title: A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans.
abstract: During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.
authors.affiliation: Division of Immunology, Children's Hospital Boston, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: María Belén
authors.initials: MB
authors.lastname: Eyheramonho
authors.forename: Muriel
authors.initials: M
authors.lastname: Pichavant
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez Cambaceres
authors.forename: Ponpan
authors.initials: P
authors.lastname: Matangkasombut
authors.forename: Guillermo
authors.initials: G
authors.lastname: Cervio
authors.forename: Silvina
authors.initials: S
authors.lastname: Kuperman
authors.forename: Rita
authors.initials: R
authors.lastname: Moreiro
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Konduru
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Manangeeswaran
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Kaplan
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
mesh_terms: D001118:Argentina; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006506:Hepatitis A / Q000276:immunology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D030041:Hepatitis A virus / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000821:virology; D008107:Liver Diseases / Q000821:virology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D011991:Receptors, Virus / Q000235:genetics* / Q000502:physiology*; D012306:Risk
chemical_list: C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D011991:Receptors, Virus