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Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

2016; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/srep35842

2045-2322

Federico Martinón‐Torres, Eileen Png, Chiea Chuen Khor, Sonia Dávila, Victoria Wright, Kar Seng Sim, Ana Vega, Laura Fachal, David Inwald, Simon Nadel, Enitan D. Carrol, Federico Martinón‐Torres, Sonia Marcos Alonso, Ángel Carracedo, Elvira Morteruel, J. López Bayón, Andrés Concha, Cristina Calvo Monge, Pilar Azcón González de Aguilar, Elisabeth Esteban, María del Carmen Martínez‐Padilla, José María Martinón‐Sánchez, Michael Levin, Martin L. Hibberd, Antonio Salas, Alberto Gómez‐Carballa, Miriam Cebey‐López, Natalia García Sánchez, Irene Rivero‐Calle, Antonio Justicia Grande, Jacobo Pardo‐Seco, Ruth Barral‐Arca, Sara Pischedda, María José Currás-Tuala, Carmen Rodrı́guez-Tenreiro, Lorenzo Redondo-Collazo, Fernanda Pardo Sánchez, Jesús de la Cruz Moreno, Ma. Leticia Millán Miralles, José Luis García García, Susana Rey García, Ana Hurtado Doce, Armando Bautista Barba, Manuel Ortiz Pallares, Alfredo Reparaz Romero, J.I. Muñoz Bonet, Manuel Silveira Cancela, Eider Oñate Bergara, A. Bustinza Arriortúa, María Luisa Navarro Gómez, Mario Sánchez Fernández, Xavier Allué Martínez, Álvaro Castellanos-Ortega, S Rosso, C. Pérez Caballero Macarrón, N. Molini Menchón, F. Giménez Sánchez, Manuel González-Ripoll Garzón, María del Mar Ballesteros García, José Manuel Sánchez Granados, Olga Serrano Ayestarán, Roman Payo, Sonia Cañadas, Maria Cruz León León, Susana Reyes, David Arjona Villanueba, J. Antonio Alonso Martín, Concepción Goñi Orayen, E. Bernaola Iturbe, María Teresa Alonso Salas, Isabel Quintela Fernández, Robert Booy, Lachlan Coin, Hariklia Eleftherohorinou, Saul N. Faust, Rachel Galassini, Parviz Habibi, Elene Haralambous, Simon Kroll, Paul R. Langford, Nazima Pathan, Andrew J. Pollard, Farhana Abdulla, Paul‐Michael Agapow, Evangelos Bellos, Shea Hamilton, Jethro Herberg, Clive Hoggart, Myrsini Kaforou, Meg Mashbat, Sobia Mustafa, Vanessa Sancho‐Shimizu,

Genetics and Neurodevelopmental Disorders

Abstract Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association ( P -value ≤ 5 × 10 −8 ) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52–0.73; P -value = 9.62 × 10 −9 ). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55–0.76, P-value = 3.25 × 10 −8 ). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.