title: Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.
abstract: Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Nada
authors.identifier: 0000-0002-8200-347X
authors.initials: N
authors.lastname: Abdelmagid
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Biborka
authors.initials: B
authors.lastname: Bereczky-Veress
authors.affiliation: Division of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Santosh
authors.initials: S
authors.lastname: Atanur
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Musilová
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.affiliation: Department of Pharmacology, University of Colorado, Denver School of Medicine, Denver, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Saba
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnecke
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Studahl
authors.affiliation: Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Aurelius
authors.affiliation: Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hjalmarsson
authors.affiliation: Division of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Garcia-Diaz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France.
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.affiliation: Department of Clinical Virology, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Bergström
authors.affiliation: Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sköldenberg
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Division of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Aitman
authors.affiliation: Max-Delbruck-Center for Molecular Medicine, Berlin-Buch, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Margarita
authors.initials: M
authors.lastname: Diez
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D020803:Encephalitis, Herpes Simplex / Q000235:genetics*; D060005:Genotyping Techniques; D018259:Herpesvirus 1, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D051381:Rats; D011918:Rats, Inbred SHR; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D014841:von Willebrand Factor