Headings], Polymorphism (computer science), Risk Factors, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Body Weight::Overweight::Obesity [Medical Subject Headings], Chemicals and Drugs::Inorganic Chemicals::Elements::Arsenic [Medical Subject Headings], Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], education.field_of_study, Multidisciplinary, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Chronic Disease [Medical Subject Headings], Genètica humana, Middle Aged, Prognosis, Receptor, Endothelin A, Polimorfismo de nucleótido único, Anatomy::Cells::Connective Tissue Cells::Adipocytes [Medical Subject Headings], Obesitat, Medicine, Female, Tomografía computarizada por rayos X, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Endothelin receptor, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Image Interpretation, Computer-Assisted::Tomography, X-Ray Computed [Medical Subject Headings], Research Article, medicine.hormone, medicine.medical_specialty, Genotype, Phenomena and Processes::Mathematical Concepts::Probability::Risk [Medical Subject Headings], Science, Population, Single-nucleotide polymorphism, Phenomena and Processes::Metabolic Phenomena::Metabolism::Lipid Metabolism::Lipolysis [Medical Subject Headings], Biology, Polymorphism, Single Nucleotide, Arsenic, Receptores de endotelinas, Internal medicine, Adipocitos, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Peptide::Receptors, Endothelin [Medical Subject Headings], medicine, Humans, Genetic Predisposition to Disease, Obesity, education, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Adiponectin, Haplotype, Enfermedad crónica, medicine.disease, Endocrinology, Haplotypes, Spain, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Adipokines::Adiponectin [Medical Subject Headings], Genotipo, Follow-Up Studies, Arsénico
Abstract

Background/objectivesObesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity.Subjects/methodsWe analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex.ResultsWe found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53).ConclusionsOur results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.

Published
2015

6. Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population

Author

Fernando Martinez, Sonsoles Morcillo, Juan Carlos Martín-Escudero, Gemma Rojo, María Teresa Martínez-Larrad, Federico Soriguer, Josep Redon, Manuel Serrano-Ríos, Felipe J. Chaves, Maria L. Mansego, Carina Zabena, [Mansego,ML, Chaves,FJ] Genotyping and Genetic Diagnosis Unit, Fundación de Investigación del Hospital Clínico de Valencia-INCLIVA, Valencia, Spain [Martínez,F, Redon,J] Fundación de Investigación del Hospital Clínico de Valencia- INCLIVA, Hypertension Clinic, Hospital Clínico Universitario, University of Valencia, Valencia, Spain. [Martínez-Larrad,MT, Zabena,C, Serrano-Ríos,M] Hospital Clínico San Carlos, Department of Internal Medicine II, Madrid, Spain. [Rojo,G, Morcillo,S, Soriguer,F] Endocrinology and Nutrition Department, Carlos Haya University Hospital, Málaga, Spain. [Martín-Escudero,JC] Internal Medicine department. Hospital Rio Hortega, University of Valladolid, Valladolid, Spain. [Mansego,ML, Chaves,FJ] Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas ‘‘CIBERDEM’’, Institute of Health Carlos III, Ministry of Health, Madrid, Spain. [Martínez,F, Redon,J] Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología, Obesidad y Nutrición [CIBEROB (CIBER 03/06)], Institute of Health Carlos III, Ministry of Health, Madrid, Spain. [Martínez-Larrad,MT, Serrano-Ríos,M, Rojo,G, Soriguer,F] Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Institute of Health Carlos III, Ministry of Health, Madrid, Spain., Funding: This study was supported by grants SAF2005-02883 from the Interministry Commission of Science and Technology (CICYT), Biomedical Research Centers (CIBER) of Physiopathology, Obesity and Nutrition (CIBEROB), CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Carlos III Health Institute Madrid, the Spanish Health Ministry, GRUPOS 03/101 and 2005/027 from the Valencian Government and European Network of Excellence Ingenious Hypercare (EPSS-037093) from the European Commission, and and Biobank grant from the National Health Institute Carlos III FEDER RD09/0076/00132 (Madrid, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects
Male, Anatomy and Physiology, España, Diabetes Mellitus Tipo 2, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Type 2 diabetes, Resistencia a la Insulina, Variación Genética, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Endocrinology, Polymorphism (computer science), Risk Factors, Análisis de Regresión, Factores de Riesgo, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Genetics, education.field_of_study, Multidisciplinary, Adulto, Middle Aged, Cardiovascular Diseases, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Regression Analysis, Medicine, Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Fatty Acid Binding Protein 3, Research Article, Adult, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Genotype, Science, Population, Check Tags::Male [Medical Subject Headings], Single-nucleotide polymorphism, Endocrine System, Biology, Fatty Acid-Binding Proteins, Polymorphism, Single Nucleotide, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance [Medical Subject Headings], Insulin resistance, Genetic variation, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], medicine, Humans, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], education, Diseases::Cardiovascular Diseases [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Alleles, Aged, Diabetic Endocrinology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Regression Analysis [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Polymorphism, Genetic, Endocrine Physiology, Haplotype, Genetic Variation, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], medicine.disease, Obesity, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Fatty Acid-Binding Proteins [Medical Subject Headings], Check Tags::Female [Medical Subject Headings], Diabetes Mellitus, Type 2, Haplotypes, Spain, Metabolic Disorders, Mutation, Insulin Resistance, Population Genetics
Abstract

Journal Article; Research Support, Non-U.S. Gov't; SUMMARY The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. METHODS 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. RESULTS One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. CONCLUSIONS The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians. Yes

Published
2011

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