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1. OP0133 INVESTIGATING THE GENETIC BACKGROUND OF THE SEX DIMORPHISM IN SYSTEMIC SCLEROSIS

Author

Rodriguez-Martin, I., primary, Kerick, M., additional, Rosa-Baez, C., additional, Borrego-Yaniz, G., additional, Ortiz-Fernández, L., additional, Guillen-Del-Castillo, A., additional, Simeón-Aznar, C. P., additional, Callejas, J. L., additional, Assassi, S., additional, Ssc Group, I., additional, Proudman, S. M., additional, Nikpour, M., additional, Interest Group (Asig), A. S., additional, Hunzelmann, N., additional, Moroncini, G., additional, De Vries-Bouwstra, J. K., additional, Orozco, G., additional, Barton, A., additional, Herrick, A. L., additional, Allanore, Y., additional, Fonseca, C., additional, Beretta, L., additional, Denton, C. P., additional, Mayes, M. D., additional, Martin, J., additional, and Acosta-Herrera, M., additional

Published
2024
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2. POS0056 UNVEILING VASCULAR, PRO-FIBROTIC AND INTERFERON-RELATED ABNORMALITIES THROUGH AN EPIGENOME-WIDE ANALYSIS IN SYSTEMIC SCLEROSIS

Author

Martinez-Lopez, J., primary, Estupiñán-Moreno, E., additional, Ortiz-Fernández, L., additional, Kerick, M., additional, Andrés-León, E., additional, Terrón-Camero, L. C., additional, Carnero-Montoro, E., additional, Barturen, G., additional, Beretta, L., additional, Clinical Consortium, P., additional, Alarcon-Riquelme, M., additional, Acosta-Herrera, M., additional, Ballestar, E., additional, and Martin, J., additional

Published
2024
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4. OP0102 IDENTIFICATION OF NEW RISK LOCI AND PATHWAYS INVOLVED IN GCA PATHOGENESIS BY A GENOME-WIDE STUDY

Author

Borrego-Yaniz, G., primary, Ortiz-Fernández, L., additional, Kerick, M., additional, Madrid-Paredes, A., additional, Vaglio, A., additional, Hernández-Rodríguez, J., additional, Mackie, S., additional, Castañeda, S., additional, Solans-Laqué, R., additional, Mestre, J., additional, Dasgupta, B., additional, Watts, R., additional, Khalidi, N., additional, Langford, C., additional, Ytterberg, S. R., additional, Beretta, L., additional, Govoni, M., additional, Emmi, G., additional, Cimmino, M. A., additional, Witte, T., additional, Neumann, T., additional, Holle, J., additional, Schönau, V., additional, Pugnet, G., additional, Papo, T., additional, Haroche, J., additional, Mahr, A., additional, Mouthon, L., additional, Molberg, Ø., additional, Diamantopoulos, A., additional, Voskuyl, A., additional, Daikeler, T., additional, Berger, C., additional, Molloy, E., additional, Blockmans, D., additional, Consortium, U. G., additional, Gca Consortium, I., additional, Ortego, N., additional, Brouwer, E., additional, Lamprecht, P., additional, Klapa, S., additional, Salvarani, C., additional, Merkel, P. A., additional, Cid, M. C., additional, González-Gay, M. A., additional, Morgan, A., additional, Martin Ibanez, J., additional, and Márquez, A., additional

Published
2023
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5. POS1276 A SINGLE CELL TRANSCRIPTOMIC ANALYSIS REVEALS A PRO-INFLAMMATORY PROFILE IN PERIPHERAL BLOOD CD14+ MONOCYTES OF SYSTEMIC SCLEROSIS PATIENTS

Author

Villanueva-Martin, G., primary, Acosta-Herrera, M., additional, Carmona, E., additional, Kerick, M., additional, Ortego, N., additional, Callejas-Rubio, J. L., additional, Mages, N., additional, Klages, S., additional, Boerno, S., additional, Timmermann, B., additional, Bossini-Castillo, L., additional, and Martin Ibanez, J., additional

Published
2023
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8. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Author

Kerick, M., Acosta-Herrera, M., Simeón-Aznar, C.P., Callejas, J.L., Assassi, S., Proudman, S.M., Nikpour, M., Hunzelmann, N., Moroncini, G., Vries-Bouwstra, J.K. de, Orozco, G., Barton, A., Herrick, A.L., Terao, C., Allanore, Y., Fonseca, C., Alarcón-Riquelme, M.E., Radstake, T.R., Beretta, L., Denton, C.P., Vonk, M.C., Mayes, M.D., Martin, J., Kerick, M., Acosta-Herrera, M., Simeón-Aznar, C.P., Callejas, J.L., Assassi, S., Proudman, S.M., Nikpour, M., Hunzelmann, N., Moroncini, G., Vries-Bouwstra, J.K. de, Orozco, G., Barton, A., Herrick, A.L., Terao, C., Allanore, Y., Fonseca, C., Alarcón-Riquelme, M.E., Radstake, T.R., Beretta, L., Denton, C.P., Vonk, M.C., Mayes, M.D., and Martin, J.

Abstract

Item does not contain fulltext, Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Published
2022

9. The Effect of Body Fat Distribution on Systemic Sclerosis

Author

Villanueva-Martin, G, Acosta-Herrera, M, Kerick, M, Lopez-Isac, E, Simeon, CP, Callejas, JL, Assassi, S, Beretta, L, Allanore, Y, Proudman, SM, Nikpour, M, Fonseca, C, Denton, CP, Radstake, TRDJ, Mayes, MD, Jiang, X, Martin, J, Bossini-Castillo, L, Villanueva-Martin, G, Acosta-Herrera, M, Kerick, M, Lopez-Isac, E, Simeon, CP, Callejas, JL, Assassi, S, Beretta, L, Allanore, Y, Proudman, SM, Nikpour, M, Fonseca, C, Denton, CP, Radstake, TRDJ, Mayes, MD, Jiang, X, Martin, J, and Bossini-Castillo, L

Abstract

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genome-wide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.

Published
2022

10. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Author

Kerick, M, Acosta-Herrera, M, Pilar Simeon-Aznar, C, Luis Callejas, J, Assassi, S, Proudman, SM, Nikpour, M, Hunzelmann, N, Moroncini, G, de Vries-Bouwstra, JK, Orozco, G, Barton, A, Herrick, AL, Terao, C, Allanore, Y, Fonseca, C, Eugenia Alarcon-Riquelme, M, Radstake, TRDJ, Beretta, L, Denton, CP, Mayes, MD, Martin, J, Kerick, M, Acosta-Herrera, M, Pilar Simeon-Aznar, C, Luis Callejas, J, Assassi, S, Proudman, SM, Nikpour, M, Hunzelmann, N, Moroncini, G, de Vries-Bouwstra, JK, Orozco, G, Barton, A, Herrick, AL, Terao, C, Allanore, Y, Fonseca, C, Eugenia Alarcon-Riquelme, M, Radstake, TRDJ, Beretta, L, Denton, CP, Mayes, MD, and Martin, J

Abstract

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Published
2022

11. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author

López-Isac, E., Acosta-Herrera, M., Kerick, M., Assassi, S., Satpathy, A.T., Granja, J., Mumbach, M.R., Beretta, L., Simeón, C.P., Carreira, P., Ortego-Centeno, N., Castellvi, I., Bossini-Castillo, L., Carmona, F.D., Orozco, G., Hunzelmann, N., Distler, J.H.W., Franke, A., Lunardi, C., Moroncini, G., Gabrielli, A., de Vries-Bouwstra, J., Wijmenga, C., Koeleman, B.P.C., Nordin, A., Padyukov, L., Hoffmann-Vold, A.-M., Lie, B., Ríos, R., Callejas, J.L., Vargas-Hitos, J.A., García-Portales, R., Camps, M.T., Fernández-Nebro, A., González-Escribano, M.F., García-Hernández, F.J., Castillo, M.J., Aguirre, M.A., Gómez-Gracia, I., Fernández-Gutiérrez, B., Rodríguez-Rodríguez, L., García de la Peña, P., Vicente, E., Andreu, J.L., Fernández de Castro, M., López-Longo, F.J., Martínez, L., Fonollosa, V., Guillén, A., Espinosa, G., Tolosa, C., Pros, A., Rodríguez-Carballeira, M., Narváez, F.J., Rubio-Rivas, M., Ortiz-Santamaría, V, Madroñero, A.B., González-Gay, M.A., Díaz, B., Trapiella, L., Sousa, A., Egurbide, M.V., Fanlo-Mateo, P., Sáez-Comet, L., Díaz, F., Hernández, V, Beltrán, E., Román-Ivorra, J.A., Grau E., Alegre-Sancho, J.J., Freire, M., Blanco-García, F.J., Oreiro, N., Witte, T., Kreuter, A., Riemekasten, G., Airó P., Magro, C., Voskuyl, A.E., Vonk, M.C., Hesselstrand, R., Proudman S., Stevens, W., Nikpour, M., Zochling, J., Sahhar, J., Roddy, J., Nash, P., Tymms, K., Rischmueller, M., Lester, S., Vyse, T., Herrick, A.L., Worthington, J., Denton C.P., Allanore, Y., Brown, M.A., Radstake, T.R.D.J., Fonseca, C., Chang H.Y., Mayes, M.D., Martin, J., European Scleroderma Group, Australian Scleroderma Interest Group (ASIG), Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), Universidad de Cantabria, [López-Isac E, Acosta-Herrera M, Kerick M] Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain. [Assassi S] The University of Texas Health Science Center-Houston, Houston, USA. [Satpathy AT, Granja J] Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, USA. Howard Hughes Medical Institute, Stanford University, Stanford, USA. [Simeón CP] Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Rheumatology, and AII - Inflammatory diseases

Subjects
0301 basic medicine, Chemistry(all), AUTOIMMUNITY, Àcids nucleics, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, Biochemistry, ANNOTATION, 0302 clinical medicine, Phosphopantothenoylcysteine decarboxylase, Single nucleotide, Non-U.S. Gov't, lcsh:Science, skin and connective tissue diseases, características del estudio::metaanálisis [CARACTERÍSTICAS DE PUBLICACIONES], Multidisciplinary, Nucleid acid conformation, integumentary system, Research Support, Non-U.S. Gov't, High-Throughput Nucleotide Sequencing, Genètica - Tècnica, 3. Good health, Nucleic acids, Sequence analysis DNA, Medical genetics, medicine.medical_specialty, Chromatin Immunoprecipitation, GENES, Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Science, Non-P.H.S, Single-nucleotide polymorphism, Scleroderma systemic, Computational biology, Physics and Astronomy(all), Biology, Research Support, Study Characteristics::Meta-Analysis [PUBLICATION CHARACTERISTICS], Genetic polymorphisms, enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES], Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Functional genomics, Genome-wide association studies, Systemic sclerosis, Rheumatic diseases, CLASSIFICATION, N.I.H, 03 medical and health sciences, Research Support, N.I.H., Extramural, Diacylglycerol kinase theta, Molecular genetics, REVEALS, Journal Article, medicine, Humans, Vascular Diseases, Risk factor, Polymorphism, Genomes, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030203 arthritis & rheumatology, Scleroderma, Systemic, Biochemistry, Genetics and Molecular Biology(all), Polimorfisme genètic, HUMAN-CELLS, Extramural, Bayes Theorem, General Chemistry, Sequence Analysis, DNA, Fibrosis, 030104 developmental biology, Scleroderma (Disease), Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Nucleic Acid Conformation, VISUALIZATION, lcsh:Q, U.S. Gov't, Esclerodèrmia, Research Support, U.S. Gov't, Non-P.H.S, Metaanàlisi, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments., We thank Sofia Vargas, Sonia García, and Gema Robledo for their excellent technical assistance and all the patients and control donors for their essential collaboration. We thank National DNA Bank Carlos III (University of Salamanca, Spain) that supplied part of the control DNA samples from Spain, WTCCC and EIRA Consortiums, and PopGen 2.0 network. This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50- HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1- 0423 and DoD W81XWH-16-1-0296, respectively

Published
2019
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12. Admixture mapping analysis reveals differential genetic ancestry associated with Chagas disease susceptibility in the Colombian population.

Author

Red Iberoamericana de Medicina Genómica en Enfermedad de Chagas, Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo, Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Cabildo de Tenerife, Casares-Marfil, D, Guillén-Guío, Beatriz, Lorenzo-Salazar, José M., Rodríguez-Pérez, Héctor, Kerick, M., Jaimes-Campos, M. A., Díaz, M. L., Estupiñán-Moreno, Elkyn, Echeverría, L.E., González, C. I., Martin, Javier, Flores, C., Acosta-Herrera, Marialbert, Red Iberoamericana de Medicina Genómica en Enfermedad de Chagas, Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo, Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Cabildo de Tenerife, Casares-Marfil, D, Guillén-Guío, Beatriz, Lorenzo-Salazar, José M., Rodríguez-Pérez, Héctor, Kerick, M., Jaimes-Campos, M. A., Díaz, M. L., Estupiñán-Moreno, Elkyn, Echeverría, L.E., González, C. I., Martin, Javier, Flores, C., and Acosta-Herrera, Marialbert

Abstract

Chagas disease is an infection caused by the parasite Trypanosoma cruzi, endemic in Latino America. Leveraging the three-way admixture between Native American (AMR), European (EUR) and African (AFR) populations in Latin Americans, we aimed to better understand the genetic basis of Chagas disease by performing an admixture mapping study in a Colombian population. A two-stage study was conducted, and subjects were classified as seropositive and seronegative for T. cruzi. In stage 1, global and local ancestries were estimated using reference data from the 1000 Genomes Project (1KGP), and local ancestry associations were performed by logistic regression models. The AMR ancestry showed a protective association with Chagas disease within the major histocompatibility complex region [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.66–0.83, lowest P-value = 4.53 × 10−8]. The fine mapping assessment on imputed genotypes combining data from stage 1 and 2 from an independent Colombian cohort, revealed nominally associated variants in high linkage disequilibrium with the top signal (rs2032134, OR = 0.93, 95% CI = 0.90–0.97, P-value = 3.54 × 10−4) in the previously associated locus. To assess ancestry-specific adaptive signals, a selective sweep scan in an AMR reference population from 1KGP together with an in silico functional analysis highlighted the Tripartite Motif family and the human leukocyte antigen genes, with crucial role in the immune response against pathogens. Furthermore, these analyses emphasized the macrophages, neutrophils and eosinophils, as key players in the defense against T. cruzi. This first admixture mapping study in Chagas disease provided novel insights underlying the host immune response in the pathogenesis of this neglected disease.

Published
2021

16. OP0137 GENOME-WIDE WHOLE-BLOOD TRANSCRIPTOME PROFILING IN A LARGE EUROPEAN COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Author

Beretta, L., primary, Barturen, G., additional, Vigone, B., additional, Bellocchi, C., additional, Hunzelmann, N., additional, Delanghe, E., additional, Kovács, L., additional, Cervera, R., additional, Gerosa, M., additional, Ortega Castro, R., additional, Almeida, I., additional, Cornec, D., additional, Chizzolini, C., additional, Pers, J. O., additional, Makowska, Z., additional, Buttgereit, A., additional, Lesche, R., additional, Kerick, M., additional, Alarcon-Riquelme, M., additional, and Martin Ibanez, J., additional

Published
2020
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19. Molecular stratification of autoimmune diseases based on epigenetic profiles

Author

Barturen, G, Kerick, M, Alvarez-Errico, D, Quintares, R, Carnero, E, Gemperline, D, Dow, E, Beretta, Lorenzo, Pers, J.O., Renaudineau, Yves, Frostegard, J, Juárez, Manuela, Consortium, Clinical, Flow Cytometry, Group, Rao, S, Chamberlain, C, Wojcik, J., Segura, A, Martin, J, Ballestar, Esteban, Alarcon-Riquelme, Marta E., Centre for Genomics and Oncological Reearch (GENYO), Instituto de Parasitología y Biomedicina 'López-Neyra' (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Departmento de Quimica-Analitica, Granada, Eli Lilly, Indianapolis, USA, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Laboratoire d'Immunologie et Immunothérapie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unit of Chronic Diseases, Solna, Sweden, UCB Pharma Slough, Sanofi Genzyme, Quartzbio, Geneva, Departamento de Quimica-Analitica, Granada, Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

20. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Acosta-Herrera, M., Kerick, M., Gonzalez-Serna, D., Wijmenga, C., Franke, A., Gregersen, P.K., Padyukov, L., Worthington, J., Vyse, T.J., Alarcon-Riquelme, M.E., Vonk, M.C., Riel, P.L.C.M. van, Broen, J.C.A., Coenen, M.J.H., Radstake, T.R., Mayes, M.D., Martin, J., Acosta-Herrera, M., Kerick, M., Gonzalez-Serna, D., Wijmenga, C., Franke, A., Gregersen, P.K., Padyukov, L., Worthington, J., Vyse, T.J., Alarcon-Riquelme, M.E., Vonk, M.C., Riel, P.L.C.M. van, Broen, J.C.A., Coenen, M.J.H., Radstake, T.R., Mayes, M.D., and Martin, J.

Abstract

Contains fulltext : 202242.pdf (publisher's version ) (Closed access), OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Published
2019

21. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author

Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., Satpathy A.T., Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., and Satpathy A.T.

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Copyright © 2019, The Author(s).

Published
2019

22. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author

Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, Martin, J, Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, and Martin, J

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Published
2019

23. Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases.

Author

European Commission, Ministerio de Economía y Competitividad (España), Innovative Medicines Initiative, Fundación Genzyme, Carnero-Montoro, Elena, Barturen, Guillermo, Povedano, E, Kerick, M, Martínez-Bueno, Manuel, PRECISESADS Clinical Consortium, Ballestar, Estéban, Martín, J., Teruel, M, Alarcón-Riquelme, M. E., European Commission, Ministerio de Economía y Competitividad (España), Innovative Medicines Initiative, Fundación Genzyme, Carnero-Montoro, Elena, Barturen, Guillermo, Povedano, E, Kerick, M, Martínez-Bueno, Manuel, PRECISESADS Clinical Consortium, Ballestar, Estéban, Martín, J., Teruel, M, and Alarcón-Riquelme, M. E.

Abstract

Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Due to its low prevalence, this disease has been very poorly studied at the molecular level. We performed for the first time an epigenome-wide association study interrogating DNA methylation data obtained with the Infinium MethylationEPIC array from whole blood samples in 31 patients diagnosed with MCTD and 255 healthy subjects. We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. We mostly identified epigenetic signals at genes previously implicated in other SADs, for example MX1, PARP9, DDX60, or IFI44L, for which we also observed that MCTD patients exhibit higher DNA methylation variability compared with controls, suggesting that these sites might be involved in plastic immune responses that are relevant to the disease. Through methylation quantitative trait locus (meQTL) analysis we identified widespread local genetic effects influencing DNA methylation variability at MCTD-associated sites. Interestingly, for IRF7, IFI44 genes, and the HLA region we have evidence that they could be exerting a genetic risk on MCTD mediated through DNA methylation changes. Comparison of MCTD-associated epigenome with patients diagnosed with SLE, or Sjögren's Syndrome, reveals a common interferon-related epigenetic signature, however we find substantial epigenetic differences when compared with patients diagnosed with rheumatoid arthritis and systemic sclerosis. Furthermore, we show that MCTD-associated CpGs are potential epigenetic biomarkers with high diagnostic value. Our study serves to reve

Published
2019

24. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author

Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., Martín, J., Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., and Martín, J.

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Published
2019

25. Genomic and transcriptomic heterogeneity of colorectal tumors arising in Lynch Syndrome

Author

Binder, H., Hopp, L., Schweiger, M., Hoffmann, S., Jühling, F., Kerick, M., Timmermann, B., Siebert, S., Grimm, C., Nersisyan, L., Arakelyan, A., Herberg, M., Buske, P., Loeffler-Wirth, H., Rosolowski, M., Engel, C., Przybilla, J., Peifer, M., Friedrichs, N., Moeslein, G., Odenthal, M., Hussong, M., Peters, S., Holzapfel, S., Nattermann, J., Hueneburg, R., Schmiegel, W., Royer-Pokora, B., Aretz, S., Kloth, M., Kloor, M., Buettner, R., Galle, J., and Loeffler, M.

Published
2017

26. S1A:5 Molecular stratification of autoimmune diseases based on epigenetic profiles

Author

Barturen, G, primary, Kerick, M, additional, Alvarez-Errico, D, additional, Quintares, R, additional, Carnero, E, additional, Gemperline, D, additional, Dow, E, additional, Beretta, L, additional, Pers, JO, additional, Renadineau, Y, additional, Frostegard, J, additional, Juarez, M, additional, Consortium, Clinical, additional, Group, Flow Cytometry, additional, Rao, S, additional, Chamberlain, C, additional, Wojcik, J, additional, Segura, A, additional, Martin, J, additional, Ballestar, E, additional, and Alarcón-Riquelme, ME, additional

Published
2018
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27. Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

Author

Marquez, A, Kerick, M, Zhernakova, A, Gutierrez-Achury, J, Chen, W, Onengut-Gumuscu, S, Gonzalez-Alvaro, I, Rodriguez-Rodriguez, L, Rios-Fernandez, R, Gonzalez-Gay, M, Mayes, M, Raychaudhuri, S, Rich, S, Wijmenga, C, Martin, J, Barisani, D, Chen, WM, Gonzalez-Gay, MA, Mayes, MD, Rich, SS, Marquez, A, Kerick, M, Zhernakova, A, Gutierrez-Achury, J, Chen, W, Onengut-Gumuscu, S, Gonzalez-Alvaro, I, Rodriguez-Rodriguez, L, Rios-Fernandez, R, Gonzalez-Gay, M, Mayes, M, Raychaudhuri, S, Rich, S, Wijmenga, C, Martin, J, Barisani, D, Chen, WM, Gonzalez-Gay, MA, Mayes, MD, and Rich, SS

Abstract

Background: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. Methods: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. Results: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. Conclusions: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied

Published
2018

28. Campylobacter jejuni impairs sodium transport and epithelial barrier function via cytokine release in human colon

Author

Bucker, R., Krug, S. M., Moos, V., Bojarski, C., Schweiger, M. R., Kerick, M., Fromm, A., Janssen, S., Fromm, M., Hering, N. A., Siegmund, B., Schneider, T., Barmeyer, C., Schulzke, J. D., Bucker, R., Krug, S. M., Moos, V., Bojarski, C., Schweiger, M. R., Kerick, M., Fromm, A., Janssen, S., Fromm, M., Hering, N. A., Siegmund, B., Schneider, T., Barmeyer, C., and Schulzke, J. D.

Abstract

Campylobacter jejuni is the most prevalent cause of foodborne bacterial enteritis worldwide. Patients present with diarrhea and immune responses lead to complications like arthritis and irritable bowel syndrome. Although studies exist in animal and cell models, we aimed at a functional and structural characterization of intestinal dysfunction and the involved regulatory mechanisms in human colon. First, in patients' colonic biopsies, sodium malabsorption was identified as an important diarrheal mechanism resulting from hampered epithelial ion transport via impaired epithelial sodium channel (ENaC) beta- and gamma-subunit. In addition, barrier dysfunction from disrupted epithelial tight junction proteins (claudin-1, -3, -4, -5, and -8), epithelial apoptosis, and appearance of lesions was detected, which cause leak-flux diarrhea and can perpetuate immune responses. Importantly, these effects in human biopsies either represent direct action of Campylobacter jejuni (ENaC impairment) or are caused by proinflammatory signaling (barrier dysfunction). This was revealed by regulator analysis from RNA-sequencing (cytometric bead array-checked) and confirmed in cell models, which identified interferon-gamma, TNF alpha, IL-13, and IL-1 beta. Finally, bioinformatics' predictions yielded additional information on protective influences like vitamin D, which was confirmed in cell models. Thus, these are candidates for intervention strategies against C. jejuni infection and post-infectious sequelae, which result from the permissive barrier defect along the leaky gut.

Published
2018

29. Transcriptional signature induced by a C-terminal c-Src mutant in a human breast cell line

Author

Broecker, F., Hardt, C., Herwig, R., Timmermann, B., Kerick, M., Wunderlich, A., Schweiger, M.R., Borsig, L., Heikenwälder, M., Lehrach, H., and Moelling, K.

Subjects
Oncogene, Pdz Domain, C-src, Metastasis, Migration, Transcriptome
Abstract

Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are characteristic of the viral oncogene protein v-Src and are present in some advanced human colon cancers. They are associated with increased kinase activity and elevated cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant of c-Src, c-Src(mt), in comparison to its wildtype protein, c-Src(wt), expressed in the human non-transformed breast epithelial cell line MCF-10A. We demonstrated previously that the mutant changed migratory and metastatic properties. Genome-wide transcriptome analysis revealed that c-Src(mt) deregulated the expression levels of about 430 mRNAs whose gene products are mainly involved in the cellular processes of migration and adhesion, apoptosis and protein synthesis. More than 80% of these genes have previously been linked to cellular migration, while the others play roles, for instance, in RNA transport and splicing processes. Consistent with the transcriptome data, c-Src(mt)-, but not c-Src(wt)-expressing cells showed the capacity to metastasize into mouse lung tissue in vivo. The mRNA expression profile of c-Src(mt)-expressing cells shows significant overlap with that of various primary human tumor samples, perhaps reflecting elevated Src activity in some cancerous cells. Expression of c-Src(mt) lead to elevated migratory potential. We used this model system to analyze the transcriptional changes associated with an invasive cellular phenotype. We identified genes and pathways deregulated by c-Src(mt) as biomarkers with potential interest for diagnostics or therapy of metastatic cells.

Published
2016

33. Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis

Author

Timmermann, B., Kerick, M., Roehr, C., Fischer, A., Isau, M., Boerno, S., Wunderlich, A., Barmeyer, C., Seemann, P., Koenig, J., Lappe, M., Kuss, A., Garshasbi, M., Bertram, L., Trappe, K., Werber, M., Herrmann, B., Zatloukal, K., Lehrach, H., Schweiger, M., and This work was supported by the German Federal Ministry of Education and Research (01GS08105 'Mutanom,' 01GS08111 'Intestinal Modifers') and the Max Planck Society.

Subjects
neoplasms, digestive system diseases
Abstract

BACKGROUND: Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations.

Published
2010

36. The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response

Author

Hussong, M., Boerno, S. T., Kerick, M., Wunderlich, A., Franz, A., Sueltmann, H., Timmermann, B., Lehrach, H., Hirsch-Kauffmann, M., Schweiger, M. R., Hussong, M., Boerno, S. T., Kerick, M., Wunderlich, A., Franz, A., Sueltmann, H., Timmermann, B., Lehrach, H., Hirsch-Kauffmann, M., and Schweiger, M. R.

Abstract

The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress.

Published
2014

39. Campylobacter jejuniimpairs sodium transport and epithelial barrier function via cytokine release in human colon

Author

Bücker, R, Krug, S M, Moos, V, Bojarski, C, Schweiger, M R, Kerick, M, Fromm, A, Janßen, S, Fromm, M, Hering, N A, Siegmund, B, Schneider, T, Barmeyer, C, and Schulzke, J D

Abstract

Campylobacter jejuniis the most prevalent cause of foodborne bacterial enteritis worldwide. Patients present with diarrhea and immune responses lead to complications like arthritis and irritable bowel syndrome. Although studies exist in animal and cell models, we aimed at a functional and structural characterization of intestinal dysfunction and the involved regulatory mechanisms in human colon. First, in patients’ colonic biopsies, sodium malabsorption was identified as an important diarrheal mechanism resulting from hampered epithelial ion transport via impaired epithelial sodium channel (ENaC) β- and γ-subunit. In addition, barrier dysfunction from disrupted epithelial tight junction proteins (claudin-1, -3, -4, -5, and -8), epithelial apoptosis, and appearance of lesions was detected, which cause leak-flux diarrhea and can perpetuate immune responses. Importantly, these effects in human biopsies either represent direct action of Campylobacter jejuni(ENaC impairment) or are caused by proinflammatory signaling (barrier dysfunction). This was revealed by regulator analysis from RNA-sequencing (cytometric bead array-checked) and confirmed in cell models, which identified interferon-γ, TNFα, IL-13, and IL-1β. Finally, bioinformatics’ predictions yielded additional information on protective influences like vitamin D, which was confirmed in cell models. Thus, these are candidates for intervention strategies against C. jejuniinfection and post-infectious sequelae, which result from the permissive barrier defect along the leaky gut.

Published
2018
Full Text
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40. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.

Author

Krawitz, P.M., Schweiger, M.R., Rodelsperger, C., Marcelis, C.L.M., Kolsch, U., Meisel, C., Stephani, F., Kinoshita, T., Murakami, Y., Bauer, S., Isau, M., Fischer, A., Dahl, A., Kerick, M., Hecht, J., Kohler, S., Jager, M. de, Grunhagen, J., Condor, B.J. de, Doelken, S., Brunner, H.G., Meinecke, P., Passarge, E., Thompson, M.D., Cole, D.E., Horn, D., Roscioli, T., Mundlos, S., Robinson, P.N., Krawitz, P.M., Schweiger, M.R., Rodelsperger, C., Marcelis, C.L.M., Kolsch, U., Meisel, C., Stephani, F., Kinoshita, T., Murakami, Y., Bauer, S., Isau, M., Fischer, A., Dahl, A., Kerick, M., Hecht, J., Kohler, S., Jager, M. de, Grunhagen, J., Condor, B.J. de, Doelken, S., Brunner, H.G., Meinecke, P., Passarge, E., Thompson, M.D., Cole, D.E., Horn, D., Roscioli, T., Mundlos, S., and Robinson, P.N.

Abstract

1 oktober 2010, Contains fulltext : 88212.pdf (publisher's version ) (Closed access), Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

Published
2010

41. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

Author

Krawitz, PM, Schweiger, MR, Rödelsperger, C, Marcelis, C, Kölsch, U, Meisel, C, Stephani, F, Kinoshita, T, Murakami, Y, Bauer, S, Isau, M, Fischer, A, Dahl, A, Kerick, M, Hecht, J, Köhler, S, Jäger, M, Grünhagen, J, De Condor, BJ, Doelken, S, Brunner, HG, Meinecke, P, Passarge, E, Thompson, MD, Cole, DE, Horn, D, Roscioli, T, Mundlos, S, Robinson, PN, Krawitz, PM, Schweiger, MR, Rödelsperger, C, Marcelis, C, Kölsch, U, Meisel, C, Stephani, F, Kinoshita, T, Murakami, Y, Bauer, S, Isau, M, Fischer, A, Dahl, A, Kerick, M, Hecht, J, Köhler, S, Jäger, M, Grünhagen, J, De Condor, BJ, Doelken, S, Brunner, HG, Meinecke, P, Passarge, E, Thompson, MD, Cole, DE, Horn, D, Roscioli, T, Mundlos, S, and Robinson, PN

Abstract

Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families. © 2010 Nature America, Inc. All rights reserved.

Published
2010

43. Erratum: Campylobacter jejuniimpairs sodium transport and epithelial barrier function via cytokine release in human colon

Author

Bücker, R., Krug, S.M., Moos, V., Bojarski, C., Schweiger, M.R., Kerick, M., Fromm, A., Janßen, S., Fromm, M., Hering, N.A., Siegmund, B., Schneider, T., Barmeyer, C., and Schulzke, J.D.

Abstract

Correction to: Mucosal Immunology, advance online publication 2 August 2017; doi:10.1038/mi.2017.66 The advance online version of this paper was inadvertently published with Figures 2 and 4 in black and white. The color versions appear below and in the issue version of the paper in print and online.The publisher regrets the error.

Published
2018
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44. Translation of next-generation sequencing (NGS) into molecular diagnostics.

Author

Kotschote S, Wagner C, Marschall C, Mayer K, Hirv K, Kerick M, Timmermann B, and Klein H

Abstract

In the past 5 years, next-generation sequencing (NGS) has been established as a valuable tool for several research applications. Commercially available platforms from Helicos, Illumina, Life Technologies, Pacific Biosciencies, and Roche allow for massively parallel sequencing and analysis in the fields of genomics, transcriptomics, and epigenomics. As in most projects, data throughput of the sequencers is not the limiting factor; genomic DNA samples are directly prepared for sequencing without prior conditioning. However, there are some applications such as targeted resequencing that do not require sequencing of whole genomes. Therefore, a technology called target enrichment was established more than 2 years ago. Different PCR- or hybridization-based approaches were further commercially developed and refined. The combination of this method with NGS can improve analysis of disease-related gene sets in molecular diagnostics by reducing time and costs. By taking advantage of the enormous data output, several genes and patients can be analyzed in parallel in one single instrument run. [ABSTRACT FROM AUTHOR]

Published
2010
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45. Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing

Author

Ortiz-Fernández, Lourdes, Carmona, Elio G, Kerick, Martin, Lyons, Paul, Carmona, Francisco David, López Mejías, Raquel, Khor, Chiea Chuen, Grayson, Peter C, Tombetti, Enrico, Jiang, Lindi, Direskeneli, Haner, Saruhan-Direskeneli, Guher, Callejas-Rubio, José-Luis, Vaglio, Augusto, Salvarani, Carlo, Hernández-Rodríguez, Jose, Cid, Maria Cinta, Morgan, Ann W, Merkel, Peter A, Burgner, David, Smith, Kenneth Gc, Gonzalez-Gay, Miguel Angel, Sawalha, Amr H, Martin, Javier, Marquez, Ana, Ortiz-Fernández, Lourdes [0000-0002-0247-4280], Carmona, Francisco David [0000-0002-1427-7639], Grayson, Peter C [0000-0002-8269-9438], Salvarani, Carlo [0000-0003-3708-3148], Hernández-Rodríguez, Jose [0000-0002-2357-2015], Cid, Maria Cinta [0000-0002-4730-0938], Gonzalez-Gay, Miguel Angel [0000-0002-7924-7406], Martin, Javier [0000-0002-2202-0622], Marquez, Ana [0000-0001-9913-7688], Apollo - University of Cambridge Repository, and Ortiz-Fernandez L., Carmona E. G., Kerick M., Lyons P., Carmona F. D., Mejias R. L., Khor C. C., Grayson P. C., Tombetti E., Jiang L., et al.

Subjects
Internal Diseases, Vasculitis, Immunology, Autoimmunity, SUSCEPTIBILITY, VARIANTS, Sağlık Bilimleri, İmmünoloji ve Romatoloji, İç Hastalıkları, Clinical Medicine (MED), General Biochemistry, Genetics and Molecular Biology, Immunology and Rheumatology, ACTIVATION, Genetic, Rheumatology, Health Sciences, Humans, Immunology and Allergy, Klinik Tıp (MED), CTLA-4 Antigen, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, ROMATOLOJİ, Internal Medicine Sciences, Polymorphism, Genetic, Klinik Tıp, Systemic Vasculitis, Drug Repositioning, Dahili Tıp Bilimleri, CLINICAL MEDICINE, Tıp, Medicine, Romatoloji, Apoptosis Regulatory Proteins
Abstract

Objectives The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. Methods Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. Results Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. Conclusions We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis., HELICAL Innovative Training Network, European Commission funded-under the Marie Sklodowska-Curie 813545, Cooperative Research Thematic Network programme RD16/0012/0013, Redes de Investigacion Cooperativa Orientadas a Resultados en Salud (RICORS) RD21/0002/0039, Instituto de Salud Carlos III PI18/00040, Juan de la Cierva Incorporacion fellowship IJC2019- 040746-I, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA, NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) R01 AR070148, National Health and Medical Research Council (NHMRC) of Australia GTN1175744, Victorian Government's Operational Infrastructure Support Program, Rare Diseases Clinical Research Network (RDCRN), initiative of the Office of Rare Diseases Research (ORDR), NIH National Center for Advancing Translational Sciences (NCATS), NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) U54 AR057319, NIH National Center for Research Resources (NCRR) U54 RR019497

Published
2023

46. The Effect of Body Fat Distribution on Systemic Sclerosis

Author

Gonzalo Villanueva-Martin, Marialbert Acosta-Herrera, Martin Kerick, Elena López-Isac, Carmen P. Simeón, José L. Callejas, Shervin Assassi, Lorenzo Beretta, International SSc Group, Australian Scleroderma Interest Group (ASIG), Yannick Allanore, Susanna M. Proudman, Mandana Nikpour, Carmen Fonseca, Christopher P. Denton, Timothy R. D. J. Radstake, Maureen D. Mayes, Xia Jiang, Javier Martin, Lara Bossini-Castillo, Institut Català de la Salut, [Villanueva-Martin G, Kerick M, López-Isac E] Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. [Acosta-Herrera M] Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs, Granada, Spain. [Simeón CP] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Callejas JL] Department of Internal Medicine, Hospital San Cecilio, Granada, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
obesity, systemic sclerosis, mendelian randomization, Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], Esclerosi sistemàtica progressiva, Obesitat, Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Overweight::Obesity [DISEASES], General Medicine, afecciones patológicas, signos y síntomas::signos y síntomas::peso corporal::sobrepeso::obesidad [ENFERMEDADES], enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES]
Abstract

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genomewide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc., MCIN/AEI RTI2018101332-B-100 IJC2018-038026-I IJC2019-040080-I PRE2019-087586, "ERDF A way of making Europe" - European Union, Red de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013, ESF Investing in your future

Published
2022

47. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Author

Kerick, Martin, Acosta-Herrera, Marialbert, Simeón-Aznar, Carmen Pilar, Callejas, José Luis, Assassi, Shervin, International SSc Group, Proudman, Susanna M, Nikpour, Mandana, Australian Scleroderma Interest Group (ASIG), PRECISESADS Clinical Consortium, Hunzelmann, Nicolas, Moroncini, Gianluca, de Vries-Bouwstra, Jeska K, Orozco, Gisela, Barton, Anne, Herrick, Ariane L, Terao, Chikashi, Allanore, Yannick, Fonseca, Carmen, Alarcón-Riquelme, Marta Eugenia, Radstake, Timothy R D J, Beretta, Lorenzo, Denton, Christopher P, Mayes, Maureen D, Martin, Javier, Institut Català de la Salut, [Kerick M] Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. [Acosta-Herrera M] Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain. [Simeón-Aznar CP] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Callejas JL] Department of Internal Medicine, Hospital San Cecilio, Granada, Spain. [Assassi S] Department of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA, Vall d'Hebron Barcelona Hospital Campus, Rheumatology, and AII - Inflammatory diseases

Subjects
Otros calificadores::Otros calificadores::/genética [Otros calificadores], Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], Genetics, Other subheadings::Other subheadings::/genetics [Other subheadings], Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Esclerosi sistemàtica progressiva - Aspectes genètics, Genetic Phenomena::Genetic Phenomena::Genetic Structures::Transcriptome [PHENOMENA AND PROCESSES], Molecular Biology, Expressió gènica, enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES], Genetics (clinical), fenómenos genéticos::expresión génica [FENÓMENOS Y PROCESOS]
Abstract

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals., MCIN/AEI by "ERDF A way of making Europe" RTI2018101332-B-100, Red de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013, Innovative Medicines Initiative 1 & 2 Joint Undertaking (JU) 115565 831434, European Union's FP7 and Horizon 2020 research and innovation programs, EFPIA, Juan de la Cierva Incorporacion program - MCIN/AEI IJC2018-035131-I

Published
2022
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48. GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

Author

Desiré Casares-Marfil, Martin Kerick, Eduardo Andrés-León, Pau Bosch-Nicolau, Israel Molina, Chagas Genetics CYTED Network, Javier Martin, Marialbert Acosta-Herrera, Institut Català de la Salut, [Casares-Marfil D, Kerick M, Andrés-León E, Chagas Genetics CYTED Network] Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. [Bosch-Nicolau P, Molina I] Unitat de Medicina Tropical i Salud Internacional, Vall d’Hebron Hospital Universitari, Barcelona, Spain. PROSICS, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Chagas Cardiomyopathy, Male, Single Nucleotide Polymorphisms, RC955-962, Genome-wide association study, Cardiovascular Medicine, Biochemistry, fenómenos químicos::fenómenos bioquímicos::alquilación::metilación::metilación del ADN [FENÓMENOS Y PROCESOS], Medical Conditions, Arctic medicine. Tropical medicine, Medicine and Health Sciences, Genetics, DNA methylation, Chemical Reactions, ADN - Metilació, Genomics, Methylation, Middle Aged, Chemical Phenomena::Biochemical Phenomena::Alkylation::Methylation::DNA Methylation [PHENOMENA AND PROCESSES], Chromatin, Nucleic acids, Chemistry, Infectious Diseases, Cardiovascular Diseases, Physical Sciences, Phospholipases A2, Calcium-Independent, Epigenetics, Female, Public aspects of medicine, RA1-1270, Cardiomyopathies, DNA modification, Chromatin modification, Research Article, Neglected Tropical Diseases, Chromosome biology, Adult, Cell biology, Chagas, Malaltia de, Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Quantitative Trait Loci, Cardiology, Miocardi - Malalties, Single-nucleotide polymorphism, Locus (genetics), Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Parasitic Diseases::Protozoan Infections::Euglenozoa Infections::Trypanosomiasis::Chagas Disease::Chagas Cardiomyopathy [DISEASES], Parasitic Diseases, Genome-Wide Association Studies, Humans, Chagas Disease, Aged, Genetic association, Protozoan Infections, Tumor Suppressor Proteins, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Computational Biology, dNaM, Human Genetics, DNA, enfermedades parasitarias::infecciones por protozoos::infecciones por Euglenozoa::tripanosomiasis::enfermedad de Chagas::miocardiopatía chagásica [ENFERMEDADES], Tropical Diseases, Genome Analysis, DNA Polymerase I, Repressor Proteins, Genetic Loci, Genetics of Disease, técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Gene expression, Carrier Proteins, Genome-Wide Association Study
Abstract

A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) levels as cis methylation quantitative trait loci (cis-mQTL) within this region. A total of 2,611 SNPs were tested against 2,647 DNAm sites, in a subset of 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals from the GWAS. We identified 6,958 significant cis-mQTLs (False Discovery Rate [FDR], Author summary Genome-wide association studies (GWAS) have provided extensive information regarding the genetic component of complex traits, including parasitic diseases such as Chagas disease. However, these associations mapped in regulatory regions of the genome and assigning them a functional consequence have been cumbersome. In this study we aimed to evaluate the functional mechanism underlying the previously reported genomic association with chronic Chagas cardiomyopathy, by assessing the correlation between methylation changes and the underlying genetic variations within the region. These methylation quantitative trait loci (mQTLs) may be involved in gene expression regulation. We identified mQTLs in three genes that have been associated with cardiovascular diseases in previous studies. Interestingly, one of these genes was previously identified as differentially methylated and expressed in heart biopsies of chronic Chagas cardiomyopathy patients. Our results suggest novel genes that could play a role in the chronic Chagas cardiomyopathy, evidencing the functional relevance of the previously associated loci.

Published
2021

49. Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Author

Acosta-Herrera, Marialbert, Kerick, Martin, Lopéz-Isac, Elena, Assassi, Shervin, Beretta, Lorenzo, Simeón-Aznar, Carmen Pilar, Ortego-Centeno, Norberto, International SSc Group, Proudman, Susanna M, Australian Scleroderma Interest Group (ASIG), Hunzelmann, Nicolas, Moroncini, Gianluca, de Vries-Bouwstra, Jeska K, Orozco, Gisela, Barton, Anne, Herrick, Ariane L, Terao, Chikashi, Allanore, Yannick, Brown, Matthew A, Radstake, Timothy Rdj, Fonseca, Carmen, Denton, Christopher P, Mayes, Maureen D, Martin, Javier, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, National Institutes of Health (US), Manchester Biomedical Research Centre, Universidad de Cantabria, Institut Català de la Salut, [Acosta-Herrera M, Kerick M, Lopéz-Isac E] Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain. [Assassi S] Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA. [Beretta L] Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy. [Simeón-Aznar CP] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, autoantibodies, systemic sclerosis, Immunology, Locus (genetics), Single-nucleotide polymorphism, Human leukocyte antigen, Major histocompatibility complex, General Biochemistry, Genetics and Molecular Biology, polymorphism, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, Antígens HLA, Rheumatology, Polymorphism (computer science), Other subheadings::Other subheadings::/immunology [Other subheadings], Immunology and Allergy, Medicine, Humans, Genetic Predisposition to Disease, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], Allele, skin and connective tissue diseases, Alleles, 030203 arthritis & rheumatology, Skin and Connective Tissue Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Scleroderma, Systemic [DISEASES], Scleroderma, Systemic, Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Histocompatibility Antigens Class II [CHEMICALS AND DRUGS], biology, immune complex diseases, business.industry, enfermedades de la piel y tejido conjuntivo::enfermedades de la piel y tejido conjuntivo::enfermedades de la piel::esclerodermia sistémica [ENFERMEDADES], Autoantibody, 030104 developmental biology, biology.protein, Esclerosi sistemàtica progressiva, genetic, Immunogenètica, business, Immune complex disease, aminoácidos, péptidos y proteínas::proteínas::glicoproteínas::glicoproteínas de membranas::antígenos de histocompatibilidad de clase II [COMPUESTOS QUÍMICOS Y DROGAS], Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression., This work was supported by the Spanish Ministry of Science and Innovation (grant ref. SAF2015-66761-P and RTI20181013 (32-B-100)), Red de Investigación en Inflamación y Enfermedades Reumáticas from Instituto de Salud Carlos III (RD16/0012/0013) and grants from National Institutes of Health (R01AR073284) and DoD (W81XWH-16-1-0296). MAH was funded by the Spanish Ministry of Science and Innovation through the Juan de la Cierva Incorporacion program (ref. IJC2018-035131-I). GO, AB and ALH were supported by the NIHR Manchester Biomedical Research Centre and Versus Arthritis (grant ref 21754)

Published
2021

50. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Author

Teruel, María, Barturen, Guillermo, Martínez Bueno, Manuel, Castellini Pérez, Olivia, Barroso Gil, Miguel, Povedano, Elena, Kerick, Martin, Català Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Beretta, Lorenzo, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Rodriguez Maresca, Manuel, López Berrio, Antonio, Aguilar Quesada, Rocío, Navarro Linares, Héctor, Alvarez, Montserrat, Álvarez Errico, Damiana, Azevedo, Nancy, Barbarroja, Nuria, Cheng, Qingyu, Cremer, Jonathan, Groof, Aurélie de, Langhe, Ellen de, Ducreux, Julie, Dufour, Aleksandra, Hernández Fuentes, María, Khodadadi, Laleh, Kniesch, Katja, Li, Tianlu, López Pedrera, Chary, Marañón, Concepción, Muchmore, Brian, Neves, Esmeralda, Rouvière, Bénédicte, Simon, Quentin, Trombetta, Elena, Varela, Nieves, Witte, Torsten, Pers, Jacques-olivier, Ballestar, Esteban, Martin, Javier, Carnero Montoro, Elena, Alarcón Riquelme, Marta, Precisesads Clinical Consortium, Precisesads Flow Cytometry Study Group, Vigone, Barbara, Pers, Jacques Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Maudoux, Anne-lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Ángel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Rodríguez Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega Castro, Rafaela, Aguirre Zamorano, Mª Angeles, Escudero Contreras, Alejandro, Castro Villegas, Mª Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, Ramon, Enrique de, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Study Group, [Teruel,M, Barturen,G, Martínez-Bueno,M, Castellini-Pérez,O, Barroso-Gil,M, Povedano,E, Marañón,C, Carnero-Montoro,E, Alarcón-Riquelme,ME] GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain. [Kerick,M, Martin,J] IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científcas, Granada, Spain. [Català-Moll,F, Ballestar,E] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain. [Català-Moll,F, Ballestar,E] IDIBELL, Bellvitge Biomedical Research Institute L’Hospitalet de Llobregat, Barcelona, Spain. [Makowska,Z, Buttgereit,A] Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Pers,JO] Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France.[Alarcón-Riquelme,ME] Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden., and Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.

Subjects
Epigenomics, Male, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Autoimmune diseases, Gene Expression, Quantitative trait, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings], 0302 clinical medicine, Rheumatic diseases, HLA Antigens, Genetics, Regulation of gene expression, 0303 health sciences, education.field_of_study, Multidisciplinary, Malalties autoimmunitàries, Molecular medicine, Epigenetic, Autoanticuerpos, Genomics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings], 3. Good health, Sjogren's Syndrome, DNA methylation, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings], Medicine, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings], Epigenetics, Female, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Extracellular matrix organization, Science, Population, Check Tags::Male [Medical Subject Headings], Human leukocyte antigen, Biology, Variación genética, Article, 03 medical and health sciences, Rheumatology, Enfermedades autoinmunes, Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings], Immunogenetics, Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid::Sjogren's Syndrome [Medical Subject Headings], Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [Medical Subject Headings], education, Gene, 030304 developmental biology, Autoantibodies, 030203 arthritis & rheumatology, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], Genetic Variation, DNA Methylation, Epigenètica, Check Tags::Female [Medical Subject Headings], Gene Expression Regulation, Epigenómica, Síndrome de Sjögren, Interferons, Expresión génica
Abstract

Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support., Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population., Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565, EFPIA companies, Junta de Andalucia PI/0017/2016, Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme, EFPIA, Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652

Published
2021

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