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1. Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease.

Author

Nagelkerke, Sietse Q, Tacke, Carline E, Breunis, Willemijn B, Tanck, Michael WT, Geissler, Judy, Png, Eileen, Hoang, Long T, van der Heijden, Joris, Naim, Ahmad NM, Yeung, Rae SM, Levin, Michael L, Wright, Victoria J, Burgner, David P, Ponsonby, Anne-Louise, Ellis, Justine A, Cimaz, Rolando, Shimizu, Chisato, Burns, Jane C, Fijnvandraat, Karin, van der Schoot, C Ellen, van den Berg, Timo K, de Boer, Martin, Davila, Sonia, Hibberd, Martin L, Kuijpers, Taco W, and International Kawasaki Disease Genetics Consortium

Subjects
International Kawasaki Disease Genetics Consortium, Humans, Mucocutaneous Lymph Node Syndrome, Genetic Predisposition to Disease, Receptors, IgG, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Gene Frequency, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Ethnic Groups, Genome-Wide Association Study, Genetic Loci, Genetic Association Studies, DNA Copy Number Variations, FCGR polymorphism, Fc-gamma receptor, Kawasaki disease, immunogenetics, linkage disequilibrium, Receptors, IgG, Polymorphism, Single Nucleotide, Immunology, Medical Microbiology
Abstract

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r 2 = 0.63). LD between these two variants was weaker (r 2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency

Published
2019

2. Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility.

Author

Chang, Chia-Jung, Kuo, Ho-Chang, Chang, Jeng-Sheng, Lee, Jong-Keuk, Tsai, Fuu-Jen, Khor, Chiea Chuen, Chang, Li-Ching, Chen, Shih-Ping, Ko, Tai-Ming, Liu, Yi-Min, Chen, Ying-Ju, Hong, Young Mi, Jang, Gi Young, Hibberd, Martin L, Kuijpers, Taco, Burgner, David, Levin, Michael, Burns, Jane C, Davila, Sonia, International Kawasaki Disease Genetics Consortium, Korean Kawasaki Disease Genetics Consortium, Taiwan Kawasaki Disease Genetics Consortium, Chen, Yuan-Tsong, Chen, Chien-Hsiun, Wu, Jer-Yuarn, and Lee, Yi-Ching

Subjects
International Kawasaki Disease Genetics Consortium, Korean Kawasaki Disease Genetics Consortium, Taiwan Kawasaki Disease Genetics Consortium, B-Lymphocytes, Cell Line, Transformed, Humans, Mucocutaneous Lymph Node Syndrome, Genetic Predisposition to Disease, src-Family Kinases, Cohort Studies, Reproducibility of Results, Gene Expression Regulation, Enzymologic, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Taiwan, Promoter Regions, Genetic, Genome-Wide Association Study, Genetic Loci, Republic of Korea, General Science & Technology
Abstract

The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10(-31)). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.

Published
2013

3. Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease

Author

Shimizu, Chisato, Matsubara, Tomoyo, Onouchi, Yoshihiro, Jain, Sonia, Sun, Shelly, Nievergelt, Caroline M, Shike, Hiroko, Brophy, Victoria H, Takegawa, Tsuyoshi, Furukawa, Susumu, Akagi, Teiji, Newburger, Jane W, Baker, Annette L, Burgner, David, Hibberd, Martin L, Davila, Sonia, Levin, Michael, Mamtani, Manju, He, Weijing, Ahuja, Sunil K, and Burns, Jane C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Heart Disease - Coronary Heart Disease, Autoimmune Disease, Cardiovascular, Clinical Research, Atherosclerosis, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Child, Coronary Aneurysm, Female, Haplotypes, Humans, Male, Matrix Metalloproteinases, Mucocutaneous Lymph Node Syndrome, Multigene Family, Polymorphism, Single Nucleotide, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Published
2010

4. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.

Author

Burgner, David, Davila, Sonia, Breunis, Willemijn B, Ng, Sarah B, Li, Yi, Bonnard, Carine, Ling, Ling, Wright, Victoria J, Thalamuthu, Anbupalam, Odam, Miranda, Shimizu, Chisato, Burns, Jane C, Levin, Michael, Kuijpers, Taco W, Hibberd, Martin L, and International Kawasaki Disease Genetics Consortium

Subjects
International Kawasaki Disease Genetics Consortium, Humans, Mucocutaneous Lymph Node Syndrome, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Chi-Square Distribution, Case-Control Studies, Chromosome Mapping, Gene Expression, Gene Frequency, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genes, Databases, Genetic, Adult, Child, Ethnic Groups, Gene Regulatory Networks, Genome-Wide Association Study, Databases, Genetic, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p(combined) = 1.13 x 10(-6)) and ZFHX3 (rs7199343, p(combined) = 2.37 x 10(-6)) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10(-13)) containing five fine-mapped genes-LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1-with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.

Published
2009

5. Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis.

Author

Davila, Sonia, Hibberd, Martin L, Hari Dass, Ranjeeta, Wong, Hazel EE, Sahiratmadja, Edhyana, Bonnard, Carine, Alisjahbana, Bachti, Szeszko, Jeffrey S, Balabanova, Yanina, Drobniewski, Francis, van Crevel, Reinout, van de Vosse, Esther, Nejentsev, Sergey, Ottenhoff, Tom HM, and Seielstad, Mark

Subjects
Cell Line, Chromosomes, Human, X, Humans, Tuberculosis, Pulmonary, Genetic Predisposition to Disease, RNA, Messenger, Case-Control Studies, Gene Expression, Sex Characteristics, Gene Frequency, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Indonesia, Female, Male, Toll-Like Receptor 8, and over, Chromosomes, Human, X, Polymorphism, Single Nucleotide, RNA, Messenger, Tuberculosis, Pulmonary, Genetics, Developmental Biology
Abstract

Despite high rates of exposure, only 5-10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02-1.48). Combined evidence for association is P = 1.2x10(-3)-6x10(-4). In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36x10(-5)), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guérin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.

Published
2008

6. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, Vikrant, Pouw, Richard B, Autio, Matias I, Sagmeister, Manfred G, Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J, Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee, Binder, Alexander, Brouwer, Mieke C, Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M, Hoffmann, Per, EUCLIDS consortium, Schlapbach, Luregn J, Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L, Levin, Michael, Kuijpers, Taco W, Davila, Sonia, consortium, EUCLIDS, Pediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, and ARD - Amsterdam Reproduction and Development

Subjects
CFHR3, Genotype, Meningococcal disease, infectious disease, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Complement, in-depth sequencing, Blood Proteins, Complement System Proteins, Neisseria meningitidis, factor H, QR, Meningococcal Infections, Factor H-related protein, genotyping, Complement Factor H, Genetics, Humans, CFH, Genetic Predisposition to Disease, Genetics (clinical), RC
Abstract

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10−16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10−11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Published
2022

7. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J, Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, Gormley, Stuart, Hamilton, Shea, Herberg, Jethro, Hourmat, Bernardo, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Bokhandi, S, Power, Sue, Barham, Heather, Pathan, N, Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S, Patel, S, McCorkell, Jenni, Davies, P, Cratev, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R, Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C, White, Sonia, Fortune, PM, Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, Martinon-Torres, Nazareth, Martinon Sanchez, Jose Maria, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero Calle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J, Palacios, Alba, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, AM Tutu, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Paulus, Stephane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Agbeko, Rachel, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngane, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumatta, Thomas, Gilleh, Antonio, Martin, Walcher, Wolfgang, Geishofer, Gotho, Klobassa, Daniela, Martin, Mueller, Pfurtscheller, Klaus, Reiter, Karl, Roedl, Siegfried, Zobel, Gerfried, Zoehrer, Bettina, Toepke, Baerbel, Fucik, Peter, Gabriel, Markwart, Penzien, Johann M, Diab, Gedeon, Miething, Robert, Deeg, KH, Hammer, Jurg, Varnholt, Verena, Schmidt, Andreas, Bindl, Lutz, Sillaber, Ursula, Huemer, Christian, Meier, Primrose, Simic-Schleicher, G, Markart, Markus, Pfau, Eberhard, Broede, Hans, Ausserer, Bernd, Kalhoff, Hermann, Arpe, Volker, Schweitzer-Krantz, Susanne, Kasper, Johannes-Martin, Loranth, Kathrin, Bittrich, Hans J, Simma, Burkhard, Klinge, Jens, Fedlmaier, Michael, Weigand, Nicola, Herting, Egbert, Grube, Regina, Fusch, Christoph, Gruber, Alois, Schimmel, Ulf, Knaufer-Schiefer, Suzanne, Laessig, Wolfgang, Hennenberger, Axel, von der Wense, Axel, Tillmann, Roland, Schwarick, Juergen, Sitzmann, Friedrich C, Streif, Werner, Mueller, Herbert, Kurnik, Peter, Groneck, Peter, Weiss, Ute, Groeblacher-Roth, Helene, Bensch, Juergen, Moser, Reinhard, Schwarz, Rudolf, Lenz, Kurt, Hofmann, Thomas, Goepel, Wolfgang, Schulz, Dietrich, Berger, Thomas, Hauser, Erwin, Foerster, Kai Martin, Peters, Jochen, Nicolai, T Homas, Kumlien, Bjoern, Beckmann, Regina, Seitz, Christiane, Hueseman, D, Schuermann, Roland, Ta, Van Hop, Weikmann, Eckart, Evert, W, Hautz, Juergen, Seidenberg, Juergen, Wocko, Lucia, Luigs, Petra, Reiter, Hans-Ludwig, Quietzach, J, Koenig, Michael, Herrmann, Johanna, Mitter, Horst, Seidler, Ekkehard, Maak, Bernhard, Sperl, Wolfgang, Zwiauer, Karl, Meissl, Manfred, Koch, Reinhard, Cremer, Manfred, Breuer, HA, Goerke, W, Nossal, Robert, Pernice, Walter, Brangenberg, Ralf, Salzer, Hans R, Koch, Hartmut, Schaller, Gerhard, Paky, Franz, Strasser, Friedrich, Eitelberger, Franz, Sontheimer, D, Lischka, Andreas, Kronberger, Martina, Dilch, Alfred, Scheibenpflug, Christian, Bruckner, Robert, Mahler, Klaus, Runge, Klaus, Kunze, Wolfgang, Schermann, Peter, Consortium, EUCLIDS, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, University of Zurich, Borghini, Lisa, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Png, Eileen [0000-0001-5586-6395], Wright, Victoria J [0000-0001-7826-1516], Schlapbach, Luregn J [0000-0003-2281-2598], Salas, Antonio [0000-0002-2336-702X], Martinon-Torres, Federico [0000-0002-9023-581X], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, AII - Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Neurology, ANS - Neuroinfection & -inflammation, Medical Microbiology and Infection Prevention, Pediatrics, Public Health, Posfay Barbe, Klara, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), APH - Aging & Later Life, Amsterdam Reproduction & Development (AR&D), and Pediatric surgery

Subjects
0301 basic medicine, Candidate gene, Hypopharyngeal Neoplasms / microbiology, Meningococcal Infections / microbiology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MathematicsofComputing_GENERAL, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], lcsh:Medicine, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, Cohort Studies, 0302 clinical medicine, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, Hypopharyngeal Neoplasms / pathology, BINDING, Tumor Cells, Cultured, lcsh:Science, Genetics, Multidisciplinary, ddc:618, Cultured, TheoryofComputation_GENERAL, High-Throughput Nucleotide Sequencing, Genomics, Phenotype, 3. Good health, ddc, Tumor Cells, Multidisciplinary Sciences, GENOME, Science & Technology - Other Topics, Neisseria meningitidis / isolation & purification, Single-nucleotide polymorphism, 610 Medicine & health, KAPPA-B, Biology, Hypopharyngeal Neoplasms / genetics, Polymorphism, Single Nucleotide, Article, Meningococcal Infections / epidemiology, 03 medical and health sciences, SEQUENCE VARIATION, Genetic predisposition, Journal Article, Humans, Meningitis, Meningococcal Infections / genetics, Genetic Predisposition to Disease, Nucleic Acid, Polymorphism, General, Gene, Genotyping, Neisseria meningitidis / genetics, Genetic Association Studies, Genetic association, Genetic association study, 1000 Multidisciplinary, Science & Technology, Hypopharyngeal Neoplasms, genetic variants, meningococcal disease, lcsh:R, Single Nucleotide, EUCLIDS consortium, Gene regulation, Meningococcal Infections, 030104 developmental biology, 10036 Medical Clinic, Case-Control Studies, lcsh:Q, Software_PROGRAMMINGLANGUAGES, Regulatory Sequences, 030217 neurology & neurosurgery
Abstract

EUCLIDS consortium., Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes., This work has been partially funded by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. The UK meningococcal cohort was established with support from Meningitis Research Foundation through grants to Imperial College London. The Research from Newcastle partners was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The ESIGEM Research group activities were supported by grants from Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2016), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and ‘fondos FEDER’ (F.M.T.). The Swiss Pediatric Sepsis study was funded by grants from the Swiss National Science Foundation (342730_153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. The Western Europe Meningococcal Study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006–9 of the Department for Science and Research of the Styrian federal government (Austria) and the non for profit association ‘In Vita’, Graz (Austria).

Published
2019

8. HPV Could be a Potential Factor of Survival in Laryngeal Cancer: a Preliminary Study in Mexican Patients

Author

Peralta, Raul, Garcia, Paola, Valdivia, Alejandra, Lopez, Arianna, Apresa, Teresa, Hernandez, Dulce M., Gallegos, Francisco, Alvarado-Cabrero, Isabel, Vargas-De-Leon, Cruz, Davila, Sonia, Romero, Pablo, and Salcedo, Mauricio

Subjects
Male, HPV, EGFR, Papillomavirus Infections, Middle Aged, Prognosis, ErbB Receptors, Survival Rate, DNA, Viral, Carcinoma, Squamous Cell, laryngeal cancer, Humans, Female, Laryngeal Neoplasms, Mexico, Papillomaviridae, Research Article, Follow-Up Studies
Abstract

Introduction: In Head and Neck (HN) cancer, the High-Risk Human Papillomavirus (hr HPV) infection has been associated in about 40% of these tumors. The hr HPV infection is one of the etiological factors of several epithelial tumors; however, its association with the prognosis has not yet been established for patients with Laryngeal Squamous Cell Carcinoma (LSCC). On the other hand, Epidermal Growth Factor Receptor (EGFR) is a molecular marker widely studied in cancer and its overexpression has been associated with poor prognosis in some types of cancer, including the HN cancer. In the present study, we analyzed EGFR expression and HPV detection in a cohort of Mexican patients with LSCC and define their association with clinical-pathological and survival parameters. Methods: EGFR expression analysis was performed by immunohistochemistry assay. A tissue array was constructed based on 30 paraffin-embedded tissue samples. HPV detection was performed by PCR. The results were then compared with the clinical-pathological variables and outcome measures (Kaplan Meier and Cox analysis). Results: High expression of EGFR was observed in 43% of the samples and 20% of HPV detection. The statistical analyses provided evidence of disassociation between clinical-pathological parameters and EGFR expression, but there was an association with poor prognosis. Interestingly, HPV detection is slightly associated with good prognosis. Conclusion: Both, EGFR overexpression and HPV presence could be associated with an unfavorable prognosis in patients with LSCC, independently of other clinical-pathological factors.

Published
2018

9. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Schlapbach, Luregn J, Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, and EUCLIDS Consortium

Subjects
Hypopharyngeal Neoplasms, High-Throughput Nucleotide Sequencing, Genomics, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, 3. Good health, Cohort Studies, Meningococcal Infections, Phenotype, Case-Control Studies, Tumor Cells, Cultured, Humans, Genetic Predisposition to Disease, Genetic Association Studies
Abstract

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

10. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

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