title: Host genetic risk factors for West Nile virus infection and disease progression.
abstract: West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, United States of America. awb150@u.washington.edu
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.forename: Sofia
authors.initials: S
authors.lastname: Husain
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Bofferding
authors.forename: Heidi
authors.initials: H
authors.lastname: Gildersleeve
authors.forename: Ann
authors.initials: A
authors.lastname: Rutherford
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Astakhova
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Perelygin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Busch
authors.forename: Kristy O
authors.initials: KO
authors.lastname: Murray
authors.forename: James J
authors.initials: JJ
authors.lastname: Sejvar
authors.forename: Sharone
authors.initials: S
authors.lastname: Green
authors.forename: John
authors.initials: J
authors.lastname: Kriesel
authors.forename: Margo A
authors.initials: MA
authors.lastname: Brinton
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014901:West Nile Fever / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D064547:Myxovirus Resistance Proteins; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins