Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.
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.
Davila
Sonia
S
Infectious Diseases, Genome Institute of Singapore, Singapore. sonia@gis.a-star.edu.sg
Wright
Victoria J
VJ
Khor
Chiea Chuen
CC
Sim
Kar Seng
KS
Binder
Alexander
A
Breunis
Willemijn B
WB
Inwald
David
D
Nadel
Simon
S
Betts
Helen
H
Carrol
Enitan D
ED
de Groot
Ronald
R
Hermans
Peter W M
PW
Hazelzet
Jan
J
Emonts
Marieke
M
Lim
Chui Chin
CC
Kuijpers
Taco W
TW
Martinon-Torres
Federico
F
Salas
Antonio
A
Zenz
Werner
W
Levin
Michael
M
Hibberd
Martin L
ML
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
D017242:Complement Factor H