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1. Systemic iron homeostasis and erythropoiesis

Author

George Papanikolaou and Kostas Pantopoulos

Subjects
0301 basic medicine, Anemia, Iron, Clinical Biochemistry, Ferroportin, Transferrin receptor, Biochemistry, 03 medical and health sciences, Hepcidins, Hepcidin, hemic and lymphatic diseases, Genetics, medicine, Homeostasis, Humans, Erythropoiesis, Iron Regulatory Protein 1, Cation Transport Proteins, Iron Regulatory Protein 2, Molecular Biology, Hemochromatosis, Erythroid Precursor Cells, Anemia, Iron-Deficiency, biology, Cell Differentiation, Cell Biology, Erythroferrone, medicine.disease, Cell biology, 030104 developmental biology, Gene Expression Regulation, Erythropoietin, Immunology, biology.protein, Signal Transduction, medicine.drug
Abstract

Iron is an essential nutrient that is potentially toxic due to its redox reactivity. Insufficient iron supply to erythroid cells, the major iron consumers in the body, leads to various forms of anemia. On the other hand, iron overload (hemochromatosis) is associated with tissue damage and diseases of liver, pancreas, and heart. Physiological iron balance is tightly controlled at the cellular and systemic level by iron regulatory proteins (IRP1, IRP2) and the iron regulatory hormone hepcidin, respectively. Underlying mechanisms often intersect to achieve optimal iron utilization, to control immune responses, and to prevent iron toxicity. This review focuses on systemic iron homeostasis in the context of erythropoiesis, a highly iron-demanding process. We discuss the function and regulation of hepcidin by various stimuli, and highlight hepcidin-dependent and -independent mechanisms that link iron utilization with maturation of erythroid progenitor cells. © 2017 IUBMB Life, 69(6):399-413, 2017.

Published
2017

2. Iron Homeostasis in Elite Athletes and Ultramarathon Runners

Author

Maria Tsironi, Tzortzis Nomikos, Yannis Kotsis, George Papanikolaou, and Katerina Skenderi

Subjects
medicine.medical_specialty, biology, Athletes, business.industry, Sports anemia, lcsh:A, Football, biology.organism_classification, Ferritin, Endocrinology, Iron homeostasis, Hepcidin, Internal medicine, Heart rate, medicine, biology.protein, elite athletes, heart rate, Elite athletes, iron homeostasis, lcsh:General Works, business, ultramarathon
Abstract

AIM: The present study was aimed at determining the effect of two different types of exercise (elite athletes playing football and ultramarathon runners on iron metabolism and, especially, the role of hepcidin in iron homeostasis. MATERIAL & METHOD: Two groups of athletes were investigated. The first group consisted of 19 male elite football athletes and the second group of 41 ultramarathon runners. In both cases, blood samples were taken pre-race (t1), immediately post-race (t2), and 24 hours post-race for football athletes or 36-48 hours post-race for ultramarathon athletes (t3). RESULTS: The iron levels in time t3 were found to have statistically significant decreases compared with the iron levels in pre-race and post-race period. Moreover, ferritin levels increased significantly in times t2 and t3. Hepcidin levels increased in time t2 in football players (from 27.45 ± 12.98 to 37.42 ± 13.74 ng/mL) and decreased in time t3. However, in ultramarathon runners, hepcidin levels significantly increased in time t2 (from 29.16 ± 10.92 to 58.81 ± 16.97 ng/mL) and remained increased in time t3 (37.69 ± 16.38 ng/mL), despite a trend for decrease. In football players, sTfR levels did not change, contrary to ultramarathon runners, where sTfR levels were found decreased in times t2 and t3. CONCLUSIONS: Iron metabolism in athletes can be impacted by the type of exercise. Ferritin is not a reliable marker for iron balance because, in the present study, it is more likely an acute-phase protein. The main regulator of iron homeostasis, hepcidin, increased, showing the body’s response to inflammation, by trapping iron in the macrophages and by altering iron absorption. Finally, a strenuous and prolonged exercise can lead to sports anemia.

Published
2019

3. Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

Author

George Dedoussis, Rui Li, Elaine G.Y. Chew, George Papanikolaou, Tim D. Spector, David A. Hinds, Susanne Moebus, Asif Javed, Dale R. Nyholt, Axel M. Hillmer, Gérard Waeber, Zoltán Kutalik, Nicholas G. Martin, Michael P. Philpott, Lara M. Hochfeld, Tessel E. Galesloot, Xiu Ting Heng, Rico Rueedi, Thomas Anhalt, Markus M. Nöthen, Dmitriy Drichel, Michael Nothnagel, Stavroula Kanoni, Ralf Paus, Lambertus A. Kiemeney, Christine Herold, Stefanie Heilmann-Heimbach, J. Brent Richards, Tim Becker, Panos Deloukas, Peter Vollenweider, Julian Hecker, Sonali Pechlivanis, Ricardo C.H. del Rosario, Heide Loehlein Fier, and Shyam Prabhakar

Subjects
0301 basic medicine, Male, Candidate gene, genetics [Trans-Activators], SRD5A2 protein, human, Medizin, General Physics and Astronomy, genetics [3-Oxo-5-alpha-Steroid 4-Dehydrogenase], Genome-wide association study, Bioinformatics, 0302 clinical medicine, genetics [Interferon Regulatory Factors], Genotype, Melatonin, Genetics, Multidisciplinary, Adipogenesis, EBF1 protein, human, integumentary system, genetics [Intercellular Signaling Peptides and Proteins], Phenotype, FGF5 protein, human, genetics [Membrane Proteins], 030220 oncology & carcinogenesis, Meta-analysis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Interferon Regulatory Factors, Intercellular Signaling Peptides and Proteins, Male-pattern baldness, ddc:500, Signal Transduction, DKK2 protein, human, Fibroblast Growth Factor 5, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics, Adipogenesis/genetics, Alopecia/genetics, Case-Control Studies, Fibroblast Growth Factor 5/genetics, Genetic Association Studies, Genome-Wide Association Study, Humans, Intercellular Signaling Peptides and Proteins/genetics, Interferon Regulatory Factors/genetics, Membrane Proteins/genetics, Signal Transduction/genetics, Trans-Activators/genetics, Science, Genomics, Biology, genetics [Signal Transduction], General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, interferon regulatory factor-4, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, medicine, genetics [Adipogenesis], genetics [Alopecia], Case-control study, Membrane Proteins, Alopecia, General Chemistry, medicine.disease, genetics [Fibroblast Growth Factor 5], 030104 developmental biology, Trans-Activators
Abstract

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P, Male-pattern baldness is a common condition in which hair is progressively lost from the scalp. Here, the authors find 23 new genetic variants associated with this condition and suggest that it is not an isolated trait but may share an underlying biological basis with various diseases.

Published
2017

4. Feasibility of Surgery After Systemic Treatment with the Humanized Recombinant Antibody Bevacizumab in Heavily Pretreated Patients with Advanced Epithelial Ovarian Cancer

Author

Elena-Ioana Braicu, Christina Fotopoulou, George Papanikolaou, Klaus Pietzner, Jalid Sehouli, and P. Neuhaus

Subjects
Adult, medicine.medical_specialty, Bevacizumab, Fistula, Perforation (oil well), Angiogenesis Inhibitors, Carcinoma, Ovarian Epithelial, Antibodies, Monoclonal, Humanized, Surgical oncology, medicine, Humans, Neoplasms, Glandular and Epithelial, Aged, Neoplasm Staging, Retrospective Studies, Ovarian Neoplasms, Wound Healing, biology, business.industry, Palliative Care, Middle Aged, medicine.disease, Short bowel syndrome, Surgery, Bowel obstruction, Treatment Outcome, Oncology, Intestinal Perforation, biology.protein, Feasibility Studies, Female, Antibody, Ovarian cancer, business, Intestinal Obstruction, medicine.drug
Abstract

The aim of this study was to assess operative feasibility and outcome after bevacizumab treatment (BT) in ovarian cancer (OC) patients. We retrospectively identified all OC patients operated between April 2006 and September 2010 after BT. We identified 733 OC operations, 10 of which (1.36%) were performed in a mean time of 134 days (range, 10–288) after BT. Indication was secondary cytoreduction in 3 patients (mean days after BT, 181; range, 82–256) and palliation in 7 due to bowel obstruction and/or intestinal perforation or fistula (mean days after BT, 114; range, 10–288). All but 1 acutely operated patients developed a secondary wound healing, but none of the 3 patients after planned cytoreduction did. Of these 3 patients, 1 suddenly died on the 36th postoperative day, presumably of thromboembolism. None of the patients developed postoperatively a gastrointestinal morbidity; however, in 1 patient operated 21 days after BT due to a vesicointestinal fistula the bladder reconstruction could not heal and developed a permanent fistula. Emergency surgery after BT due to bowel obstruction and/or fistulas seems to be associated with an impaired wound healing in advanced heavily pretreated platinum-resistant OC patients, while this does not appear the case in planned cytoreduction. Prospective evaluations are warranted to assess surgical safety after BT in this special patients’ collective.

Published
2011

5. Conditional disruption of mouse HFE2 gene: Maintenance of systemic iron homeostasis requires hepatic but not skeletal muscle hemojuvelin

Author

Konstantinos Gkouvatsos, John Wagner, George Papanikolaou, Giada Sebastiani, and Kostas Pantopoulos

Subjects
Male, medicine.medical_specialty, Iron, Biology, GPI-Linked Proteins, Mice, Hepcidins, Hepcidin, Internal medicine, medicine, Animals, Homeostasis, Hemochromatosis Protein, Muscle, Skeletal, Hemochromatosis, Hemojuvelin, Integrases, Hepatology, medicine.diagnostic_test, Transferrin saturation, Membrane Proteins, Skeletal muscle, medicine.disease, Juvenile hemochromatosis, Mice, Mutant Strains, Mice, Inbred C57BL, Bone morphogenetic protein 6, Endocrinology, medicine.anatomical_structure, Liver, Mutagenesis, Organ Specificity, biology.protein, Serum iron, Female, Antimicrobial Cationic Peptides
Abstract

Mutations of the HFE2 gene are linked to juvenile hemochromatosis, a severe hereditary iron overload disease caused by chronic hyperabsorption of dietary iron. HFE2 encodes hemojuvelin (Hjv), a membrane-associated bone morphogenetic protein (BMP) coreceptor that enhances expression of the liver-derived iron regulatory hormone hepcidin. Hjv is primarily expressed in skeletal muscles and at lower levels in the heart and the liver. Moreover, a soluble Hjv form circulates in plasma and is thought to act as a decoy receptor, attenuating BMP signaling to hepcidin. To better understand the regulatory function of Hjv, we generated mice with tissue-specific disruption of this protein in hepatocytes or in muscle cells. The hepatic ablation of Hjv resulted in iron overload, quantitatively comparable to that observed in ubiquitous Hjv−/− mice. Serum iron and ferritin levels, transferrin saturation, and liver iron content were significantly (P < 0.001) elevated in liver-specific Hjv−/− mice. Hepatic Hjv mRNA was undetectable, whereas hepcidin expression was markedly suppressed (12.6-fold; P < 0.001) and hepatic BMP6 mRNA up-regulated (2.4-fold; P < 0.01), as in ubiquitous Hjv−/− counterparts. By contrast, the muscle-specific disruption of Hjv was not associated with iron overload or altered hepcidin expression, suggesting that muscle Hjv mRNA is dispensable for iron metabolism. Our data do not support any significant iron-regulatory function of putative muscle-derived soluble Hjv in mice, at least under physiological conditions. Conclusion: The hemochromatotic phenotype of liver-specific Hjv−/− mice suggests that hepatic Hjv is necessary and sufficient to regulate hepcidin expression and control systemic iron homeostasis. (HEPATOLOGY 2011;)

Published
2011

6. Genetic Heterogeneity Underlies Juvenile Hemochromatosis Phenotype: Analysis of Three Families of Northern Greek Origin

Author

Dimitris Loukopoulos, P. Tsiatsiou, George Papanikolaou, Marianna Politou, N. Vavatsi, Anna Kioumi, M. Papaioannou, P. Marinaki, and John Christakis

Subjects
Adult, Male, Genetic Linkage, DNA Mutational Analysis, Biology, Genetic Heterogeneity, Genetic linkage, medicine, Humans, Molecular Biology, Gene, Hemochromatosis, Family Health, Genetics, Greece, Genetic heterogeneity, Chromosome, Cell Biology, Hematology, medicine.disease, Phenotype, Juvenile hemochromatosis, Pedigree, Haplotypes, Chromosomes, Human, Pair 1, Hereditary hemochromatosis, Molecular Medicine, Female
Abstract

Hereditary hemochromatosis is a genetically heterogeneous disease. Common HFE mutations (C282Y and H63D) are related to the majority of hereditary hemochromatosis cases in populations of Northern European ancestry (HFE1). Juvenile hemochromatosis (JH) is a more severe iron overload disorder, usually presenting at the second decade of life. The gene responsible for JH lies on a genetic locus at chromosome 1q. We have performed a genetic linkage study in three families of Northern Greek origin with typical clinical features of JH. In two families results were in accordance with linkage to chromosome 1q. In one family linkage of the disease to the genetic loci at 1q21, 7q22, and 6p22 was excluded. We suggest that more than one gene may underlie the JH phenotype. This genetic type of hemochromatosis may be designated 1q unlinked juvenile hemochromatosis. Family studies are necessary to establish the genetic diagnosis of JH.

Published
2002

7. Natural history of juvenile haemochromatosis

Author

George Papanikolaou, Antonella Roetto, Paolo Gasparini, Alberto Piperno, Thimoty M. Cox, Federica Alberti, Gillian Lockitch, Silvia Fargion, Raffaella Mariani, Marianna Politou, Marco De Gobbi, Domenico Girelli, Clara Camaschella, and Mario Cazzola

Subjects
medicine.medical_specialty, Haemochromatosis type 3, Case-control study, Physiology, Hematology, Disease, Ethnic origin, Biology, medicine.disease, Juvenile hemochromatosis, Natural history, Endocrinology, Internal medicine, medicine, Hemochromatosis, Hemojuvelin
Abstract

Juvenile haemochromatosis or haemochromatosis type 2 is a rare autosomal recessive disorder which causes iron overload at a young age, affects both sexes equally and is characterized by a prevalence of hypogonadism and cardiopathy. Patients with haemochromatosis type 2 have been reported in different ethnic groups. Linkage to chromosome 1q has been established recently, but the gene remains unknown. We report the analysis of the phenotype of 29 patients from 20 families of different ethnic origin with a juvenile 1q-associated disease. We also compared the clinical expression of 26 juvenile haemochromatosis patients with that of 93 C282Y homozygous males and of 11 subjects with haemochromatosis type 3. Patients with haemochromatosis type 2 were statistically younger at presentation and had a more severe iron burden than C282Y homozygotes and haemochromatosis type 3 patients. They were more frequently affected by cardiopathy, hypogonadism and reduced glucose tolerance. In contrast cirrhosis was not statistically different among the three groups. These data suggest that the rapid iron accumulation in haemochromatosis type 2 causes preferential tissue damage. Our results clarify the natural history of the disease and are compatible with the hypothesis that the HFE2 gene has greater influence on iron absorption than other haemochromatosis-associated genes.

Published
2002

8. Familial Mediterranean Fever and E148Q Pyrin Gene Mutation in Greece

Author

George Papanikolaou, Konstantinos Lilakos, Alexandra Kanta, Ioannis Meletis, and Kostas Konstantopoulos

Subjects
Genetics, Greece, Point mutation, Proteins, Familial Mediterranean fever, Hematology, Disease, Pyrin, Biology, Gene mutation, Compound heterozygosity, medicine.disease, MEFV, Pyrin domain, Familial Mediterranean Fever, Cytoskeletal Proteins, Mutation (genetic algorithm), medicine, Humans, Point Mutation
Abstract

Familial Mediterranean fever (FMF) is an inherited disease characterized by recurrent inflammatory polyserositis. Although FMF is classically expected only in Middle East populations, it is becoming evident that the disease affects more groups than initially thought. The disease is associated with a number of mutations of the MEFV gene, which codes for a protein named pyrin. The role of E148Q pyrin gene mutation in the development of FMF remains inconclusive. Some authors believe it causes the disease, whereas others favor the concept of a noncausative role. To understand better the role of this mutation, gathering data from different populations may be of value. We studied 60 Greek cases fulfilling the criteria for FMF diagnosis, 30 cases being a definite FMF diagnosis and 30 a probable diagnosis. Twenty-one of the patients, carried mutation E148Q. One was a homozygote (E148Q/E148Q), and 20 carried mutation E148Q in combination with other mutations (compound heterozygotes). In 6 of the 60 cases studied, no mutations were found. Compared with the results for healthy controls, E148Q mutation is significantly frequent. Because different populations may exhibit different patterns of pyrin mutations, association of the E148Q mutation with FMF should be considered in connection with origin data.

Published
2005

9. A novel immunological assay for hepcidin quantification in human serum

Author

George Papanikolaou, Theodoros P. Vassilakopoulos, Vasiliki Koliaraki, George V. Papatheodoridis, Martha Marinou, Avgi Mamalaki, Gerassimos A. Pangalis, Dorine W. Swinkels, Eustathios Vavourakis, Emmanuel Tsochatzis, and Alexandra Stamoulakatou

Subjects
medicine.medical_specialty, Anemia, lcsh:Medicine, Enzyme-Linked Immunosorbent Assay, Biochemistry, Sensitivity and Specificity, Molecular epidemiology [NCEBP 1], Hepcidins, Translational research [ONCOL 3], Hepcidin, Internal medicine, hemic and lymphatic diseases, medicine, Iron metabolism [IGMD 7], Humans, lcsh:Science, Hemochromatosis, Multidisciplinary, Anemia, Iron-Deficiency, biology, medicine.diagnostic_test, Chemistry, lcsh:R, nutritional and metabolic diseases, Iron deficiency, medicine.disease, Hodgkin Disease, Juvenile hemochromatosis, Endocrinology, Iron-deficiency anemia, Immunoassay, Hereditary hemochromatosis, Immunology, biology.protein, lcsh:Q, Hematology/Anemias, Research Article, Biotechnology, Antimicrobial Cationic Peptides
Abstract

Contains fulltext : 81054.pdf (Publisher’s version ) (Open Access) BACKGROUND: Hepcidin is a 25-aminoacid cysteine-rich iron regulating peptide. Increased hepcidin concentrations lead to iron sequestration in macrophages, contributing to the pathogenesis of anaemia of chronic disease whereas decreased hepcidin is observed in iron deficiency and primary iron overload diseases such as hereditary hemochromatosis. Hepcidin quantification in human blood or urine may provide further insights for the pathogenesis of disorders of iron homeostasis and might prove a valuable tool for clinicians for the differential diagnosis of anaemia. This study describes a specific and non-operator demanding immunoassay for hepcidin quantification in human sera. METHODS AND FINDINGS: An ELISA assay was developed for measuring hepcidin serum concentration using a recombinant hepcidin25-His peptide and a polyclonal antibody against this peptide, which was able to identify native hepcidin. The ELISA assay had a detection range of 10-1500 microg/L and a detection limit of 5.4 microg/L. The intra- and interassay coefficients of variance ranged from 8-15% and 5-16%, respectively. Mean linearity and recovery were 101% and 107%, respectively. Mean hepcidin levels were significantly lower in 7 patients with juvenile hemochromatosis (12.8 microg/L) and 10 patients with iron deficiency anemia (15.7 microg/L) and higher in 7 patients with Hodgkin lymphoma (116.7 microg/L) compared to 32 age-matched healthy controls (42.7 microg/L). CONCLUSIONS: We describe a new simple ELISA assay for measuring hepcidin in human serum with sufficient accuracy and reproducibility.

Published
2009

10. Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39G mutation of L-ferritin IRE

Author

Helen Chandrinou, Ioannis Asproudis, Danai Palaiologou, Konstantinos Prentzas, Despina G. Contopoulos-Ioannidis, Nikos Sakellaropoulos, George Papanikolaou, Konstantinos Lilakos, Evrydiki Bouzas, Vassiliki Kalotychou, Ioannis Papassotiriou, and Evangelos Premetis

Subjects
Male, Mutant, Biology, medicine.disease_cause, Cataract, medicine, Humans, Point Mutation, Molecular Biology, Gene, Genes, Dominant, Genetics, Mutation, Greece, Point mutation, fungi, Autosomal dominant trait, Heterozygote advantage, Cell Biology, Hematology, Syndrome, Phenotype, Iron Metabolism Disorders, Pedigree, Ferritin, Ferritins, biology.protein, Molecular Medicine, Nucleic Acid Conformation, Female, 5' Untranslated Regions
Abstract

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a well-characterized autosomal dominant disease caused by mutations in the iron responsive element (IRE) of ferritin L-chain (FTL) mRNA. Mutations in the IRE result in reduced binding of the trans-acting iron regulatory proteins (IRPs) and hence in upregulation of ferritin L-chain synthesis. The disease is characterized by increased L-ferritin in serum and tissues and early onset of bilateral cataracts. Iron metabolism is normal, and there is no tissue iron overload. At least 25 nucleotide substitutions and deletions in the L-ferritin IRE have been described in families with HHCS, originating from diverse European, Australian and North American populations. We studied the molecular pathogenesis of HHCS in three unrelated kinderships of western Greek origin, with 19 affected members. We identified a relatively rare C39G mutation located in the hexanucleotide loop of L-ferritin IRE. Computational analysis of mRNA folding of mutant FTL IRE predicted that the C39 > G mutation leads to a rearrangement of base pairing in this critical region, which is likely to modify the IRP binding affinity. All subjects with HHCS were heterozygotes for the same C39G mutation. Clinical and laboratory phenotypes were described. Moreover, there was evidence of an association between this FTL IRE stem-loop mutation and very high ferritin levels. Our findings broaden the list of populations where HHCS has been described.

Published
2005

11. Hepcidin in iron overload disorders

Author

Dionisios Bogdanos, Y. Paul Goldberg, Tomas Ganz, Nikos Sakellaropoulos, John Christakis, Elizabeta Nemeth, Konstantina Tsimirika, Julie MacFarlane, George Papanikolaou, and Michalis Tzilianos

Subjects
inorganic chemicals, Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Iron Overload, Immunology, Ferroportin, Red Cells, Transferrin receptor, Biochemistry, digestive system, Hepcidins, Hepcidin, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Hemochromatosis, Hemojuvelin, Aged, biology, business.industry, nutritional and metabolic diseases, Cell Biology, Hematology, Middle Aged, medicine.disease, Juvenile hemochromatosis, Endocrinology, Hereditary hemochromatosis, biology.protein, Female, HAMP, business, Antimicrobial Cationic Peptides
Abstract

Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin–ferroportin interaction in iron homeostasis.

Published
2005

12. Iron metabolism and toxicity

Author

George Papanikolaou and Kostas Pantopoulos

Subjects
Pharmacology, Programmed cell death, Iron Overload, Free Radicals, Iron, Metabolism, Biology, Toxicology, medicine.disease, Malignant transformation, chemistry.chemical_compound, Oxidative Stress, chemistry, Biochemistry, Liver, Hereditary hemochromatosis, Toxicity, medicine, Cancer research, Animals, Humans, Siderosis, Heme, Homeostasis
Abstract

Iron is an essential nutrient with limited bioavailability. When present in excess, iron poses a threat to cells and tissues, and therefore iron homeostasis has to be tightly controlled. Iron's toxicity is largely based on its ability to catalyze the generation of radicals, which attack and damage cellular macromolecules and promote cell death and tissue injury. This is lucidly illustrated in diseases of iron overload, such as hereditary hemochromatosis or transfusional siderosis, where excessive iron accumulation results in tissue damage and organ failure. Pathological iron accumulation in the liver has also been linked to the development of hepatocellular cancer. Here we provide a background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level. In addition, we provide an overview of the various disorders of iron overload, which are directly linked to iron's toxicity. Finally, we discuss the potential role of iron in malignant transformation and cancer.

Published
2004

13. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis

Author

Patrick Franchini, Jay Thompson, Ryan Babakaiff, Y. Paul Goldberg, Gillian Lockitch, Marie-Pierre Dubé, Elizabeta Nemeth, Michael R. Hayden, Jenni Risler, C Radomski, Lisa Andres, Marcia L.E. MacDonald, George Papanikolaou, Catherine Zaborowska, Terry D Pape, Mark E. Samuels, Erwin H. Ludwig, Marianna Politou, Julie MacFarlane, John Christakis, Pierre Brissot, Owen Davidas, Tomas Ganz, and Nikos Sakellaropoulos

Subjects
Adult, medicine.medical_specialty, Iron Overload, Positional cloning, Adolescent, Ferroportin, Molecular Sequence Data, Locus (genetics), GPI-Linked Proteins, Hepcidin, Internal medicine, Genetics, medicine, Humans, Amino Acid Sequence, Child, Hemochromatosis Protein, Hemochromatosis, Hemojuvelin, biology, Base Sequence, Membrane Proteins, Middle Aged, medicine.disease, Juvenile hemochromatosis, Endocrinology, Chromosomes, Human, Pair 1, Mutation, biology.protein, HAMP
Abstract

Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3–6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism7,8,9. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.

Published
2003

14. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis

Author

John Christakis, Dimitris Loukopoulos, George Papanikolaou, Antonella Roetto, Domenico Girelli, Federica Alberti, Marianna Politou, Clara Camaschella, Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., and Camaschella, Clara

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, Ferroportin, Mutant, DNA Mutational Analysis, Molecular Sequence Data, Hepcidins, Hepcidin, Genetics, medicine, Humans, Amino Acid Sequence, Child, Peptide sequence, Hemochromatosis, Polymorphism, Single-Stranded Conformational, Hemojuvelin, biology, Base Sequence, medicine.disease, Juvenile hemochromatosis, Pedigree, Mutation, biology.protein, Female, HAMP, Antimicrobial Cationic Peptides
Abstract

Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM 606464) is probably a key regulator of iron absorption in mammals. Here we report the identification of two mutations (93delG and 166C--T) in HAMP on 19q13 in two families with a new type of juvenile hemochromatosis.

Published
2002

15. Effects Of Prolonged And Brisk Exercise On Iron Metabolism And Hepcidin Levels

Author

Avgi Mamalaki, Petros Eliadis, George Papanikolaou, Demosthenes B. Panagiotakos, Eleni Kyratzopoulou, Maria Tsironi, and Katerina Skenderi

Subjects
medicine.medical_specialty, Endocrinology, biology, business.industry, Hepcidin, Internal medicine, biology.protein, Medicine, Physical Therapy, Sports Therapy and Rehabilitation, Orthopedics and Sports Medicine, Metabolism, business
Published
2014

16. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis

Author

Clara Camaschella, Dimitris Loukopoulos, Antonella Roetto, Nikos Sakelaropoulos, Marianna Politou, Sandra Bosio, and George Papanikolaou

Subjects
Adult, Male, Genetic Linkage, Locus (genetics), Biology, Polymerase Chain Reaction, Consanguinity, HLA Antigens, Ethnicity, medicine, Humans, Age of Onset, Child, Hemochromatosis Protein, Chromosomes, Artificial, Yeast, Molecular Biology, Hemochromatosis, Genetics, Greece, Genetic heterogeneity, Histocompatibility Antigens Class I, Haplotype, Chromosome Mapping, Membrane Proteins, Hemochromatosis type 3, Cell Biology, Hematology, medicine.disease, Juvenile hemochromatosis, Founder Effect, Pedigree, Haplotypes, Italy, Chromosomes, Human, Pair 1, Genetic marker, Hereditary hemochromatosis, Molecular Medicine, Chromosomes, Human, Pair 6, Female
Abstract

Hereditary hemochromatosis (HH) is a genetically heterogeneous disease. The HFE gene resides on chromosome 6 and its mutations account for the majority of HH cases in populations of northern European ancestry. Recently, two new types of hemochromatosis have been identified: Juvenile hemochromatosis (JH or HFE2), which maps to chromosome 1q21, and an adult form defined as HFE 3, which results from mutations of the TFR 2 gene, located at 7q22. We have performed a linkage study in five unrelated families of Greek origin with non-HFE hemochromatosis. Linkage at the chromosome 1q21 JH locus was detected in affected members with the use of polymorphic markers. Comparison of haplotypes between Greek and Italian JH patients revealed the presence of a common haplotype. However, the fact that many other haplotypes carrying the JH defect were observed in the two populations indicates that the respective mutations may have occurred in different genetic backgrounds. We suggest that hemochromatosis patients without HFE mutations should be evaluated for other possible types of hemochromatosis since hemochromatosis type 3 (HFE3) has a clinical appearance similar to HFE 1, and JH may have a late onset in some cases.

Published
2001

17. Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity

Author

Dimitris Loukopoulos, George Papanikolaou, Stefanos Fourlemadis, Nikos Sakellaropoulos, Marianna Politou, and Evangelos Terpos

Subjects
Adult, Male, Biology, HLA Antigens, medicine, Humans, Allele, Hemochromatosis Protein, Molecular Biology, Allele frequency, Hemochromatosis, Genetics, Greece, Genetic heterogeneity, Histocompatibility Antigens Class I, Genetic Variation, Membrane Proteins, Cell Biology, Hematology, Middle Aged, medicine.disease, Juvenile hemochromatosis, Penetrance, Hereditary hemochromatosis, Mutation (genetic algorithm), Mutation, Molecular Medicine, Female
Abstract

ABSTRACT Hereditary hemochromatosis (HH) is common among Caucasians; reported disease frequencies vary from 0.3 to 0.8%. Identification of a candidate HFE gene in 1996 was soon followed by the description of two ancestral mutations, i.e., c.845G→A (C282Y) and c.187C→G (H63D). To these was recently added the mutation S65C, which may represent a simple polymorphism. The incidence of HH in Greece is unknown but clinical cases are rare. Also unknown is the carrier frequency of the two mutant alleles. A first estimate of the latter is given in the present report. It is based on data from the genetic analysis of 10 unrelated patients of Greek origin who were referred to our center for genotyping and 158 unselected male blood donors. The allele frequencies for the C282Y and H63D mutations were 0.003 and 0.145, respectively. The C282Y allele was detected in 50% of HH patients. This is considerably lower than the frequencies reported for HH patients in the U.S.A. (82%) and France (91%) and closer to that reported in Italy (64%). Five patients did not carry any known HFE mutation; three may represent cases of juvenile hemochromatosis, given their early onset with iron overload, hypogonadism, and heart disease. We suggest that genetic heterogeneity is more prominent in Southern Europe. It is also possible that the penetrance of the responsible genes is different across the Mediterranean.

Published
2000

18. Commentary: Juvenile Hemochromatosis in a Spanish Family (by Montes-Cano et al.)

Author

Clara Camaschella, George Papanikolaou, and Antonella Roetto

Subjects
Adult, Family Health, Male, Iron Overload, Cell Biology, Hematology, Biology, medicine.disease, Juvenile hemochromatosis, Diagnosis, Differential, Molecular Diagnostic Techniques, Spain, Mutation, medicine, Humans, Molecular Medicine, Ethnology, Female, Hemochromatosis, Age of Onset, Molecular Biology
Published
2002

19. Hepcidin Expression Is Correlated with Erythropoietic Indexes and Non-Transferrin-Bound Iron Levels in Patients with Thalassemia Major

Author

Ioannis Papassotiriou, George Papanikolaou, Antonios Kattamis, Danai Palaiologou, Kalliopi Drakaki, and Filia Apostolopoulou

Subjects
chemistry.chemical_classification, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Liver Iron Concentration, biology, medicine.diagnostic_test, Transferrin saturation, Thalassemia, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Ferritin, Endocrinology, chemistry, Hepcidin, Transferrin, hemic and lymphatic diseases, Internal medicine, medicine, biology.protein, Serum iron, Erythropoiesis
Abstract

Hepcidin plays a central role in iron homeostasis. Hepcidin seems to be the common final mediator of both erythroid and stores regulators, and coordinates intestinal iron absorption and iron release from reticuloendothelial macrophages. The erythroid regulator probably dominates over the stores regulator. Iron overload in thalassemia major is attributed mainly to blood transfusions and partly to increased iron absorption. Urine hepcidin levels in regularly-transfused thalassemia patients are inappropriately low in regards to their iron stores. Liver hepcidin expression is suppressed in the murine model of human thalassemia (Hbbth3/+). We evaluated the correlation between indexes of iron stores and of erythropoiesis and liver hepcidin expression in patients with thalassemia major. Nineteen transfusion-dependent thalassemic patients (14 females) of 20±7.2 years of age underwent liver biopsy. Fourteen patients were seronegative for hepatitis C. Liver iron concentration (LIC) was estimated by atomic absorption spectrometry. Hepcidin mRNA expression levels were estimated by quantitative Real-Time PCR (Lightcycler, Roche) from isolated RNA from liver tissue. Hematologic and blood chemistry parameters were determined by standard methods. NTBI was measured in 13 patients by atomic absorption spectrometry. Statistical analysis was performed using non-parametric tests. Hepcidin expression ranged from 0.08 to 38.4 (median 1.13) arbitrary units. The most significant correlations between hepcidin and indexes of erythropoesis and of iron load are shown on the table. Variable median (range) hepcidin LIC NTBI r = Spearman’s rho, n.s. = non statistical Ferritin (μg/L) 2174 (990–5963) n.s. n.s. n.s. Hb (g/dL) 12 (11.2 – 13.4) r:0.55, P:.017 r:-0.43, P:.071 n.s. sTfR (mg/L) 2.64 (0.75 – 5.75) r:-0.59, P:.01 r:0.51, P:.03 r:0.71, P:.006 EPO (IU/L) 21.6 (2.9 – 106) r:-0.61, P:.007 r:0.56, P:.015 r:0.63, P:.02 NTBI (μmol/L) 3.1 (0.9 – 4.5) r:0.56, P:.047 r:0.67, P:.012 LIC (μg Fe/d.w.tissue) 8.3 (3.1 – 18.9) n.s. The correlations between hepcidin and Hb, sTfR, EPO were stronger when patients with infectious hepatitis were excluded from analysis. Hepcidin did not correlate with any indexes of iron load, including LIC, ferritin, serum iron, transferrin saturation and annual transfusional iron load. Our results provide additional evidence that increased erythropoietic activity down-regulates hepcidin expression. The lack of correlation between iron stores and hepcidin expression is in consistency with the hypothesis that increased erythropoietic activity dominates over iron stores in the regulation of hepcidin expression in patients with thalassemia major. Furthermore, the negative correlation between NTBI and hepcidin RNA levels underlies the role of hepcidin in iron body trafficking even in hemosiderotic patients.

Published
2005

20. Novel genetic loci associated with hippocampal volume

Author

Benjamin S. Aribisala, Marjolein M.J. van Donkelaar, Randy L. Gollub, Rachel M. Brouwer, Norman Delanty, Tomas Axelsson, Oscar L. Lopez, Thomas Espeseth, Alejandro Arias-Vasquez, Kristel R. van Eijk, Tien Yin Wong, Jeroen van der Grond, Georg Homuth, James T. Becker, Sebastian Guelfi, Anton J. M. de Craen, Bruno Vellas, Christopher R.K. Ching, Charles C. DeCarli, Janita Bralten, Lars T. Westlye, Ryota Hashimoto, Sampath Arepalli, Bertram Müller-Myhsok, Loes M. Olde Loohuis, Sudha Seshadri, Simon E. Fisher, K Hegenscheid, Konstantinos Arfanakis, Zdenka Pausova, Robert C. Green, Simone Reppermund, Katie L. McMahon, Ashley Beecham, Daan van Rooij, Marcel P. Zwiers, Karen A. Mather, Randy L. Buckner, Edith Hofer, Marcella Rietschel, Fabrice Crivello, Ronald H. Zielke, G. Bruce Pike, Thomas W. Mühleisen, Myriam Fornage, Kazutaka Ohi, Gareth E. Davies, Chantal Depondt, Gabriel Cuellar-Partida, Iryna O. Fedko, Peter R. Schofield, Steven G. Potkin, Albert Hofman, Paul M. Thompson, Wiro J. Niessen, Deborah Janowitz, Nicholas G. Martin, Li Shen, Mina Ryten, Meike W. Vernooij, Michael E. Weale, Tonya White, Dennis van 't Ent, Sudheer Giddaluru, Nanda Rommelse, Wei Wen, Sven J. van der Lee, Eco J. C. de Geus, Aaron Goldman, Joanne E. Curran, Qiang Chen, Jean Shin, Wayne C. Drevets, Thomas H. Mosley, Matthias Nauck, Massimo Pandolfo, Anders M. Dale, Paul A. Nyquist, Girma Woldehawariat, Francis J. McMahon, Najaf Amin, Emma J. Rose, Norbert Hosten, David J. Stott, Sigurdur Sigursson, Andrew J. Saykin, M. Kamran Ikram, Pieter J. Hoekstra, Neda Jahanshad, Grant W. Montgomery, Michael Weiner, Aad van der Lugt, Esther Walton, Gunter Schumann, Clyde Francks, Narelle K. Hansell, Xinmin Liu, Herve Lemaitre, Cornelia M. van Duijn, Ralph L. Sacco, Clinton B. Wright, Arvin Saremi, Clifford R. Jack, Andre G. Uitterlinden, G. Donohoe, Tomáš Paus, Michael Griswold, Peter T. Fox, Alan B. Zonderman, Lukas Pirpamer, Christiane Wolf, Aiden Corvin, Shannon L. Risacher, Ian Ford, Philippe Amouyel, Henrik Walter, Beng-Choon Ho, William T. Longstreth, M. Arfan Ikram, Hieab H.H. Adams, Colin Smith, Sungeun Kim, Simon Lovestone, Stefan Ehrlich, Benno Pütz, Markus M. Nöthen, Susana Muñoz Maniega, Ian J. Deary, Elena Shumskaya, Susan H. Blanton, Jerome I. Rotter, Neeltje E.M. van Haren, Mar Matarin, I. Kloszewska, Ganesh Chauhan, Anita L. DeStefano, Barbara Franke, Lars Nyberg, Tatiana Foroud, Tianye Jia, Manon Bernard, Unn K. Haukvik, Rebecca F. Gottesman, Srdjan Djurovic, Ching-Yu Cheng, Lachlan T. Strike, Alex P. Zijdenbos, Jouke-Jan Hottenga, Vince D. Calhoun, Yuri Milaneschi, David C. Glahn, Phil Lee, Amelia A. Assareh, Adaikalavan Ramasamy, Emma Sprooten, Debra A. Fleischman, David R. McKay, J. Raphael Gibbs, Bruce M. Psaty, Kazima B. Bulayeva, Bryan J. Traynor, Vilmundur Gudnason, Jessika E. Sussmann, Alexander Teumer, Guillén Fernández, Katharina Wittfeld, Christophe Tzourio, Dennis van der Meer, Wolfgang Hoffmann, Sebastian Mohnke, David C. Liewald, Jordan W. Smoller, Theo G.M. van Erp, Marcel Van Der Brug, Dara M. Cannon, Lenore J. Launer, D. Ames, Juan C. Troncoso, Brenda W.J.H. Penninx, Dhananjay Vaidya, Thomas D. Dyer, Marie-José van Tol, Han G. Brunner, Andrew Singleton, Lavinia Athanasiu, Adam M. Brickman, Eric Westman, P. Mecocci, Sandra Barral, Dick J. Veltman, Catharina A. Hartman, Benedicto Crespo-Facorro, Alexa S. Beiser, Vincent Chouraki, Nhat Trung Doan, Marieke Klein, Jaap Oosterlaan, Natalie A. Royle, John B.J. Kwok, Saud Alhusaini, Ingrid Melle, Roberto Toro, Ravi Duggirala, Allissa Dillman, Reinhold Schmidt, Lisa R. Yanek, Anbupalam Thalamuthu, Helena Schmidt, Derrek P. Hibar, Albert V. Smith, Jean-Luc Martinot, Thomas H. Wassink, Jennifer S. Richards, Oliver Martinez, Joshua L. Roffman, Sylvane Desrivières, Hilkka Soininen, Rene L. Olvera, Ole A. Andreassen, Diana Tordesillas-Gutiérrez, Claudia L. Satizabal, Owen Carmichael, Lianne Schmaal, Bernd Kraemer, Martine Hoogman, Daniah Trabzuni, Oliver Grimm, Andrew M. McIntosh, René S. Kahn, Nazanin Karbalai, Margaret J. Wright, Harald H.H. Göring, Martina Papmeyer, Roberto Roiz-Santiañez, Luigi Ferrucci, David A. Bennett, Kwangsik Nho, Gianpiero L. Cavalleri, Andreas Meyer-Lindenberg, Masashi Ikeda, Avram J. Holmes, Greig I. de Zubicaray, Andreas Heinz, Tatjana Rundek, Maria del C. Valdés Hernández, Dalia Kasperaviciute, Dan L. Longo, Matthew J. Huentelman, Wiepke Cahn, Beverly G. Windham, Michael A. Nalls, Philipp G. Sämann, Stella Trompet, Vidar M. Steen, Marc M. Bohlken, Christopher D. Whelan, Hilleke E. Hulshoff Pol, Susanne Erk, Dorret I. Boomsma, Dirk J. Heslenfeld, Masaki Fukunaga, D. Hoehn, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, M. R. Cookson, C. McDonald, Magda Tsolaki, Badri N. Vardarajan, Jason L. Stein, Jan K. Buitelaar, Erik G. Jönsson, Oliver Gruber, Robert Johnson, Jingyun Yang, Joshua C. Bis, J. Wouter Jukema, Tulio Guadalupe, Nina Romanczuk-Seiferth, Kjetil Nordbø Jørgensen, Henry Brodaty, Diane M. Becker, Anouk den Braber, Allison C. Nugent, Thomas Wolfers, John Hardy, Joanna M. Wardlaw, Michelle Luciano, Christine Macare, Dena G. Hernandez, D. Morris, John Blangero, Andrew J. Schork, Daniel R. Weinberger, Johanna Hass, Andrew Simmons, Micael Andersson, Lucija Abramovic, David S. Knopman, Mark Jenkinson, Roel A. Ophoff, Sanjay M. Sisodiya, Boris A. Gutman, Asta Håberg, Stephanie Le Hellard, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Hans J. Grabe, Henry Völzke, Thomas E. Nichols, Manuel Mattheisen, Sven Cichon, Venkata S. Mattay, Ingrid Agartz, Stefan Ropele, Lorna M. Lopez, Hans van Bokhoven, Philip L. De Jager, Miguel E. Rentería, Laura Almasy, Arthur W. Toga, Michael Czisch, Florian Holsboer, Ryota Kanai, Nic J.A. van der Wee, Peter Kochunov, Perminder S. Sachdev, Andre F. Marquand, Christian Enzinger, Anderson M. Winkler, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Metacohorts Consortium, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, sans affiliation, QIMR Berghofer Medical Research Institute, University of Washington [Seattle], Department of Psychiatry, Donders Centre for Neuroscience, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University Medical Center [Utrecht], Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Sahlgrenska University Hospital [Gothenburg], Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), Assistance Publique - Hôpitaux de Marseille (APHM), University of Oslo (UiO), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), Douglas Mental Health University Institute, McGill University = Université McGill [Montréal, Canada], Université Lille Nord de France (COMUE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Haukeland University Hospital, University of Bergen (UiB), Ames Laboratory [Ames, USA], Iowa State University (ISU)-U.S. Department of Energy [Washington] (DOE), Johns Hopkins University School of Medicine [Baltimore], Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Laboratory of Neuro Imaging [Los Angeles] (LONI), Department of Mathematics [UCLA], Georgia Institute of Technology [Atlanta], Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany, Greifswald University Hospital, Beijing Normal University (BNU), Aalborg University [Denmark] (AAU), UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Imperial College London, Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Department of Neurology, Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Department of Neurology [Austria], Medical University Graz, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [San Diego], Wuhan University [China], Plymouth University, Dpt of Psychiatry [New Haven], Yale University School of Medicine, Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre, Depts of Radiology, Leiden University Medical Center (LUMC), University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), RCMG Ghent, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), National Institutes of Health [Bethesda] (NIH), Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Université de Lille, Department of Clinical Genetics, Department of Experimental Physics, National University of Ireland Maynooth (Maynooth University), Texas Biomedical Research Institute [San Antonio, TX], The University of Texas Health Science Center at Houston (UTHealth), 849 Department of Human Genetics, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], The Mind Research Network, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Northwestern Polytechnical University [Xi'an] (NPU), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], York Structural Biology Laboratory, Department of Chemistry, University of York [York, UK], Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], School of Psychology, University of Queensland, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), École des hautes études en sciences sociales (EHESS), Department of Radiology, Mayo Clinic, Robertson Centre for Biostatistics, University of Glasgow, Human Genetics Center, Department of Medical and Molecular Genetics, Rensselaer Polytechnic Institute (RPI), Department of Physics, Okayama University, Okayama University, University of New Haven [Connecticut], Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., University of Science, VNU-HCM, University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Medical Genetics, HMNC Brain Health, University of Oxford [Oxford], University of Florida [Gainesville] (UF), Göteborgs Universitet (GU), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Brain Centre Rudolf Magnus [Utrecht], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Institute of Cognitive Neuroscience, University College of London [London] (UCL), Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Psychiatry Institute, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, University of Mississippi Medical Center (UMMC), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Department of Statistics [Coventry], University of Warwick [Coventry], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Osaka University [Osaka], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Politecnico di Milano [Milan] (POLIMI), University of Applied Sciences [Munich], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, National Institute of Aging, 3rd Department of Neurology, Aristotle University of Thessaloniki-General Hospital of Thessaloniki George Papanikolaou, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Pretoria [South Africa], University of Missouri [Columbia] (Mizzou), University of Missouri System, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of Southern California (USC), University of California (UC)-University of California (UC), Sans affiliation, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], University of Toronto, Radboud University [Nijmegen], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universität Bonn = University of Bonn, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Universiteit Gent = Ghent University (UGENT), Centre épigénétique et destin cellulaire (EDC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], University of Oxford, University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, University of Eastern Finland, Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Radboud University [Nijmegen]-Radboud University [Nijmegen], School of Medicine / Clinical Medicine, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, Adult Psychiatry, ARD - Amsterdam Reproduction and Development, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], McGill University-McGill University, Sahlgrenska University Hospital, McGill University, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), University of Bergen (UIB), Iowa State University (ISU)-U.S. Department of Energy (DOE), Beijing Normal University, Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Gènes, Synapses et Cognition, Ghent University [Belgium] (UGENT), National University of Ireland Maynooth (NUIM), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], University of Florida [Gainesville], Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Aristotle University of Thessaloniki-G. Papanikolaou Hospital, Humboldt Universität zu Berlin, University of Missouri [Columbia], Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Neurology, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, Cognitive Psychology, IBBA, APH - Personalized Medicine, Amsterdam Neuroscience - Brain Imaging, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, APH - Digital Health, Hal, GIN, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Universidad de Cantabria, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Male, Netherlands Twin Register (NTR), Genome-wide association study, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Spatial memory, 0302 clinical medicine, 610 Medicine & health, Child, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Episodic memory, Aged, 80 and over, Subiculum, 220 Statistical Imaging Neuroscience, COMMON VARIANTS, ALZHEIMERS-DISEASE, ddc:500, Alzheimer's disease, genetics [Methionine Sulfoxide Reductases], Science, Locus (genetics), genetics [Protein-Serine-Threonine Kinases], Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Alzheimer Disease, ASTN2 protein, human, Humans, GENOME-WIDE ASSOCIATION, METAANALYSIS, Aged, Glycoproteins, Dentate gyrus, MEMORY, medicine.disease, R1, 030104 developmental biology, nervous system, Genetic Loci, MSRB3 protein, human, 030217 neurology & neurosurgery, 0301 basic medicine, General Physics and Astronomy, genetics [Alzheimer Disease], Hippocampal formation, Hippocampus, Genome-wide association studies, Taugasjúkdómar, Cohort Studies, DPP4 protein, human, TEMPORAL-LOBE EPILEPSY, BRAIN-REGIONS, genetics [Dipeptidyl Peptidase 4], genetics [Nerve Tissue Proteins], Genetics, Multidisciplinary, Neurodegenerative diseases, BIPOLAR DISORDER, Organ Size, Middle Aged, SUBFIELDS, Protein-Serine-Threonine Kinases, growth & development [Hippocampus], Female, genetics [Glycoproteins], Microtubule-Associated Proteins, Medical Genetics, Neuroinformatics, Adult, genetics [Microtubule-Associated Proteins], Adolescent, SUSCEPTIBILITY LOCI, Dipeptidyl Peptidase 4, genetics [Protein Serine-Threonine Kinases], Nerve Tissue Proteins, Bioinformatik och systembiologi, Protein Serine-Threonine Kinases, Biology, physiopathology [Alzheimer Disease], 150 000 MR Techniques in Brain Function, Young Adult, MAST4 protein, human, medicine, Journal Article, Erfðafræði, Genetic Predisposition to Disease, ddc:610, Medicinsk genetik, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Bioinformatics and Systems Biology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Rannsóknir, General Chemistry, Methionine Sulfoxide Reductases, 150 Psychology, Genome-Wide Association Study
Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness., published version, peerReviewed

Published
2017

21. Alzheimer's disease biomarker discovery using in silico literature mining and clinical validation

Author

Hilkka Soininen, Nicola C. Day, Simon Lovestone, Iwona Kłoszewska, Patrizia Mecocci, Christian Spenger, Lars-Olof Wahlund, Joanna Riddoch-Contreras, Ines Greco, Julie C. Barnes, Andrew Simmons, Bruno Vellas, Jane Z. Reed, Magda Tsolaki, Psychiatry Institute, King‘s College London, BioWisdom Ltd, Harston Mill, Department of Neurology, University of Eastern Finland-University Hospital of Kuopio, Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Łódź (MUL), 3rd Department of Neurology, Aristotle University of Thessaloniki-General Hospital of Thessaloniki George Papanikolaou, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Science, Intervention and Technology, Karolinska Institutet [Stockholm], Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Department of Neurobiology, Care Sciences and Society, Somaxa Ltd, Abcodia Ltd, BMC, Ed., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Università degli Studi di Perugia (UNIPG)

Subjects
Proteomics, Choline acetyltransferase (ChAt), Bioinformatics, In silico, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, lcsh:Medicine, Information Storage and Retrieval, Disease, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Dementia, Humans, Biomarker discovery, 030304 developmental biology, Intelligence network, Medicine(all), 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biochemistry, Genetics and Molecular Biology(all), Research, lcsh:R, General Medicine, Alzheimer's disease, medicine.disease, Urokinase-type plasminogen activator receptor (PLAUR), 3. Good health, in silico, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Valid Biomarker, Biomarker (medicine), Alzheimer’s disease, Literature mining, 030217 neurology & neurosurgery, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MRI
Abstract

Background Alzheimer’s Disease (AD) is the most widespread form of dementia in the elderly but despite progress made in recent years towards a mechanistic understanding, there is still an urgent need for disease modification therapy and for early diagnostic tests. Substantial international efforts are being made to discover and validate biomarkers for AD using candidate analytes and various data-driven 'omics' approaches. Cerebrospinal fluid is in many ways the tissue of choice for biomarkers of brain disease but is limited by patient and clinician acceptability, and increasing attention is being paid to the search for blood-based biomarkers. The aim of this study was to use a novel in silico approach to discover a set of candidate biomarkers for AD. Methods We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of assertional metadata derived from relevant legacy information. We then assessed the validity of this approach using direct assays of the identified biomarkers in plasma by immunodetection methods. Results Using this in silico approach, we identified 25 biomarker candidates, at least three of which have subsequently been reported to be altered in blood or CSF from AD patients. Two further candidate biomarkers, indicated from the in silico approach, were choline acetyltransferase and urokinase-type plasminogen activator receptor. Using immunodetection, we showed that, in a large sample set, these markers are either altered in disease or correlate with MRI markers of atrophy. Conclusions These data support as a proof of concept the use of data mining and in silico analyses to derive valid biomarker candidates for AD and, by extension, for other disorders.

Published
2012

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