Genetic risk for dengue hemorrhagic fever and dengue fever in multiple ancestries
Guillaume Pare,
Binod Neupane,
Sasha Eskandarian,
Eva Harris,
Scott Halstead,
Lionel Gresh,
Guillermina Kuan,
Angel Balmaseda,
Luis Villar,
Elsa Rojas,
Jorge E. Osorio,
Dang Duc Anh,
Aruna Dharshan De Silva,
Sunil Premawansa,
Gayani Premawansa,
Ananda Wijewickrama,
Ivette Lorenzana,
Leda Parham,
Cynthia Rodriguez,
Ildefonso Fernandez-Salas,
Rosa Sanchez-Casas,
Esteban E. Diaz-Gonzalez,
Khin Saw Aye,
Win Lai May,
Min Thein,
Filemon Bucardo,
Yaoska Reyes,
Patricia Blandon,
Kenji Hirayama,
Lan Weiss,
Pardeep Singh,
Jennifer Newton,
Mark Loeb
Affiliations
Guillaume Pare
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada; Department of Health Research, Methods, Evidence, and Impact, Canada
Binod Neupane
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada
Sasha Eskandarian
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada
Eva Harris
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, United States
Scott Halstead
Department of Preventive Medicine and Biometrics, Uniformed University of the Health Sciences, Bethesda, MD, United States
Lionel Gresh
Sustainable Sciences Institute, Managua, Nicaragua
Guillermina Kuan
Health Center Sócrates Flores Vivas, Ministry of Health, Managua, Nicaragua
Angel Balmaseda
Sustainable Sciences Institute, Managua, Nicaragua; Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministry of Health, Managua, Nicaragua
Luis Villar
Clinical Epidemiology Unit, Universidad Industrial de Santander, Bucaramanga, Colombia
Elsa Rojas
Centro de Atención y Diagnóstico de Enfermedades Infecciosas, Bucaramanga, Colombia
Jorge E. Osorio
University of Wisconsin, Wisconsin, United States
Dang Duc Anh
National Institute of Hygiene and Epidemiology, Hanoi, Vietnam
Aruna Dharshan De Silva
Genetech Research Institute, Sri Lanka
Sunil Premawansa
Department of Zoology and Environmental Sciences, University of Colombo, Sri Lanka
Gayani Premawansa
Genetech Research Institute, Sri Lanka
Ananda Wijewickrama
Genetech Research Institute, Sri Lanka
Ivette Lorenzana
Department of National Autonomous University of Honduras, Tegucigalpa, Honduras
Leda Parham
Department of National Autonomous University of Honduras, Tegucigalpa, Honduras
Cynthia Rodriguez
Department of National Autonomous University of Honduras, Tegucigalpa, Honduras
Ildefonso Fernandez-Salas
Universidad Autonoma de Nuevo Leon, Mexico
Rosa Sanchez-Casas
Universidad Autonoma de Nuevo Leon, Mexico
Esteban E. Diaz-Gonzalez
Universidad Autonoma de Nuevo Leon, Mexico
Khin Saw Aye
Medical Research, Ministry of Health, Myanmar
Win Lai May
Medical Research, Ministry of Health, Myanmar
Min Thein
Medical Research, Ministry of Health, Myanmar
Filemon Bucardo
The Faculty of Medical Sciences at the National Autonomous University of León, Nicaragua
Yaoska Reyes
The Faculty of Medical Sciences at the National Autonomous University of León, Nicaragua
Patricia Blandon
The Faculty of Medical Sciences at the National Autonomous University of León, Nicaragua
Kenji Hirayama
Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagaski, Japan
Lan Weiss
Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagaski, Japan; Department of Immunology and Microbiology, Pasteur Institute, Ho Chi Minh City, Vietnam
Pardeep Singh
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada
Jennifer Newton
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada
Mark Loeb
Department of Pathology and Molecular Medicine, McMaster University, Ontario L8N 3Z5, Canada; Department of Health Research, Methods, Evidence, and Impact, Canada; Institute for Infectious Diseases Research, McMaster University Hamilton, Canada; Corresponding author at: Department of Pathology and Molecular Medicine, McMaster University Hamilton, Ontario L8N 3Z5, Canada.
Background: Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations. Methods: We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls. Findings: The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other. Interpretation: There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries. Keywords: Dengue, Genetics, Risk, GWAS, Ancestry
