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1. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, Norberto, Radstake, Timothy R.D.J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, Javier, Márquez, Ana, Assassi, Shervin, Zhou, Xiaodong, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Gorlova, Olga, Chen, Wei V., Ying, Jun, Gregersen, Peter K., Lee, Annette T., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Broen, Jasper, Koeleman, Bobby P.C., Simeón, Carmen P., Fonollosa, Vicente, Guillén, Alfredo, Carreira, Patricia, Castellví, Iván, González-Gay, Miguel A., Ríos, Raquel, Callejas-Rubio, Jose Luis, Vargas-Hitos, José A., García-Portales, Rosa, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Aguirre, Ma Ángeles, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Fernández-Gutiérrez, Benjamín, de la Peña, Paloma García, Vicente, Esther, Andreu, José Luis, Fernández de Castro, Mónica, López-Longo, Francisco Javier, Martínez, Lina, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Rodríguez-Carballeira, Mónica, Narváez, Francisco Javier, Rubio-Rivas, Manel, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Fanlo-Mateo, Patricia, Sáez-Comet, Luis, Díaz-González, Federico, Hernández, Vanesa, Beltrán, Emma, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco-García, Francisco J., Oreiro, Natividad, Freire, Mayka, Balsa, Alejandro, Ortiz, Ana M., Hunzelmann, Nicolas, Riemekasten, Gabriela, Distler, Jörg H.W., Witte, Torsten, Airó, Paolo, Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), Rheumatology, AII - Inflammatory diseases, Julià, Antonio [0000-0001-6064-3620], Franke, Andre [0000-0003-1530-5811], Mayes, Maureen D [0000-0001-5070-2535], Apollo - University of Cambridge Repository, Mayes, Maureen D. [0000-0001-5070-2535], and Universidad de Cantabria

Subjects
0301 basic medicine, Male, Settore MED/09 - Medicina Interna, 692/699/249/2510, 45/43, Gene Expression, lcsh:Medicine, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Disease, Inflammatory diseases, SLC22A5, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, medicine, Humans, Genetic Predisposition to Disease, Allele, lcsh:Science, Genetic association, 030203 arthritis & rheumatology, Genetics, Crohn's disease, Multidisciplinary, Scleroderma, Systemic, 45, biology, lcsh:R, article, medicine.disease, digestive system diseases, 3. Good health, Settore MED/16 - Reumatologia, 030104 developmental biology, Risk factors, Genetic Loci, Case-Control Studies, biology.protein, Female, lcsh:Q, 692/499, Genome-Wide Association Study
Abstract

We thank Sofia Vargas and Gema Robledo for her excellent technical assistance and all the patients and control donors for their essential collaboration. We thank WTCCC (Welcome Trust Case Control Consortium) for the access to GWAS data of Crohn’s disease patients and healthy controls, Banco Nacional de ADN (University of Salamanca, Spain) who supplied part of the control DNA samples, and dbGap for granting access to the IBD Genetics Consortium (IBDGC) Crohn’s Disease GWAS data (phs000130.v1.p1). The IBDGC Crohn’s Disease Genome-Wide Association Study was conducted by the IBDGC Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This manuscript was not prepared in collaboration with Investigators of the IBDGC Crohn’s Disease Genome-Wide Association Study and does not necessarily reflect the opinions or views of the IBDGC Crohn’s Disease Genome-Wide Association Study, the NIDDK Central Repositories, or the NIDDK., Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases., This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-66761-P; IPT-010000-2010-36, cofunded by the European Regional Development Fund), Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) (P12-BIO-1395) and the Cooperative Research Thematic Network (RETICS) programme (RD16/0012/0013) (RIER) from Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy, Industry and Competitiveness). AM is recipient of a Miguel Servet fellowship (CP17/00008) from ISCIII (Spanish Ministry of Economy, Industry and Competitiveness). DGS was supported by the Spanish Ministry of Economy and Competitiveness through the FPI programme (SAF2015-66761-P). This work is part of the Doctoral Thesis “Bases Genéticas de la Esclerosis Sistémica: Integrando Genómica y Transcriptómica”.

Published
2020

2. A Genome-Wide Association Study Identifies rs116199914 As an Intergenic Variant Associated with Carotid Intima-Media Thickness in Spanish Patients with Rheumatoid Arthritis

Author

López-Mejías, Raquel, Genre, Fernanda, Remuzgo-Martínez, Sara, Carmona, David, Pulito-Cueto, Verónica, González-Juanatey, Carlos, Corrales, Alfonso, Vicente, Esther, Miranda-Filloy, J. A., Segura Tejera, Beatriz, Ramírez Huaranga, Marco A., Mijares, Verónica, Lera-Gómez, Leticia, Blanco, Ricardo, Robustillo-Villarino, Montserrat, Rodríguez-Carrio, Javier, Suárez, Ana, Alperi-López, Mercedes, Ballina García, Francisco Javier, López Longo, Francisco Javier, Narváez, Francisco Javier, Alegre, Juan José, Mera, Antonio, Perez Pampín, Eva, González, Antonio, Raya Álvarez, Enrique, López-Pedrera, Chary, Gómez Vaquero, Carmen, Balsa, Alejandro, Pascual-Salcedo, Dora, Carreira, P., González-Álvaro, Isidoro, Rodríguez Rodríguez, Luis, Fernández Gutiérrez, Benjamín, Ferraz-Amaro, Iván, Castañeda, Santos, Martín, J., Llorca, Javier, and González-Gay, M. A.

Published
2018

3. Comorbidities in Patients With Primary Sjögren's Syndrome and Systemic Lupus Erythematosus: A Comparative Registries-Based Study

Author

Rúa-Figueroa, Iñigo, Fernández Castro, Mónica, Andreu, José L, Sanchez-Piedra, Carlos, Martínez-Taboada, Víctor, Olivé, Alejandro, López-Longo, Javier, Rosas, José, Galindo, María, Calvo-Alén, Jaime, Fernández-Nebro, Antonio, Alonso, Fernando, Rodríguez-Lozano, Beatriz, Alberto García Vadillo, Jesús, Menor, Raúl, Narváez, Francisco Javier, Erausquin, Celia, García-Aparicio, Ángel, Tomero, Eva, Manrique-Arija, Sara, Horcada, Loreto, Uriarte, Esther, Gil, Susana, Blanco, Ricardo, López-González, Ruth, Boteanu, Alina, Freire, Mercedes, Galisteo, Carlos, Rodríguez-Gómez, Manuel, Díez-Álvarez, Elvira, Pego-Reigosa, José M, and Sjogrenser and Relesser Researchers and EAS-SER Group

Subjects
Adult, Male, Comorbidity, Middle Aged, Cohort Studies, Cross-Sectional Studies, Sjogren's Syndrome, Cardiovascular Diseases, Prevalence, Humans, Lupus Erythematosus, Systemic, Female, Registries, Aged
Abstract

To compare the prevalence of the main comorbidities in 2 large cohorts of patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), with a focus on cardiovascular (CV) diseases. This was a cross-sectional multicenter study where the prevalence of more relevant comorbidities in 2 cohorts was compared. Patients under followup from SJOGRENSER (Spanish Rheumatology Society Registry of Primary SS) and RELESSER (Spanish Rheumatology Society Registry of SLE), and who fulfilled the 2002 American-European Consensus Group and 1997 American College of Rheumatology classification criteria, respectively, were included. A binomial logistic regression analysis was carried out to explore potential differences, making general adjustments for age, sex, and disease duration and specific adjustments for each variable, including CV risk factors and treatments, when appropriate. A total of 437 primary SS patients (95% female) and 2,926 SLE patients (89% female) were included. The mean age was 58.6 years (interquartile range [IQR] 50.0-69.9 years) for primary SS patients and 45.1 years (IQR 36.4-56.3 years) for SLE patients (P Primary SS patients have a consistently less serious CV comorbidity burden and a lower prevalence of severe infection than those with SLE. In contrast, their risk of lymphoma is greater.

Published
2016

4. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author

López-Isac, Elena, Martín, Jose Ezequiel, Assassi, Shervin, Simeón, Carmen P., Carreira, Patricia, Ortego-Centeno, Norberto, Freire, Mayka, Beltrán, Emma, Narváez, Javier, Alegre-Sancho, Juan J., Fernández-Gutiérrez, Benjamín, Balsa, Alejandro, Ortiz, Ana M., González-Gay, Miguel A., Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, Jörg H W, Riekemasten, Gabriella, van der Helm-van Mil, Annette H., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Øyvind, Merriman, Tony, Hesselstrand, Roger, Nordin, Annika, Padyukov, Leonid, Herrick, Ariane, Eyre, Steve, Koeleman, Bobby P C, Denton, Christopher P., Fonseca, Carmen, Radstake, Timothy R D J, Worthington, Jane, Mayes, Maureen D., Martín, Javier, Ríos, Raquel, Callejas, Jose Luis, Hitos, José Antonio Vargas, Portales, Rosa García, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Ángeles Aguirre, Ma, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Peña, Paloma García de la, Vicente, Esther, Andreu, José Luis, de Castro, Mónica Fernández, López-Longo, Francisco Javier, Martínez, Lina, Fonollosa, Vicente, Guillén, Alfredo, Castellví, Iván, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Carballeira, Mónica Rodríguez, Narváez, Francisco Javier, Rivas, Manel Rubio, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Mateo, Patricia Fanlo, Sáez-Comet, Luis, Díaz, Federico, Hernández, Vanesa, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco García, Francisco J., and Oreiro, Natividad

Subjects
Rheumatology, Immunology, Journal Article, Immunology and Allergy, skin and connective tissue diseases
Abstract

Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P

Published
2016

5. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, Norberto, Radstake, Timothy R. D. J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, Javier, Márquez, Ana, Assassi, Shervin, Zhou, Xiaodong, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Gorlova, Olga, Chen, Wei V., Ying, Jun, Gregersen, Peter K., Lee, Annette T., Voskuyl, Alexandre E., De Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Broen, Jasper, Koeleman, Bobby P. C., Simeón, Carmen P., Fonollosa, Vicente, Guillén, Alfredo, Carreira, Patricia, Castellví, Iván, González-Gay, Miguel A., Ríos, Raquel, Callejas-Rubio, Jose Luis, Vargas-Hitos, José A., García-Portales, Rosa, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma. Jesús, Aguirre, Ma. Ángeles, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Fernández-Gutiérrez, Benjamín, De La Peña, Paloma García, Vicente, Esther, Andreu, José Luis, Fernández De Castro, Mónica, López-Longo, Francisco Javier, Martínez, Lina, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Rodríguez-Carballeira, Mónica, Narváez, Francisco Javier, Rubio-Rivas, Manel, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Fanlo-Mateo, Patricia, Sáez-Comet, Luis, Díaz-González, Federico, Hernández, Vanesa, Beltrán, Emma, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco-García, Francisco J., Oreiro, Natividad, Freire, Mayka, Balsa, Alejandro, Ortiz, Ana M., Hunzelmann, Nicolas, Riemekasten, Gabriela, Distler, Jörg H. W., Witte, Torsten, Airó, Paolo, Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, and Gabrielli, Armando

Subjects
45, 692/699/249/2510, 45/43, article, 692/499, 3. Good health
Abstract

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

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