Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies
Authors: Martinón-Torres Federico , Png Eileen , Khor Chiea Chuen , Davila Sonia , Wright Victoria J. , Sim Kar Seng , Vega Ana , Fachal Laura , Inwald David , Nadel Simon , Carrol Enitan D. , Martinón-Torres Nazareth , Alonso Sonia Marcos , Carracedo Angel , Morteruel Elvira , López-Bayón Julio , Torre Andrés Concha , Monge Cristina Calvo , de Aguilar Pilar Azcón González , Torné Elisabeth Esteban , Martínez-Padilla María del Carmen , Martinón-Sánchez José María , Levin Michael , Hibberd Martin L. , Salas Antonio ,   ESIGEM network, Gómez-Carballa Alberto , Cebey Miriam , Sánchez Natalia García , Calle Irene Rivero , Grande Antonio Justicia , Pardo-Seco Jacobo , Barral-Arca Ruth , Pischedda Sara , Currás-Tuala María-José , Rodriguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Sánchez Fernanda Pardo , de la Cruz Moreno Jesús , Millán Miralles Mª. Leticia , García Rodríguez José Luis , García Susana Rey , Doce Ana Hurtado , Barba Ángela Ferrer , Pallares Manuel Ortiz , Romero Alfredo Reparaz , Muñoz Bonet Juan Ignacio , Cancela Manuel Silveira , Bergara Eider Oñate , Arriortua Amaya Bustinza , Navarro Gómez María Luisa , Fernández Mario Sánchez , Martínez Xavier Allué , Ortega Álvaro Castellanos , Rosso Servando Pantoja , Caballero Macarrón César Pérez , Menchón Natalia Molini , Sánchez Francisco Giménez , Garzón Manuel González-Ripoll , García María del Mar Ballesteros , Sánchez Granados José Manuel , Ayestarán Olga Serrano , Payo Roman , Palazón Sonia Cañadas , León León Maria Cruz , Dominguez Susana Reyes , Villanueba David Arjona , Alonso Martín J. Antonio , Orayen Concepción Goñi , Iturbe Enrique Bernaola , Alonso Salas María Teresa , Fernández Isabel Quintela ,   ESPID meningococcal consortium – UK, Booy Robert , Coin Lachlan J. M. , Eleftherohorinou Hariklia , Faust Saul , Galassini Rachel , Habibi Parviz , Haralambous Elene , Kroll Simon , Langford Paul , Pathan Nazima , Pollard Andrew J. ,   EUCLIDS consortium members - Imperial College London (www.euclids-project.eu), Abdulla Farhana , Agapow Paul , Bellos Evangelos , Hamilton Shea , Herberg Jethro A. , Hoggart Clive , Kaforou Myrsini , Mashbat Meg , Mustafa Sobia , Sancho-Shimizu Vanessa 
Published: November 2016

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.