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Research Project: Intervention Strategies to Prevent and Control Crimean-Congo Hemorrhagic Fever (CCHF)

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Title: Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Author
item KOTLIAR, DYLAN - Broad Institute Of Mit/harvard
item RAJU, SIDDHARTH - Broad Institute Of Mit/harvard
item TABRIZI, SHERVIN - Broad Institute Of Mit/harvard
item ODIA, IKPONMWOSA - Irrua Specialist Teaching Hospital
item GOBA, AUGUSTINE - University Of Sierra Leone
item MOMOH, MAMBU - University Of Sierra Leone
item SANDI, JOHN DEMBY - University Of Sierra Leone
item NARI, PARVATHY - Howard Hughes Medical Institute
item PHELAN, ERIC - Prospr At Work, Inc
item TARIYAL, RIDHI - Consultant
item EROMON, PHILOMENA - Irrua Specialist Teaching Hospital
item MEHTA, SAMAR - University Of Maryland
item ROBLES-SIKISAKA, REFUGIO - Scripps Institute
item SIDDLE, KATHERINE - Broad Institute Of Mit/harvard
item Hensley, Lisa

Submitted to: Nature Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/14/2023
Publication Date: 2/7/2024
Citation: Kotliar, D., Raju, S., Tabrizi, S., Odia, I., Goba, A., Momoh, M., Sandi, J., Nari, P., Phelan, E., Tariyal, R., Eromon, P.E., Mehta, S., Robles-Sikisaka, R., Siddle, K.J., Hensley, L.E. et al. 2024. Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever. Nature Microbiology. 9:751-762. https://doi.org/10.1038/s41564-023-01589-3.
DOI: https://doi.org/10.1038/s41564-023-01589-3

Interpretive Summary: This paper investigates if differences in human genes may influence the severity of Lassa Fever virus. The study looked at persons living in Nigeria and Sierra Leone, two areas where tcases of Lassa fever are routinely seen each year. The work identified several genes that may play a role in the severity of disease. The data also suggested that there is a selection for changes in the human genes that may impact disease severity.

Technical Abstract: Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.