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Microbes and Infection 11 (2009) 143e156 www.elsevier.com/locate/micinf

Review

Human genetic determinants of dengue virus susceptibility
Lark L. Coffey a,*,1, Eva Mertens a, Anne-Claire Brehin a, Maria Dolores Fernandez-Garcia b, ´ Ali Amara b, Philippe Despres a, Anavaj Sakuntabhai c
Unite des Interactions Moleculaires Flavivirus-Hotes, Institut Pasteur, 75724 Paris, France ´ ´ ˆ b Unitede Pathogenie Virale INSERM U819, Institut Pasteur, 75724 Paris, France ´ ´ c Genetique de la reponse aux infections chez l’homme, Institut Pasteur, 75724 Paris, France ´ ´ ´ Received 2 June 2008; accepted 5 December 2008 Available online 24 December 2008
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Abstract Dengue virus (DENV) is an emerging mosquito-borne pathogen that produces significant morbidity worldwide resulting in anestimated 50e 100 million infections annually. DENV causes a spectrum of illness ranging from inapparent infection to life-threatening hemorrhagic fever and shock. The varied DENV disease outcome is determined by complex interactions between immunopathologic, viral, and human genetic factors. This review summarizes these interactions with a focus on human genetic determinants of DENV susceptibility,including human leukocyte antigens, blood type, and single nucleotide polymorphisms in immune response genes that have been associated with DENV disease. We also discuss other factors related to DENV outcome including viral genetic determinants, age, ethnicity, and nutritional status as they relate to DENV susceptibility. We emphasize the need for functional genetics studies to complementassociation-based data and we call for controlled study designs and standard clinical DENV disease definitions that will strengthen conclusions based on human genetic DENV studies. Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords: Dengue virus; Arbovirus; Human genetic susceptibility; Single nucleotide polymorphism; Dengue hemorrhagic fever

1. Introduction Inherited determinants of diseasesusceptibility have been recognized since the early 20th century when scientists observed that individuals differ in their responses to the malaria

Abbreviations: ADE, antibody dependent enhancement; DC-SIGN, dendritic cell specific ICAM-3 grabbing nonintegrin; DENV, dengue virus; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; HLA, human leukocyte antigen; HPA, humanplatelet antigen; IFN, interferon; MHC, major histocompatibility complex; OAS, oligoadenylate synthetase; PAI, plasminiogen activator inhibitor; SNP, single nucleotide polymorphism; TAP, transporter associated with antigen processing; TGF, transforming growth factor; TNF, tumor necrosis factor; VDR, vitamin D receptor; WHO, World Health Organization; WNV, West Nile virus. * Corresponding author. þ33 (0)1 45 68 80 00x3486. E-mail address: lark.coffey@pasteur.fr (L.L. Coffey). 1 ` Present address: Populations Virales et Pathogenese, Institut Pasteur, 75724 Paris, France. 1286-4579/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.micinf.2008.12.006

parasite or Mycobacterium tuberculosis. Traditionally, adopted, twin, ethnic, or family cohorts have been used tostudy genetic epidemiology of infectious diseases. The post-genomic era has produced new tools for studying disease susceptibility, including high throughput molecular typing or blind association studies to identify candidate genes. Complementary functional genetics approaches using cloned human DNA serve to validate genetic determinants of phenotype identified via association studies. Theseapplications are revolutionizing studies on human genetic susceptibility. Despite these advances, the human genetic determinants of disease susceptibility to most pathogens, including many viruses, are poorly defined. Dengue virus (DENV) is an emerging mosquito-borne arbovirus that infects approximately 50e100 million people annually. DENV has been reported in >100 countries and can potentially expand...