Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies
Martinón-Torres F., Png E., Khor CC., Davila S., Wright VJ., Sim KS., Vega A., Fachal L., Inwald D., Nadel S., Carrol ED., Martinón-Torres N., Alonso SM., Carracedo A., Morteruel E., López-Bayón J., Torre AC., Monge CC., De Aguilar PAG., Torné EE., Martínez-Padilla MDC., Martinón-Sánchez JM., Levin M., Hibberd ML., Salas A., Gómez-Carballa A., Cebey M., Sánchez NG., Calle IR., Grande AJ., Pardo-Seco J., Barral-Arca R., Pischedda S., Currás-Tuala MJ., Rodriguez-Tenreiro C., Redondo-Collazo L., Sánchez FP., De La Cruz Moreno J., Millán Miralles ML., García Rodríguez JL., García SR., Doce AH., Barba Á., Pallares MO., Romero AR., Muñoz Bonet JI., Cancela MS., Bergara EO., Arriortua AB., Navarro Gómez ML., Fernández MS., Martínez XA., Ortega Á., Rosso SP., Caballero Macarrón CP., Menchón NM., Sánchez FG., Garzón MGR., García MDMB., Sánchez Granados JM., Ayestarán OS., Payo R., Palazón SC., León León MC., Dominguez SR.
© 2016 The Author(s).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.