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16 results on '"Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings]"'

1. Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy

Author

García-Delgado, Ana B., Valdés-Sánchez, María Lourdes, Morillo-Sánchez, María José, Ponte-Zuñiga, Beatriz, Díaz-Corrales, Francisco J., Cerda, Berta de la, [Garcia-Delgado,AB, Valdes-Sanchez,L, Diaz-Corrales,FJ, de la Cerda,B] Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain. [Morillo-Sanchez,MJ, Ponte-Zuñiga,B] Department of Ophthalmology, University Hospital Virgen Macarena, Seville, Spain. [Ponte-Zuñiga,B] Retics Oftared, Institute of Health Carlos III, Madrid, Spain, This work was funded by Andalusian Ministry of Health, Equality and Social Policies (PI-0099-2018) and Fundació Privada CELLEX (113170CELLEX)., Ministerio de Sanidad, Servicios Sociales e Igualdad (España), and Fundació Privada Cellex

Subjects
Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Diseases::Eye Diseases::Retinal Diseases::Retinal Degeneration [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Ciliopathy, Advanced therapies, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], EYS, Ciliopatías, Organisms::Eukaryota::Animals [Medical Subject Headings], Degeneración retiniana, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis [Medical Subject Headings], Retinal degeneration, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Techniques, Ophthalmological::Electroretinography [Medical Subject Headings], Mutación, Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Cognition::Comprehension [Medical Subject Headings], Retinal dystrophy, Modelos animales, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Eye Proteins [Medical Subject Headings], Animal models, Retinitis pigmentosa, Distrofias retinianas, Anatomy::Sense Organs::Eye::Retina [Medical Subject Headings], Diseases::Eye Diseases::Eye Diseases, Hereditary::Retinitis Pigmentosa [Medical Subject Headings], Mutations
Abstract

Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of current technical advances into real therapeutic possibilities. This review recapitulates the present knowledge about EYS-retinopathies, their clinical presentations and proposed genotype–phenotype correlations. Molecular details of the gene and the protein, mainly based on animal model data, are analysed. The proposed cellular localisation and roles of this large multi-domain protein are detailed. Future therapeutic approaches for EYS-retinopathies are discussed. This work was funded by Andalusian Ministry of Health, Equality and Social Policies (PI-0099-2018) and Fundació Privada CELLEX (113170CELLEX).

Published
2021

2. Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Author

Patricia Perez-Carpena, Patrick May, Joseph Sollini, Juan Manuel Espinosa-Sanchez, Alvaro Gallego-Martinez, Barbara Canlon, Sana Amanat, Jose A. Lopez-Escamez, Angel Batuecas-Caletrio, Andrés Soto-Varela, Christopher R. Cederroth, Ismael Aran, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], [Amanat,S, Gallego-Martinez,A, Perez-Carpena,P, Espinosa-Sanchez,JM, Lopez-Escamez,JA] a Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO-Centre for Genomics and Oncological Research-Pfizer/University of Granada/ Junta de Andalucía, PTS, Granada, Spain. [Sollini,J, Cederroth,CR] Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK. [Perez-Carpena,P, Lopez-Escamez,JA] c Department of Otolaryngology, Instituto de Investigacion Biosanitaria, ibs.Granada, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Aran,I] Department of Otolaryngology, Complexo Hospitalario de Pontevedra, Pontevedra, Spain. [Soto-Varela,A] e Division of Otoneurology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario, Santiago de Compostela, Spain. [Batuecas-Caletrio,A] Department of Otolaryngology, Hospital Universitario de Salamanca, IBSAL Salamanca, Spain. [Canlon,B, Cederroth,CR] Laboratory of Experimental Audiology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. [May,P] Bioinformatics Core, Luxembourg Centre for System Biomedicine, University of Luxemburg, Esch-sur-Alzette, Luxembourg. [Cederroth,CR] National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Ropewalk House, Nottingham, UK. [Lopez-Escamez,JA] Department of Surgery, Division of Otolaryngology, University of Granada, Granada, Spain, This study has been funded by H2020 MSCA-ITN-2016–722046, the H2020-SC1-2019-848261, and the GNP-182 GENDER-Net Co-Plus Fund (JALE and CRC). The project leading to these results has received funding from 'la Caixa' Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002 (JALE). This project is a part of European School of Interdisciplinary Tinnitus (ESIT) research and Sana Amanat is a PhD student in Biomedicine Program at the University of Granada. CRC received additional funding from Svenska Läkaresällskapet (SLS- 779681 ), Hörselforskningsfonden (503). The data handling for STOP and SweGen cohorts were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX partially funded by the Swedish Research Council through Grant agreement No. 2018-05973 . The time provided by JS was funded by the University of Nottingham, Nottingham Research Fellowship. PM was supported by the BMBF Treat-ION Grant ( 01GM1907 ) and the DFG Research Unit FOR2715 (FNR INTER/DFG/17/ 11583046 )., and Sollini, Joseph

Subjects
0301 basic medicine, Male, Exome sequencing, Medicine (General), Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology [Medical Subject Headings], Psychiatry and Psychology::Mental Disorders [Medical Subject Headings], Anatomy::Nervous System::Synapses [Medical Subject Headings], Bioinformatics, Severity of Illness Index, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Cytoskeletal Proteins [Medical Subject Headings], Mice, Tinnitus, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], Missense mutation, 050207 economics, Anatomy::Nervous System::Neurons [Medical Subject Headings], Exome, Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Labyrinth Diseases::Endolymphatic Hydrops::Meniere Disease [Medical Subject Headings], education.field_of_study, 050208 finance, Geographical Locations::Geographic Locations::Europe::Scandinavia::Sweden [Medical Subject Headings], 05 social sciences, Extreme phenotype, Family aggregation, Brain, General Medicine, Axon initial segment, 3. Good health, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Health Status Indicators::Patient Acuity::Severity of Illness Index [Medical Subject Headings], Phenotype, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], 030220 oncology & carcinogenesis, Medicine, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Female, Genetics & genetic processes [F10] [Life sciences], medicine.symptom, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Génétique & processus génétiques [F10] [Sciences du vivant], Fenotipo, Research Paper, Population, Check Tags::Male [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, Epilepsia, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, R5-920, 0502 economics and business, medicine, otorhinolaryngologic diseases, Segmento inicial del axón, Animals, Humans, Genetic Predisposition to Disease, Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Hearing Disorders::Tinnitus [Medical Subject Headings], Generalized epilepsy, education, Genetic studies, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Alleles, Genetic Association Studies, Phenomena and Processes::Biological Phenomena [Medical Subject Headings], Sweden, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Epilepsy, Secuenciación del exoma completo, Estudios de asociación genética, business.industry, Enfermedad de Meniere, Acúfeno, Computational Biology, Genetic Variation, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Epilepsy::Epilepsy, Generalized [Medical Subject Headings], medicine.disease, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Questionnaires::Self Report [Medical Subject Headings], 030104 developmental biology, Gene Ontology, Check Tags::Female [Medical Subject Headings], Meniere disease, Synapses, business, exome sequencing
Abstract

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.

Published
2021

3. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia

Author

Ralph S. Lachman, Pavel Krejci, Wenjuan Zhang, S. Paige Taylor, Maya Barad, Deborah Krakow, Deborah A. Nickerson, Jennifer Zieba, Ivan Duran, Michael J. Bamshad, Michaela Bosakova, Jessica X. Chong, Daniel H. Cohn, Fabiana Csukasi, Jorge H. Martin, [Barad,M, Csukasi,F, Martin,JH, Paige Taylor,S, Zieba,J, Cohn,DH, Krakow,D, Duran,I] Department of Orthopaedic Surgery, University of California-Los Angeles, CA, United States. [Csukasi,F, Duran,I] Laboratory of Bioengineering and Tissue Regeneration-LABRET, Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Málaga,Spain. [Bosakova,M, Krejci,P] Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. [Bosakova,M, Krejci,P] International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic. [Zhang,W, Cohn,DH] Department of Molecular, Cell and Developmental Biology, University of California-Los Angeles, CA, United States. [Lachman,RS, Krakow,D] International Skeletal Dysplasia Registry, University of California, Los Angeles, United States. [Bamshad,M, Nickerson,D, Chong,JX] University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA, United States. [Cohn,DH, Krakow,D] Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, CA, United States. [Krakow,D] Department of Human Genetics, University of California-Los Angeles, CA, United States. [Durán,I] Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain., D.K. and D.H.C are supported by the NIH grants R01 AR066124, R01 DE019567, R01 HD070394. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UWCMG) which is funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung and Blood Institute (NHLBI) Award 1U54HG006493. P.K was supported by the Ministry of Education, Youth and Sports of the Czech Republic (Grant INTER-ACTION LTAUSA19030), the Agency for Healthcare Research of the Czech Republic (Grant NV18-08-00567), and and the Czech Science Foundation (Grant GA19-20123S).

Subjects
0301 basic medicine, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], DNA Mutational Analysis, lcsh:Medicine, Anatomy::Cells::Connective Tissue Cells::Chondrocytes [Medical Subject Headings], Diseases::Musculoskeletal Diseases::Bone Diseases::Bone Diseases, Developmental [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Laminin [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Extracellular matrix, 0302 clinical medicine, Laminin, 2.1 Biological and endogenous factors, Developmental, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis [Medical Subject Headings], Aetiology, Wnt Signaling Pathway, Anatomy::Musculoskeletal System::Skeleton::Bone and Bones [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction::Wnt Signaling Pathway [Medical Subject Headings], lcsh:R5-920, Displasia fibrosa ósea, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Adhesion [Medical Subject Headings], Wnt signaling pathway, Integrina beta1, General Medicine, Vinculin, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Cell biology, Fibrous dysplasia of bone, Phenotype, src-Family Kinases, Laminin alpha 5, 030220 oncology & carcinogenesis, Skeletal dysplasia, Public Health and Health Services, Bone Diseases, lcsh:Medicine (General), Research Paper, Signal Transduction, Cell signaling, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Clinical Sciences, Biology, Bent bone, Bone and Bones, General Biochemistry, Genetics and Molecular Biology, Focal adhesion, 03 medical and health sciences, Chondrocytes, Skeletal disorder, β1 integrin, Genetics, Cell Adhesion, Humans, LAMA5, Genetic Predisposition to Disease, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Alleles, Genetic Association Studies, Bone Diseases, Developmental, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::src-Family Kinases [Medical Subject Headings], lcsh:R, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings], Actin cytoskeleton, Focal Adhesion Kinase 2, 030104 developmental biology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Focal Adhesion Protein-Tyrosine Kinases::Focal Adhesion Kinase 2 [Medical Subject Headings], Musculoskeletal, Mutation, biology.protein, beta 1 integrin, Laminin α5
Abstract

Background Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood Methods Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities. Migration and wound healing assays examined cell migration properties. Findings This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. Interpretation This newly described mechanism revealed a LAMA5-β1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. Funding Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.

Published
2020

4. Systematic Review of Prevalence Studies and Familial Aggregation in Vestibular Migraine

Author

Paz-Tamayo, Ana, Perez-Carpena, Patricia, Lopez-Escamez, Jose A., [Paz-Tamayo,A] Division of Otolaryngology, Department of Surgery, Universidad de Granada, Granada, Spain. [Perez-Carpena,P] Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Universitario San Cecilio, Granada, Spain. [Perez-Carpena,P, and Lopez-Escamez,JA] Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research – Pfizer/University of Granada/Junta de Andalucía, PTS, Granada, Spain. [Lopez-Escamez,JA] Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Granada, Spain.

Subjects
Epidemiology, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies [Medical Subject Headings], Enfermedades del nervio vestibulococlear, Persons::Persons::Siblings [Medical Subject Headings], Vestibular disorders, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Heritability, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Diseases::Nervous System Diseases::Cranial Nerve Diseases::Vestibulocochlear Nerve Diseases [Medical Subject Headings], Vestibular migraine, Prevalence, Genetics, Epidemiología, Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Headache Disorders::Headache Disorders, Primary::Migraine Disorders [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Odds Ratio [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Prevalence [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics [Medical Subject Headings], Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age Factors::Age of Onset [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Revisión sistemática, Genética, Systematic review, Diseases::Nervous System Diseases::Neurologic Manifestations::Vertigo [Medical Subject Headings], Disciplines and Occupations::Health Occupations::Medicine::Public Health::Epidemiology [Medical Subject Headings], Prevalencia
Abstract

Background: Vestibular migraine (VM) is complex disorder consisting of episodes of migraine and vertigo with an estimated prevalence of 1-3%. As migraine, it is considered that VM has genetic predisposition; however, evidence to support a genetic contribution has not been critically appraised. Objective: The aim of this systematic review is to assess available evidence in scientific publications to determine the role of inheritance in VM. Methods: After performing the quality assessment of the retrieved records, 31 studies were included (24 epidemiological reports and 7 genetic association studies in families or case-control in candidate genes). We gathered data about prevalence of VM in different populations and in families, and also about the genetic findings reported. In addition, other variables were considered to assess the heritability of VM, such as the ancestry, the age of onset or the familial history of vertigo and migraine. Results: The estimated prevalence of VM was different between black (3.13%), white (2.64%) and Asian (1.07%) ethnicities. The reported prevalence of VM in migraine patients is higher in European countries (21%) than in Asian countries (10%). Moreover, the prevalence of the migraine-vertigo association in families is 4-10 times higher than the prevalence reported in the general population (sibling recurrence risk ratio λs = 4.31-10.42). We also found that the age of onset is lower in patients with simultaneous onset of symptoms and in those who have familial history for migraine and/or vertigo, suggesting anticipation. Although some genetic studies have reported few allelic variants associated to MV, replication studies are needed to validate these results. Conclusions: The available evidence to support heritability in VM is limited. Variability in prevalence depending on ethnicity and geographic location suggests a combined genetic and environmental contribution to VM. However, the familial aggregation observed in VM support genetic and shared familial environmental effects that remarks the necessity of twins and adoptees-based epidemiological studies to estimate its heritability. Yes

Published
2020

5. A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

Author

Amanat, Sana, Requena, Teresa, Lopez-Escamez, Jose Antonio, [Amanat,S, Lopez-Escamez,JA] Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO—Centre for Genomics and Oncological Research—Pfizer/University of Granada/Junta de Andalucía, PTS, Granada, Spain. [Requena,T] Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK. [Lopez-Escamez,JA] Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain. [Lopez-Escamez,JA] Department of Surgery, Division of Otolaryngology, Universidad de Granada, Granada, Spain., and This study was funded by H2020 MSCA-ITN-2016–722046 Grant (JALE). The project leading to these results has received funding from 'la Caixa' Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002 (JALE). This project is part of the European School of Interdisciplinary Tinnitus (ESIT) research.

Subjects
Exome sequencing, Genetic association studies, Secuenciación del exoma completo, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Estudios de asociación genética, Extreme phenotype, Acúfeno, Epidemiología molecular, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Rare Diseases [Medical Subject Headings], Diseases [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Tinnitus, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Epidemiology [Medical Subject Headings], Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Hearing Disorders::Hearing Loss [Medical Subject Headings], Genetic epidemiology, Diseases::Otorhinolaryngologic Diseases::Ear Diseases::Hearing Disorders::Tinnitus [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings]
Abstract

Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss. Yes

Published
2020

6. Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel

Author

Guillermo Antiñolo, Nereida Bravo-Gil, Salud Borrego, Cristina Méndez-Vidal, Enrique Rodríguez de la Rúa, Joaquín Dopazo, Laura Romero-Pérez, María González del Pozo, [Bravo-Gil,N, Méndez-Vidal,C, Romero-Pérez,L, González-Del Pozo,M, Borrego,S, Antiñolo,G] Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. [Bravo-Gil,N, Dopazo,J, Antiñolo,G] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain. [Rodríguez-de la Rúa,E] Department of Ophthalmology, University Hospital Virgen Macarena, Seville, Spain. [Dopazo,J] Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF).Functional Genomics Node, (INB) at CIPF, Valencia, Spain., This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI11-02923), CIBERER ACCI, CDTI FEDER-Innterconecta (EXP00052887/ITC-20111037), Regional Ministry of Economy, Innovation, Science and Employment of the Autonomous Government of Andalusia (CTS-1664) and the Foundation Ramon Areces (CIVP16A1856). The CIBERER is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. NB-G is supported by fellowship FI12/00545 from ISCIII., Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Centro para el Desarrollo Tecnológico Industrial (España), Junta de Andalucía, and Fundación Ramón Areces

Subjects
0301 basic medicine, Proband, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Heterogeneidad genética, DNA Mutational Analysis, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [Medical Subject Headings], medicine.disease_cause, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Exoma, Exome sequencing, Genetics, education.field_of_study, Mutation, Multidisciplinary, High-Throughput Nucleotide Sequencing, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Medical::Genetic Counseling [Medical Subject Headings], Phenotype, Distrofias retinianas, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Fenotipo, Retinal Dystrophies, Diseases::Eye Diseases::Retinal Diseases::Retinal Degeneration::Retinal Dystrophies [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], DNA Copy Number Variations, Genetic counseling, Population, Biology, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome [Medical Subject Headings], Article, 03 medical and health sciences, Genetic Heterogeneity, medicine, Humans, Computer Simulation, Allele, education, Eye Proteins, Alleles, Genetic Association Studies, Gene Library, Genetic heterogeneity, Estudios de asociación genética, Asesoramiento genético, Genetic Therapy, 030104 developmental biology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Genetic Heterogeneity [Medical Subject Headings], Genotipo
Abstract

Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management., This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI11-02923), CIBERER ACCI, CDTI FEDER-Innterconecta (EXP00052887/ITC-20111037), Regional Ministry of Economy, Innovation, Science and Employment of the Autonomous Government of Andalusia (CTS-1664) and the Foundation Ramon Areces (CIVP16A1856). The CIBERER is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. NB-G is supported by fellowship FI12/00545 from ISCIII.

Published
2016

7. Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

Author

Ana Márquez, Ricardo Blanco, José A. Miranda-Filloy, Trinitario Pina, Manuel León Luque, Raquel López-Mejías, Francisca González Escribano, Begoña Ubilla, Fernanda Genre, Norberto Ortego-Centeno, Eva Galíndez-Aguirregoikoa, Javier Llorca, J. M. Blanco-Madrigal, Belén Sevilla Pérez, Santos Castañeda, Marta Conde-Jaldón, Maximiliano Aragües, Diego de Argila, Miguel A. González-Gay, Verónica Mijares, E. Rubio, Antonio Navas Parejo, Javier Martín, Lourdes Ortiz-Fernández, Sara Remuzgo-Martínez, J. Gonzalo Ocejo-Vinyals, Vanesa Calvo-Río, Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Red de Investigación en Inflamación y Enfermedades Reumáticas (España), [López-Mejías,R, Genre,F, Ubilla,B, Remuzgo-Martínez,S, Mijares,V, Pina,T, Calvo-Río,V, Blanco,R, González-Gay,MA] Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. [Sevilla Pérez,B, Ortego-Centeno,N] Medicine Department, Hospital Universitario San Cecilio, Granada, Spain. [Castañeda,S] Rheumatology Department, Hospital Universitario La Princesa, IIS-Princesa, Madrid, Spain. [Llorca,J] Epidemiology and Computational Biology Department, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Santander, Spain. [Márquez,A] Institute of Parasitology and Biomedicine López-Neyra (IPBLN-CSIC). Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain. [Miranda-Filloy,JM] Division of Rheumatology, Hospital Universitario Lucus Augusti, Lugo, Spain. [Navas Parejo,A] Nephrology Department, Hospital Universitario San Cecilio, Granada, Spain. [Conde-Jaldón,M, Ortiz-Fernández,L, González Escribano,F] Immunology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain. [Argila,D, Aragües,M] Dermatology Department, IIS-IP, Hospital de la Princesa, Madrid, Spain. [Rubio,E, León Luque,M] Rheumatology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain. [Blanco-Madrigal,JM, and Galíndez-Aguirregoikoa,E] Rheumatology Department, Hospital Universitario de Basurto, Bilbao, Spain. [Ocejo-Vinyals,JG] Immunology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. [Martín,J] Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.

Subjects
Male, Henoch-Schonlein purpura, España, Adulto joven, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Preescolar, immune system diseases, hemic and lymphatic diseases, Immunology and Allergy, Masculino, Child, HLA-DRB1, Adolescente, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Purpura, Schoenlein-Henoch, Cadenas HLA-DRB1, Antígenos HLA-B, Femenino, Predisposición genética a la enfermedad, HLA-B, Humanos, Purpura, Niño, Child, Preschool, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings], Female, Estudios de seguimiento, medicine.symptom, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Vasculitis, Research Article, IgA Vasculitis, Adolescent, Immunology, Púrpura de Schoenlein-Henoch, Diseases::Immune System Diseases::Hypersensitivity::Immune Complex Diseases::Purpura, Schoenlein-Henoch [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Human leukocyte antigen, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Membrane Glycoproteins::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB1 Chains [Medical Subject Headings], Persons::Persons::Age Groups::Adolescent [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Young Adult, Rheumatology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Follow-Up Studies [Medical Subject Headings], medicine, HLA-B Antigens, Humans, Persons::Persons::Age Groups::Child [Medical Subject Headings], Genetic Predisposition to Disease, Genetic Association Studies, Estudios de asociación genética, business.industry, medicine.disease, IgA vasculitis, Check Tags::Female [Medical Subject Headings], Spain, business, Persons::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings], Follow-Up Studies, HLA-DRB1 Chains
Abstract

López-Mejías, Raquel et al., [Introduction] A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies., [Methods] The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test., [Results] A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found., [Conclusions] Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status., This study was supported by a grant from ‘Fondo de Investigaciones Sanitarias’ PI12/00193 (Spain). RLM is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III at the Spanish Ministry of Health (Spain) (CD12/00425). FG and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013).

Published
2015

8. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

Author

Víctor Noriega, Carolina Martínez-Laperche, Elena Buces, Marjorie Pion, Noemí Sánchez-Hernández, Beatriz Martín-Antonio, Vicent Guillem, Anna Bosch-Vizcaya, Leyre Bento, Milagros González-Rivera, Pascual Balsalobre, Mi Kwon, David Serrano, Jorge Gayoso, Rafael de la Cámara, Salut Brunet, Rafael Rojas-Contreras, José B Nieto, Carmen Martínez, Marcos Gónzalez, Ildefonso Espigado, Juan C Vallejo, Antonia Sampol, Antonio Jiménez-Velasco, Alvaro Urbano-Ispizua, Carlos Solano, David Gallardo, José L Díez-Martín, Ismael Buño, Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH), Universitat de Barcelona, Spanish Hematopoietic Stem Cell Transplantario and Cell Therapy Group (GETH), [Noriega,V, Martínez-Laperche,C, Buces,E, Sánchez-Hernández,N, Bento,L, Balsalobre,P, Kwon,M, Serrano,D, Gayoso,J, Díez-Martín,JL, Buño,I] Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Noriega,V, Pion,M, González-Rivera,M, Buño,I] Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. [Pion,M] Department of Inmunology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Martín-Antonio,B, Urbano-Ispizua,A] Department of Hematology, Hospital Clinic, University of Barcelona, IDIBAPS, Instituto de Investigación Josep Carreras (IJC), Barcelona, Spain. [Guillem,V, Solano,C] Department of Hematology and Medical Oncology, Hospital Clínico Universitario de Valencia, Universitat de Valencia, Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain. [Bosch-Vizcaya,A, Gallardo,D] Department of Hematology, ICO Girona, Hospital Josep Trueta, IDIBGI Foundation, Girona, Spain. [González-Rivera,M] DNA Sequencing Core Facility, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [de la Cámara,R] Department of Hematology, Hospital La Princesa, Madrid, Spain. [Brunet,S] Department of Clinical Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [Rojas-Contreras,R] Department of Hematology, Hospital Reina Sofia, Cordoba, Spain. [Nieto,JB] Department of Hematology, Hospital Morales Meseguer, Murcia, Spain. [Martínez,C] Department of Hematology, Hospital Clínic, Barcelona, Spain. [González,M] Department of Hematology, University Hospital of Salamanca, Salamanca, Spain. [Espigado,I] Department of Hematology and Hemotherapy, Hospital Universitario Virgen del Rocío, Seville, Spain. [Vallejo,JC] Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain. [Sampol,A] Department of Hematology, Hospital Universitario Son Espases, Palma de Mallorca, Islas Baleares, Spain. [Jiménez-Velasco,A] Department of Hematology, Hospital Regional Universitario de Málaga, Málaga, Spain., and This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI08/1463, PI11/00708, PI14-01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, the Fundación LAIR and Asociación Madrileña de Hematología y Hemoterapia (AMHH). ISCIII-FIS grants PI01-3624, PI08- 36173 and The Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM).

Subjects
Male, Análisis de supervivencia, trasplante de células madre hematopoyéticas, medicine.medical_treatment, humanos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Survival Analysis [Medical Subject Headings], Graft vs Host Disease, lcsh:Medicine, Polimorfismo genético, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Hematopoietic stem cell transplantation, Stem cells, Regiones promotoras genéticas, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Trasplante homólogo, IL-2 receptor, Lymphocytes, Masculino, Promoter Regions, Genetic, lcsh:Science, mediana edad, anciano, Multidisciplinary, Adulto, Femenino, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Cell Transplantation::Stem Cell Transplantation::Hematopoietic Stem Cell Transplantation [Medical Subject Headings], Hematopoietic Stem Cell Transplantation, FOXP3, Forkhead Transcription Factors, adulto, análisis de supervivencia, Middle Aged, Tissue Donors, Humanos, estudios de asociación genética, adulto joven, medicine.anatomical_structure, surgical procedures, operative, Cèl·lules T, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::Winged-Helix Transcription Factors::Forkhead Transcription Factors [Medical Subject Headings], Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Factores de transcripción en cabeza de tenedor, Cèl·lules mare, Trasplante de células madre hematopoyéticas, Research Article, Adult, Named Groups::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Genotype, Graft-vs-Leukemia Effect, Regulatory T cell, Anciano, T cells, Check Tags::Male [Medical Subject Headings], Graft vs Leukemia Effect, factores de transcripción en cabeza de tenedor, Human leukocyte antigen, Biology, Enfermedad injerto contra huésped, Limfòcits, Young Adult, Donantes de tejidos, Named Groups::Persons::Tissue Donors [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], medicine, Humans, Transplantation, Homologous, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Genetic Association Studies, Aged, Mediana edad, Transplantation, Polymorphism, Genetic, Estudios de asociación genética, Efecto injerto contra leucemia, lcsh:R, donantes de tejidos, trasplante, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], medicine.disease, Survival Analysis, Diseases::Immune System Diseases::Graft vs Host Disease [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Transplantation, Homologous [Medical Subject Headings], efecto injerto contra leucemia, Graft-versus-host disease, Check Tags::Female [Medical Subject Headings], Immunology, Phenomena and Processes::Immune System Phenomena::Immune System Processes::Transplantation Immunology::Graft vs Host Reaction::Graft vs Tumor Effect::Graft vs Leukemia Effect [Medical Subject Headings], enfermedad injerto contra huésped, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Gene Components::Regulatory Elements, Transcriptional::Promoter Regions, Genetic [Medical Subject Headings], lcsh:Q, genotipo, Genotipo
Abstract

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (, This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI08/1463, PI11/00708, PI14-01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, as well as grants from the Fundacion LAIR and Asociacion Madrilena de Hematologia y Hemoterapia (AMHH). Sequencer 3130xl Genetic Analyzer was partially supported by ISCIII-FIS grants PI01-3624, PI08-36173. VN and CML were partially supported by a Post-Residency Research Fellowship from the Instituto de Investigacion Sanitaria Gregorio Maranon (IiSGM).

Published
2015

9. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance

Author

José Manuel Fernández-Real, Gerard Pardo, Francisco J. Tinahones, Wifredo Ricart, José María Moreno-Navarrete, Francisco J. Ortega, Ester Guerra, Marta Serrano, [Moreno-Navarrete, JM, Ortega, F, Serrano, M, Guerra, E, Pardo, G, Ricart, W, Fernández-Real, JM] Department of Diabetes, Endocrinology, and Nutrition, Hospital Dr. Josep Trueta de Girona, Spain, Institut d’Investigació Biomèdica de Girona, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn) (CB06/03/010), and Instituto de Salud Carlos III, 17007 Girona, Spain. [Tinahones, F] Department of Endocrinology and Nutrition, Hospital Virgen de la Victoria de Málaga, CIBERobn (CB06/03/018), Instituto de Salud Carlos III, Málaga, Spain, and This work was supported by research grants from the Ministerio de Educación y Ciencia (Grant FISPI1100214). The Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III (Spain).

Subjects
Male, FGF21, Fibronectinas, Ratones, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Obesidad, Adipose tissue, Gene Expression, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Insulin Resistance [Medical Subject Headings], White adipose tissue, Diabetes Mellitus Tipo 2, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Resistencia a la Insulina, Biochemistry, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Fibronectins [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, Endocrinology, Brown adipose tissue, Músculo Esquelético, Organisms::Eukaryota::Animals [Medical Subject Headings], Tejido Adiposo, Cells, Cultured, PRDM16, Anatomy::Musculoskeletal System::Muscles::Muscle, Skeletal [Medical Subject Headings], Middle Aged, Thermogenin, Anatomy::Tissues::Connective Tissue::Adipose Tissue [Medical Subject Headings], Células Cultivadas, medicine.anatomical_structure, Adipose Tissue, Células 3T3-L1, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Female, Adult, medicine.medical_specialty, Expresión Génica, Adipose tissue macrophages, Check Tags::Male [Medical Subject Headings], Biology, Internal medicine, 3T3-L1 Cells, Myokine, medicine, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Animals, Humans, Obesity, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Muscle, Skeletal, Genetic Association Studies, Aged, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Biochemistry (medical), Fibronectins, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Diabetes Mellitus, Type 2, Check Tags::Female [Medical Subject Headings], Anatomy::Cells::Cells, Cultured [Medical Subject Headings], Anatomy::Cells::Cells, Cultured::Cell Line::3T3 Cells::Swiss 3T3 Cells::3T3-L1 Cells [Medical Subject Headings], Estudios de Asociación Genética, Insulin Resistance
Abstract

Context: Recently irisin (encoded by Fndc5 gene) has been reported to stimulate browning and uncoupling protein 1 expression in sc adipose tissue of mice. Objective: The objective of the study was to investigate FNDC5 gene expression in human muscle and adipose tissue and circulating irisin according to obesity, insulin sensitivity, and type 2 diabetes. Design, Patients, and Main Outcome Measure: Adipose tissue FNDC5 gene expression and circulating irisin (ELISA) were analyzed in 2 different cohorts (n = 125 and n = 76); muscle FNDC5 expression was also evaluated in a subcohort of 34 subjects. In vitro studies in human preadipocytes and adipocytes and in induced browning of 3T3-L1 cells (by means of retinoblastoma 1 silencing) were also performed. Results: In both sc and visceral adipose tissue, FNDC5 gene expression decreased significantly in association with obesity and was positively associated with brown adipose tissue markers, lipogenic, insulin pathway-related, mitochondrial, and alternative macrophage gene markers and negatively associated with LEP, TNFα, and FSP27 (a known repressor of brown genes). Circulating irisin and irisin levels in adipose tissue were significantly associated with FNDC5 gene expression in adipose tissue. In muscle, the FNDC5 gene was 200-fold more expressed than in adipose tissue, and its expression was associated with body mass index, PGC1α, and other mitochondrial genes. In obese participants, FNDC5 gene expression in muscle was significantly decreased in association with type 2 diabetes. Interestingly, muscle FNDC5 gene expression was significantly associated with FNDC5 and UCP1 gene expression in visceral adipose tissue. In men, circulating irisin levels were negatively associated with obesity and insulin resistance. Irisin was secreted from human adipocytes into the media, and the induction of browning in 3T3-L1 cells led to increased secreted irisin levels. Conclusions: Decreased circulating irisin concentration and FNDC5 gene expression in adipose tissue and muscle from obese and type 2 diabetic subjects suggests a loss of brown-like characteristics and a potential target for therapy.

Published
2013

10. Lack of association between the protein tyrosine phosphatase non-receptor type 22 R263Q and R620W functional genetic variants and endogenous non-anterior uveitis

Author

Carmen Cenit, Maria, Marquez, Ana, Cordero-Coma, Miguel, Fonollosa, Alejandro, Llorenc, Victor, Artaraz, Joseba, Diaz Valle, David, Blanco, Ricardo, Canal, Joaquin, Salom, David, Garcia Serrano, Jose Luis, Ramon, Enrique, Jose Del Rio, Maria, Begona Gorrono-Echebarria, Marina, Manuel Martin-Villa, Jose, Molins, Blanca, Ortego-Centeno, Norberto, Javier Martin, [Cénit,MC, Márquez,A, Martín,J] Instituto de Parasitología y Biomedicina López-Neyra, IPBLN, CSIC, Granada, Spain. [Cordero-Coma,M] Ophthalmology Department, Hospital de León, León, Spain. [Fonollosa,A, and Artaraz,J] Ophthalmology Department, Hospital de Cruces, Bilbao, Spain. [Llorenç,V] Ophthalmology Department, Hospital Clínic, Barcelona, Spain. [Díaz Valle, D] Ophthalmology Department, Hospital Clínico San Carlos, Madrid, Spain. [Blanco,R] Rheumatology Department, Hospital Marqués de Valdecilla, IFIMAV, Santander, Spain. [Cañal,J] Ophthalmology Department, Hospital Marqués de Valdecilla, IFIMAV, Santander, Spain. [Salom,D] Ophthalmology Department, Hospital Universitario La Fe, Valencia, Spain. [García Serrano,JL] Ophthalmology Department, Hospital Clínico San Cecilio, Granada, Spain. [Ramon,E de] Internal Medicine Department, Hospital Carlos Haya, Málaga, Spain. [Rio,MJ del] Ophthalmology Department, Hospital Carlos Haya, Málaga, Spain. [Gorroño-Echebarría,MB] Ophthalmology Department, Hospital Universitario Principe de Asturias, Alcalá de Henares, Spain. [Martín-Villa,JM] Immunology Department, Facultad de Medicina, Universidad Complutense de Madrid, Spain. [Molins,B] Instituto de Investigaciones Biomédicas, IDIBAPS, Hospital Clinic, Barcelona, Spain. [Ortego-Centeno,N] Internal Medicine Department, Hospital Clínico San Cecilio, Granada, Spain.

Subjects
Male, Proteína tirosina fosfatasa no receptora de tipo 22, España, Health Care::Population Characteristics::Demography [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Proteínas mutantes, Polymorphism, Single Nucleotide, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::Protein Tyrosine Phosphatases, Non-Receptor::Protein Tyrosine Phosphatase, Non-Receptor Type 22 [Medical Subject Headings], Gene Frequency, Humans, Demografía, Genetic Predisposition to Disease, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Mutant Proteins [Medical Subject Headings], Diseases::Eye Diseases::Uveal Diseases::Uveitis::Panuveitis::Uveitis, Anterior [Medical Subject Headings], Alleles, Genetic Association Studies, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Demography, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Mutagenesis::Amino Acid Substitution [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Estudios de casos y controles, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Estudios de asociación genética, Predisposición genética a la enfermedad, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Middle Aged, Uveitis, Anterior, Polimorfismo de nucleótido único, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], eye diseases, Frecuencia génica, Uveítis anterior, Amino Acid Substitution, Check Tags::Female [Medical Subject Headings], Spain, Case-Control Studies, Female, Mutant Proteins, Alelos, Phenomena and Processes::Genetic Phenomena::Gene Frequency [Medical Subject Headings], Research Article
Abstract

Journal Article; OBJECTIVE Endogenous uveitis is a major cause of visual loss mediated by the immune system. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes a lymphoid-specific phosphatase that plays a key role in T-cell receptor (TCR) signaling. Two independent functional missense single nucleotide polymorphisms (SNPs) located within the PTPN22 gene (R263Q and R620W) have been associated with different autoimmune disorders. We aimed to analyze for the first time the influence of these PTPN22 genetic variants on endogenous non-anterior uveitis susceptibility. METHODS We performed a case-control study of 217 patients with endogenous non-anterior uveitis and 718 healthy controls from a Spanish population. The PTPN22 polymorphisms (rs33996649 and rs2476601) were genotyped using TaqMan allelic discrimination assays. The allele, genotype, carriers, and allelic combination frequencies were compared between cases and controls with χ(2) analysis or Fisher's exact test. RESULTS Our results showed no influence of the studied SNPs in the global susceptibility analysis (rs33996649: allelic P- value=0.92, odds ratio=0.97, 95% confidence interval=0.54-1.75; rs2476601: allelic P- value=0.86, odds ratio=1.04, 95% confidence interval=0.68-1.59). Similarly, the allelic combination analysis did not provide additional information. CONCLUSIONS Our results suggest that the studied polymorphisms of the PTPN22 gene do not play an important role in the pathophysiology of endogenous non-anterior uveitis. Yes

Published
2013

11. Identification of reference genes for quantitative RT-PCR in ascending aortic aneurysms

Author

Hilja Perttunen, Dominic Henn, Doris Bandner-Risch, Wolfram Schmied, Noela Rodriguez-Losada, Hans-Joachim Schäfers, Francisco C. Ceballos, Carlos Porras, [Henn,D, Bandner-Risch,D, Perttunen,H, Schmied,W, and Schäfers,H-J] Department of Thoracic and Cardiovascular Surgery, Saarland University Hospital, Homburg/Saar, Germany. [Porras,C] Department of Cardiac Surgery, Hospital Universitario Virgen de la Victoria de Málaga, Spain. [Ceballos,F] Department of Genetics, Faculty of Biology, University of Santiago de Compostela, Spain. [Rodríguez-Losada,N] Foundation IMABIS, Carlos Haya University Hospital, Avenida Carlos Haya, Malaga, Spain.

Subjects
Aortic valve, Male, Pathology, Cardiothoracic Surgery, Anatomy and Physiology, Valvular Disease, Hemodynamics, Gene Expression, Cardiovascular, Cardiovascular System, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Aortic aneurysm, Reference genes, Factor 2B Eucariótico de Iniciación, Masculino, Aorta, Diseases::Cardiovascular Diseases::Vascular Diseases::Aneurysm::Aortic Aneurysm [Medical Subject Headings], Multidisciplinary, Cardiovascular Surgery, Reverse Transcriptase Polymerase Chain Reaction, Adulto, Femenino, Nuclear Proteins, Middle Aged, Aortic Aneurysm, Humanos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain Reaction [Medical Subject Headings], Eukaryotic Initiation Factor-2B, medicine.anatomical_structure, Hypertension, Cardiology, cardiovascular system, Medicine, Cyclophilin A, Dilatation, Pathologic, Research Article, Adult, medicine.medical_specialty, Expresión Génica, Science, Check Tags::Male [Medical Subject Headings], Biology, Receptor, Angiotensin, Type 1, Molecular Genetics, Diseases::Cardiovascular Diseases::Heart Diseases::Heart Valve Diseases [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], Vascular Biology, Anatomy::Tissues [Medical Subject Headings], medicine.artery, Internal medicine, Ascending aorta, Aneurisma de la Aorta, Enfermedades de las Válvulas Cardíacas, Hipertensión, medicine, Genetics, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Angiotensin II receptor type 1, Human Genetics, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::GTP-Binding Protein Regulators::Guanine Nucleotide Exchange Factors::Eukaryotic Initiation Factor-2B [Medical Subject Headings], medicine.disease, Reacción en Cadena de la Polimerasa de Transcriptasa Inversa, Tejidos, Check Tags::Female [Medical Subject Headings], Genetics of Disease, Cardiovascular Anatomy, Surgery, Unicuspid, Estudios de Asociación Genética, Transcription Factors
Abstract

Journal Article; Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue. Yes

Published
2013

12. A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

Author

Bossini-Castillo, L., Simeon, C.P., Beretta, L., Broen, J.C., Vonk, M.C., Rios-Fernandez, R., Espinosa, G., Carreira, P., Camps, M.T., Castillo, M.J., Gonzalez-Gay, M.A., Beltran, E., Freire, M.D., Narvaez, J., Tolosa, C., Witte, T., Kreuter, A., Schuerwegh, A.J., Hoffmann-Vold, A.M., Hesselstrand, R., Lunardi, C., Laar, J.M. van, Chee, M.M., Herrick, A., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R.D.J., Martin, J., Spanish Scleroderma Grp, The Spanish Scleroderma Group, [Bossini-Castillo,L, Martín,J] Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain. [Simeon,CP] Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain. [Beretta,L] IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena and University of Milan, Allergy, Clinical Immunology and Rheumatology, Milan, Italy. [Broen,JC, Vonk,MC] Department of Rheumatology, Radboud University Nijmegen Medical CentreNijmegen, The Netherlands. [Ríos-Fernández,R] Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain. [Espinosa,G] Servicio de Enfermedades Autoinmunes, Hospital Clinic, Barcelona, Spain. [Carreira,P] Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain. [Camps,MT] Servicio de Medicina Interna, Hospital Carlos Haya, Málaga, Spain. [Castillo,MJ] Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, Spain. [González-Gay,MA] Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain. [Beltran,E] Servicio de Reumatología, Hospital del Doctor Peset Aleixandre, Valencia, Spain. [Freire,M del C] Unidad Trombosis y Vasculitis, Servicio de Medicina Interna, Hospital Xeral-Complexo Hospitalario Universitario de Vigo, Vigo, Spain. [Narváez,J] Servicio de Reumatología, Hospital Universitario de Bellvitge, Barcelona, Spain. [Tolosa,C] Servicio de Medicina Interna, Hospital Parc Taulí, Sabadell, Spain. [Witte,T] Hannover Medical School, Hannover, Germany. [Kreuter,A] Ruhr University of Bochum, Bochum, Germany. [Schuerwegh,AJ] Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. [Hoffmann-Vold,A-M] Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway. [Hesselstrand,R] Department of Rheumatology, Lund University, Lund, Sweden. [Lunardi,C] Department of Medicine, Università degli Studi di Verona Verona, Italy. [Van Laar,JM] Institute of Cellular Medicine, Newcastle University, NewcastleUK. [Chee,MM] Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK. [Herrick,A] Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. [Koeleman,BPC] Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. [Denton,CP, Fonseca,C] Centre for Rheumatology, Royal Free and University College Medical School, University College London, London, UK. [Radstake,TRDJ] Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands., This work was supported by the following grants: GENFER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain and by Fondo Europeo de Desarrollo Regional (FEDER). The VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). The Orphan Disease Program grant from the European League Against Rheumatism (EULAR). The Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). DFG WI 1031/6.1. This study was also funded by PI-0590-2010, Consejería de Salud, Junta de Andalucía, Spain., and Universitat de Barcelona

Subjects
Antigens, Differentiation, T-Lymphocyte, Male, systemic sclerosis, CD226 gene, Autoimmune diseases, Pulmonary Fibrosis, Genome-wide association study, Chemicals and Drugs::Biological Factors::Biological Markers::Antigens, Differentiation::Antigens, Differentiation, T-Lymphocyte [Medical Subject Headings], GWAS, Genoma humà, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Diseases::Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cohort Studies, Pulmonary fibrosis, Immunology and Allergy, Antígenos de diferenciación de linfocitos T, Malalties autoimmunitàries, Fibrosi pulmonar, Infection and autoimmunity Auto-immunity, transplantation and immunotherapy [NCMLS 1], Evaluation of complex medical interventions Auto-immunity, transplantation and immunotherapy [NCEBP 2], Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Research Article, Genotype, Estudios de cohortes, Fibrosis pulmonar, Esclerodermia sistémica, Immunology, Check Tags::Male [Medical Subject Headings], Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Rheumatology, Genetic variation, medicine, Genetic predisposition, Humans, SNP, Diseases::Respiratory Tract Diseases::Lung Diseases::Pulmonary Fibrosis [Medical Subject Headings], Genetic Association Studies, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Scleroderma, Systemic, Human genome, Estudios de asociación genética, Haplotype, Autoantibody, Genetic Variation, medicine.disease, Scleroderma (Disease), Check Tags::Female [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Esclerodèrmia, Genotipo
Abstract

Introduction CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. Methods A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. Results Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (P Bonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). Conclusion Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis., This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain and by Fondo Europeo de Desarrollo Regional (FEDER).

Published
2012

13. Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations

Author

Guillermo Izquierdo, Javier Gayán, Carmen Arnal, Dorothy Ndagire, Antonio Catalá-Rabasa, Agustín Ruiz, Fuencisla Matesanz, María Fedetz, Concepción Delgado, Miguel Lucas, María M. Abad-Grau, Oscar Fernández, Antonio Alcina, [Alcina, A, Fedetz, M, Ndagire, D, Catalá-Rabasa, A, Matesanz,F] Instituto de Parasitología y Biomedicina ‘López Neyra’, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain [Abad-Grau,M del M] Departamento de Lenguajes y Sistemas Informáticos, CITIC, Universidad de Granada, Granada, Spain.[Izquierdo,G, Matesanz,F] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain.[Lucas,M] Servicio de Biología Molecular, Hospital Virgen Macarena, Sevilla, Spain. [Fernández,O] Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Carlos Haya, Málaga, Spain. [Ruiz,A, Gayán,J] Departamento de Genómica Estructural, Neocodex, Sevilla, Spain.[Delgado,C] Centro Regional de Transfusión Sanguínea Granada-Almería, Granada, Spain.[Arnal,C] Servicio de Neurología, Hospital Virgen de las Nieves, Granada, Spain., and This work was supported by the Ministerio de Ciencia e Innovación - Fondos Feder [PN-SAF2009-11491 to AA], Junta de Andalucía [P07-CVI-02551 to AA], and Fondo de Investigación Sanitaria [FIS PI081636, CP10/00526 to FM]. MF and DN are holders of a fellowship from Fundación Española de Esclerosis Múltple (FEDEM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects
Male, Genome-wide association study, Linkage Disequilibrium, Inflammatory bowel disease, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry Group [Medical Subject Headings], Grupo de Ascendencia Continental Europea, Regulación de la Expresión Génica, Masculino, lcsh:Science, 0303 health sciences, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Population [Medical Subject Headings], Genomics, Humanos, 3. Good health, Neurology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models [Medical Subject Headings], Medicine, musculoskeletal diseases, Multiple Sclerosis, Immunology, Quantitative Trait Loci, Predisposición Genética a la Enfermedad, Check Tags::Male [Medical Subject Headings], Locus (genetics), Single-nucleotide polymorphism, Human leukocyte antigen, White People, Multiple sclerosis, 03 medical and health sciences, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens::HLA-D Antigens::HLA-DQ Antigens::HLA-DQ beta-Chains [Medical Subject Headings], Genetics, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Variant genotypes, Biology, Alleles, Haplotype, lcsh:R, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Genome-Wide Association Study [Medical Subject Headings], Genetics, Population, Logistic Models, African americans, Esclerosis Múltiple, Check Tags::Female [Medical Subject Headings], lcsh:Q, Estudios de Asociación Genética, Polimorfismo de Nucleótido Simple, Gene expression, 030217 neurology & neurosurgery, Neuroscience, Desequilibrio de Ligamiento, Linkage disequilibrium, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], lcsh:Medicine, Genome-wide association studies, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings], Risk Factors, HLA-DQ beta-Chains, Multidisciplinary, Cadenas HLA-DRB1, Adulto, Femenino, Phenomena and Processes::Genetic Phenomena::Genetic Linkage::Linkage Disequilibrium [Medical Subject Headings], Cadenas HLA-DRB5, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DQ Antigens::HLA-DQ beta-Chains [Medical Subject Headings], Female, Haplotipos, Alelos, Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Research Article, Adult, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB5 Chains [Medical Subject Headings], Polymorphism, Single Nucleotide, Estudio de Asociación del Genoma Completo, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Systemic lupus erythematosus, Cadenas beta de HLA-DQ, Modelos Logísticos, Genetic Predisposition to Disease, Genética de Población, Allele, Genetic Association Studies, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], 030304 developmental biology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Sitios de Carácter Cuantitativo, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genetic Loci::Quantitative Trait Loci [Medical Subject Headings], Demyelinating Disorders, HLA-DRB5 Chains, Gene Expression Regulation, Haplotypes, Expression quantitative trait loci, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. © 2012 Alcina et al.

Published
2012

14. A Large Study of Androgen Receptor Germline Variants and Their Relation to Sex Hormone Levels and Prostate Cancer Risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Author

Peter Kraft, Loic Le Marchand, H. Bas Bueno-de-Mesquita, Pär Stattin, Stephen J. Chanock, Daniel O. Stram, Stephanie J. Weinstein, Alison M. Dunning, Jarmo Virtamo, Heather Spencer Feigelson, Richard B. Hayes, Rosario Tumino, Matthew L. Freedman, Kim Overvad, David Altshuler, Demetrius Albanes, Jing Ma, Meredith Yeager, Heiner Boeing, Carmen Martinez, Meir J. Stampfer, Rudolf Kaaks, David J. Hunter, Brian E. Henderson, Elio Riboli, Michael J. Thun, Afshan Siddiq, Edward Giovannucci, Christopher A. Haiman, Laurence N. Kolonel, Naomi E. Allen, Sara Lindström, J. Michael Gaziano, Sonja I. Berndt, Dimitrios Trichopoulos, [Lindstroem,S, Hunter,DJ, Kraft,P] Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [Lindstroem,S, Stampfer,M, Trichopoulos,D, Kraft,P] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [Giovannucci,E, Stampfer,M] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. [Kraft,P] Department of Biostatisctics, Harvard School of Public Health, Boston, Massachusetts, USA. [Ma,J, Stampfer,M] Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. [Altshuler,D] Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, Department of Genetics, Harvard Medical School, Boston, Massachusetts, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts. [Riboli,E, Siddiq,A] Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College, London, United Kingdom. [Albanes,D, Berndt,SI, Chanock,SJ, Hayes,RB, Weinstein,SJ] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. [Allen,NE] Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. [Boeing,H] German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany. [Bueno-de-Mesquita,HB] National Institute for Public Health and the Environment, Bilthoven, The Netherlands. [Dunning,AM] Department of Oncology, University of Cambridge, Cambridge, United Kingdom. [Feigelson,HS, Thun,MJ] Department of Epidemiology, American Cancer Society, Atlanta, Georgia. [Feigelson, HS] Kaiser Permanente, Denver, Colorado. [Gaziano,JM] Massachusetts Veterans Epidemiology and Research Information Center and Geriatric Research, Education, Clinical Center, Boston Veterans Affairs Healthcare System, Boston, Massachusetts, Division of Aging, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. [Haiman,CA, Henderson,BE, Stram, DO] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. [Hayes,RB] Division of Epidemiology, New York University Langone Medical Center, New York, New York. [Kaaks,R] Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. [Kolonel,LN, Le Marchand,L]Cancer Research Center, University of Hawaii, Honolulu, Hawaii. [Martinez,C] Andalusian School of Public Health. Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Granada, Spain. [Overvad,K] Clinical Epidemiology and Cardiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. [Stattin,P] Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden. [Tumino,R] Cancer Registry Azienda Ospedaliera 'Civile M.P.Arezzo', Ragusa, Italy. [Virtamo,J] Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. [Yeager,M] Core Genotyping Facility, Advanced Technology Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland. [Freedman,ML] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, and This work was supported by National Cancer Institute cooperative agreements UO1-CA98233, UO1-CA98710, UO1-CA98216, and UO1-CA98758, and by the Intramural Research Program of National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. S.L. is supported by the Swedish Research Council (Vetenskapsrådet).

Subjects
Male, Oncology, Neoplasias de la próstata, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, urologic and male genital diseases, Biochemistry, Germline, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Cohort Studies, Androgen deprivation therapy, Prostate cancer, Endocrinology, Sex hormone-binding globulin, Trinucleotide Repeats, Receptores androgénicos, Gonadal Steroid Hormones, Prostate cancer risk, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], General Medicine, Middle Aged, Receptors, Androgen, Cohort, Original Article, Female, Health Care::Health Care Economics and Organizations::Organizations::Government::Federal Government::United States Government Agencies::United States Dept. of Health and Human Services::National Institutes of Health (U.S.)::National Cancer Institute (U.S.) [Medical Subject Headings], Risk, medicine.medical_specialty, Estudios de cohortes, Breast Neoplasms, Biology, Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [Medical Subject Headings], Germline mutation, Translational Highlights from Jcem, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Internal medicine, Carcinoma, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings], Genetic Association Studies, Germ-Line Mutation, Aged, Hormonas esteroides gonadales, Estudios de asociación genética, Biochemistry (medical), Case-control study, Prostatic Neoplasms, Cancer, medicine.disease, National Cancer Institute (U.S.), United States, Androgen receptor, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gonadal Hormones::Gonadal Steroid Hormones [Medical Subject Headings], Case-Control Studies, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, Androgen [Medical Subject Headings], biology.protein
Abstract

Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes. Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels. Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively). Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

Published
2010

15. DRB1*03:01 Haplotypes: Differential Contribution to Multiple Sclerosis Risk and Specific Association with the Presence of Intrathecal IgM Bands

Author

José C. Álvarez-Cermeño, Luisa M. Villar, M. Carmen Cénit, Rafael Arroyo, Laura Leyva, Elena Urcelay, Concepción Núñez, Oscar Fernandez, Emilio G. de la Concha, María L. Cavanillas, [Concha,E G de la, Cavanillas, ML, Cénit, MC, Ircelay, E, Núñez, C] Department of Clinical Immunology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. [Arroyo, R] Department of Neurology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. [Fernández, O] Department of Neurology, Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Álvarez-Cermeño, JC] Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain. [Leyva, L] Research Laboratory. Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya and Fundación IMABIS, Málaga, Spain. [Villar, LM] Department of Immunology, Hospital Ramón y Cajal, Madrid, Spain., and This work was supported by project PI10/1985 from ‘‘Fondo de Investigaciones Sanitarias’’. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects
Inmunoglobulina M, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [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], Risk Factors, Factores de Riesgo, Genetics, Multidisciplinary, Cadenas HLA-DRB1, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Predisposición genética a la enfermedad, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Humanos, Neurology, 01 antigen [HLA-DRB1*03], Medicine, Haplotipos, Research Article, Multiple Sclerosis, Science, Immunology, Chemicals and Drugs::Biological Factors::Antigens::Isoantigens::Histocompatibility Antigens::HLA Antigens::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB1 Chains [Medical Subject Headings], Human leukocyte antigen, Biology, Autoimmune Diseases, Estudios caso-control, medicine, Humans, Diseases::Nervous System Diseases::Demyelinating Diseases::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Genetic Predisposition to Disease, Allele, Risk factor, Genotyping, Genetic Association Studies, Evolutionary Biology, Population Biology, Estudios de asociación genética, Multiple sclerosis, Haplotype, Case-control study, Computational Biology, Human Genetics, medicine.disease, Demyelinating Disorders, 01 [Antigeno HLA-DRB1*03], Haplotypes, Immunoglobulin M, Esclerosis Múltiple, Case-Control Studies, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin M [Medical Subject Headings], biology.protein, Clinical Immunology, Population Genetics, HLA-DRB1 Chains
Abstract

Journal Article; Research Support, Non-U.S. Gov't; BACKGROUND Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. METHODS Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M-, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M-) were performed with the chi-square test or the Fisher exact test. RESULTS Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB. Yes

Published
2012

16. Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder

Author

Ana M. Lendínez, Maximiliano Ruiz-Galdón, Lidia Aguado, Angel Aneiros-Guerrero, Beatriz Pérez-Nevot, Armando Reyes-Engel, A.R. Palomares, Álvaro Mayor-Olea, [Aneiros-Guerrero,A, Lendínez,AM, Palomares, AR, Aguado,L, Mayor-Olea,A, Ruiz-Galdón,M, Reyes-Éngel,A] Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Málaga, Spain. [Pérez Nevot,B, Ruiz-Galdón,M] Hospital Universitario Virgen de la Victoria, Málaga, Spain., and This study was supported by the Ministerio de Educación y Ciencia (Spain), (SAF2008-03314) and 'Programa Torres Quevedo' (PTQ-09-0100496) Grants

Subjects
Male, glutathione S-transferase M1, SHMT1 protein, human, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Pteridines::Pterins::Folic Acid [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], methionine synthase reductase, Genotype, Genetics(clinical), Genetics (clinical), Glutathione Transferase, Glycine Hydroxymethyltransferase, Genetics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], biology, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Sex Factors [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::One-Carbon Group Transferases::Hydroxymethyl and Formyl Transferases::Glycine Hydroxymethyltransferase [Medical Subject Headings], Temporomandibular Joint Disorders, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on Sulfur Group Donors::Ferredoxin-NADP Reductase [Medical Subject Headings], Null allele, Ferredoxin-NADP Reductase, DRD4 protein, human, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk [Medical Subject Headings], Named Groups::Persons::Age Groups::Adolescent [Medical Subject Headings], Female, Research Article, Adult, Risk, lcsh:Internal medicine, medicine.medical_specialty, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Alkyl and Aryl Transferases::Glutathione Transferase [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Adolescent, lcsh:QH426-470, Check Tags::Male [Medical Subject Headings], Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Young Adult, Folic Acid, Sex Factors, Diseases::Musculoskeletal Diseases::Joint Diseases::Temporomandibular Joint Disorders [Medical Subject Headings], Internal medicine, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Dopamine receptor D4, medicine, Humans, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on CH-NH Group Donors::Methylenetetrahydrofolate Dehydrogenase (NADP) [Medical Subject Headings], Allele, lcsh:RC31-1245, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Biogenic Amine::Receptors, Catecholamine::Receptors, Dopamine::Receptors, Dopamine D2::Receptors, Dopamine D4 [Medical Subject Headings], Genotyping, Genetic Association Studies, Methylenetetrahydrofolate Dehydrogenase (NADP), Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Polymorphism, Genetic, Receptors, Dopamine D4, (Methionine synthase) reductase, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], MTRR, lcsh:Genetics, stomatognathic diseases, Endocrinology, Check Tags::Female [Medical Subject Headings], Case-Control Studies, Mutation, biology.protein
Abstract

Background Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. Methods A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. Results Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). Conclusions Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome

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