Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies.
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.
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
Federico
F
Martinón-Torres
Infectious Diseases, Genome Institute of Singapore, Singapore.
Eileen
E
Png
Human Genetics, Genome Institute of Singapore, Singapore.
Chiea Chuen
CC
Khor
Human Genetics, Genome Institute of Singapore, Singapore.
Sonia
S
Davila
Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, UK.
Victoria J
VJ
Wright
Human Genetics, Genome Institute of Singapore, Singapore.
Kar Seng
KS
Sim
Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Instituto de Investigaciones Sanitarias (IDIS), and Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.
Ana
A
Vega
Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Instituto de Investigaciones Sanitarias (IDIS), and Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.
Laura
L
Fachal
Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, UK.
David
D
Inwald
Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, UK.
Simon
S
Nadel
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
Enitan D
ED
Carrol
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
Nazareth
N
Martinón-Torres
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
Sonia Marcos
SM
Alonso
Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Instituto de Investigaciones Sanitarias (IDIS), and Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPop Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Clínico Universitario de Santiago, Galicia, Spain.|Center of Excellence in Genomic Medicine Research, King Abdulaziaz University, Jeddah, Saudi Arabia.
Angel
A
Carracedo
Unidad de Cuidados Intensivos Pediátricos (UCIP), Hospital de Cruces, Bilbao, Spain.
Elvira
E
Morteruel
Unidad de Cuidados Intensivos Pediátricos (UCIP), Hospital de Cruces, Bilbao, Spain.
Julio
J
López-Bayón
Unidad de Cuidados Intensivos Pediátricos (UCIP), Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
Andrés Concha
AC
Torre
Servicio de Pediatría, Hospital de Donostia, San Sebastián, Spain.
Cristina Calvo
CC
Monge
Unidad de Cuidados Intensivos Pediátricos (UCIP), Hospital Virgen de las Nieves de Granada, Granada, Spain.
Pilar Azcón González
PA
de Aguilar
Unidad de Cuidados Intensivos Pediátricos, Hospital Sant Joan de Deu, Barcelona, Spain.
Elisabeth Esteban
EE
Torné
Unidad de Cuidados Intensivos Pediátricos, Complejo Hospitalario de Jaen, Spain.
María Del Carmen
MD
Martínez-Padilla
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
José María
JM
Martinón-Sánchez
Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, UK.
Michael
M
Levin
Infectious Diseases, Genome Institute of Singapore, Singapore.
Martin L
ML
Hibberd
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.|Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPop Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Clínico Universitario de Santiago, Galicia, Spain.
Antonio
A
Salas
D017242:Complement Factor H / Q000235:genetics*; D016208:Databases, Factual; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D008589:Meningococcal Infections / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D013030:Spain; D044465:White People / Q000235:genetics
D017242:Complement Factor H