title: Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.
abstract: Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D<E), P = 2.2 x 10(-11)) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 x 10(-13)). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H-binding protein (fHbp). Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.
authors.affiliation: Infectious Diseases, Genome Institute of Singapore, Singapore. sonia@gis.a-star.edu.sg
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.forename: Kar Seng
authors.initials: KS
authors.lastname: Sim
authors.forename: Alexander
authors.initials: A
authors.lastname: Binder
authors.forename: Willemijn B
authors.initials: WB
authors.lastname: Breunis
authors.forename: David
authors.initials: D
authors.lastname: Inwald
authors.forename: Simon
authors.initials: S
authors.lastname: Nadel
authors.forename: Helen
authors.initials: H
authors.lastname: Betts
authors.forename: Enitan D
authors.initials: ED
authors.lastname: Carrol
authors.forename: Ronald
authors.initials: R
authors.lastname: de Groot
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Jan
authors.initials: J
authors.lastname: Hazelzet
authors.forename: Marieke
authors.initials: M
authors.lastname: Emonts
authors.forename: Chui Chin
authors.initials: CC
authors.lastname: Lim
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Federico
authors.initials: F
authors.lastname: Martinon-Torres
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.forename: Werner
authors.initials: W
authors.lastname: Zenz
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008589:Meningococcal Infections / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D009345:Neisseria meningitidis / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D017242:Complement Factor H