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Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.

Hise AG, Traylor Z, Hall NB, Sutherland LJ, Dahir S, Ermler ME, Muiruri S, Muchiri EM, Kazura JW, LaBeaud AD, King CH, Stein CM - PLoS Negl Trop Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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.

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Related in: MedlinePlus

Map of the study area in Northeastern Province, Kenya.Shown are the locations of the Ijara District and, in the inset, the relative locations of the participating study villages in the Sangailu area of Kenya.
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pntd.0003584.g001: Map of the study area in Northeastern Province, Kenya.Shown are the locations of the Ijara District and, in the inset, the relative locations of the participating study villages in the Sangailu area of Kenya.

Mentions: Study participants were recruited from six villages located in the Sangailu area of Ijara District, located in Northeastern Province, Kenya (Fig. 1). All local residents were eligible for participation, with the exception of those living in the area for less than 2 years, and children < 1 year of age, who were excluded. After an initial demographic census was performed, consented subjects were enrolled, surveyed via structured interview for potential RVFV exposure history and past symptoms suggestive of RVF, and examined by a nursing officer with particular attention to current visual acuity and eye disease, as previously described [10,59]. Whole blood was collected by phlebotomy (∼ 5 mL venous blood samples from persons > 5 years of age and 1 mL from children under the age of 5). Individual sera and associated blood clots were separated and stored frozen at −80°C.


Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.

Hise AG, Traylor Z, Hall NB, Sutherland LJ, Dahir S, Ermler ME, Muiruri S, Muchiri EM, Kazura JW, LaBeaud AD, King CH, Stein CM - PLoS Negl Trop Dis (2015)

Map of the study area in Northeastern Province, Kenya.Shown are the locations of the Ijara District and, in the inset, the relative locations of the participating study villages in the Sangailu area of Kenya.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355584&req=5

pntd.0003584.g001: Map of the study area in Northeastern Province, Kenya.Shown are the locations of the Ijara District and, in the inset, the relative locations of the participating study villages in the Sangailu area of Kenya.
Mentions: Study participants were recruited from six villages located in the Sangailu area of Ijara District, located in Northeastern Province, Kenya (Fig. 1). All local residents were eligible for participation, with the exception of those living in the area for less than 2 years, and children < 1 year of age, who were excluded. After an initial demographic census was performed, consented subjects were enrolled, surveyed via structured interview for potential RVFV exposure history and past symptoms suggestive of RVF, and examined by a nursing officer with particular attention to current visual acuity and eye disease, as previously described [10,59]. Whole blood was collected by phlebotomy (∼ 5 mL venous blood samples from persons > 5 years of age and 1 mL from children under the age of 5). Individual sera and associated blood clots were separated and stored frozen at −80°C.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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.

Show MeSH
Related in: MedlinePlus