title: Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.
abstract: BACKGROUND
  Multiple recent outbreaks of Rift Valley Fever (RVF) in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/or ophthalmitis with residual retinal scarring, but the determinants for severe disease are not understood. The aim of the present study was to identify human genes associated with RVF clinical disease in a high-risk population in Northeastern Province, Kenya.
  
  
  RESULTS
  We conducted a cross-sectional survey among residents (N = 1,080; 1-85 yrs) in 6 villages in the Sangailu Division of Ijara District. Participants completed questionnaires on past symptoms and exposures, physical exam, vision testing, and blood collection. Single nucleotide polymorphism (SNP) genotyping was performed on a subset of individuals who reported past clinical symptoms consistent with RVF and unrelated subjects. Four symptom clusters were defined: meningoencephalitis, hemorrhagic fever, eye disease, and RVF-not otherwise specified. SNPs in 46 viral sensing and response genes were investigated. Association was analyzed between SNP genotype, serology and RVF symptom clusters. The meningoencephalitis symptom phenotype cluster among seropositive patients was associated with polymorphisms in DDX58/RIG-I and TLR8. Having three or more RVF-related symptoms was significantly associated with polymorphisms in TICAM1/TRIF, MAVS, IFNAR1 and DDX58/RIG-I. SNPs significantly associated with eye disease included three different polymorphisms TLR8 and hemorrhagic fever symptoms associated with TLR3, TLR7, TLR8 and MyD88.
  
  
  CONCLUSIONS
  Of the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe symptomatology, suggesting that these genes may have a robust association with RVFV-associated clinical outcomes. Studies of these and related genetic polymorphisms are warranted to advance understanding of RVF pathogenesis.
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Traylor
authors.affiliation: Division of Vector-Borne and Neglected Tropical Diseases, Ministry of Public Health and Sanitation, Nairobi, Kenya.
authors.forename: Noémi B
authors.initials: NB
authors.lastname: Hall
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sutherland
authors.affiliation: Division of Vector-Borne and Neglected Tropical Diseases, Ministry of Public Health and Sanitation, Nairobi, Kenya.
authors.forename: Saidi
authors.initials: S
authors.lastname: Dahir
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Ermler
authors.affiliation: Division of Vector-Borne and Neglected Tropical Diseases, Ministry of Public Health and Sanitation, Nairobi, Kenya.
authors.forename: Samuel
authors.initials: S
authors.lastname: Muiruri
authors.affiliation: Division of Vector-Borne and Neglected Tropical Diseases, Ministry of Public Health and Sanitation, Nairobi, Kenya.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Muchiri
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Kazura
authors.affiliation: Division of Pediatric Infectious Diseases, UCSF Benioff Children's Hospital Oakland, Children's Hospital Oakland Research Institute, Oakland, California, United States of America; Department of Pediatrics, Stanford University, Department of Pediatrics, Stanford, California, United States of America.
authors.forename: A Desirée
authors.initials: AD
authors.lastname: LaBeaud
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Charles H
authors.initials: CH
authors.lastname: King
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Stein
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012295:Rift Valley Fever / Q000235:genetics* / Q000276:immunology*; D012296:Rift Valley fever virus / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics; D055815:Young Adult
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3