부산대학교 도서관

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. Methodology/Principal Findings: 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/Significance: 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. Author Summary: The underlying risk factors that lead to severe human Rift Valley Fever disease are unknown, but are likely multi-factorial. Host factors, such as innate immune genetic makeup, are likely important determinants of disease phenotype. This study investigated the association of 46 single nucleotide polymorphisms (SNPs) in genes encoding innate immune receptors, signaling pathways or mediators with RVF disease phenotype. Of the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe RVF symptomatology, suggesting that these genes may have a robust association with RVFV-associated clinical outcomes. [ABSTRACT FROM AUTHOR]