title: Polymorphisms in chemokine receptor 5 and Toll-like receptor 3 genes are risk factors for clinical tick-borne encephalitis in the Lithuanian population.
abstract: BACKGROUND
  Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups.
  
  
  METHODS
  117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models.
  
  
  RESULTS
  The prevalence of CCR5Δ32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (p<0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively).
  
  
  CONCLUSIONS
  Independently of age, nonfunctional CCR5Δ32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms in susceptibility to TBEV infection.
authors.affiliation: Department of Infectious Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania; Unit for Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Auksė
authors.initials: A
authors.lastname: Mickienė
authors.affiliation: Department of Infectious Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Jolita
authors.initials: J
authors.lastname: Pakalnienė
authors.affiliation: Division of Molecular Virology, Medical Faculty, Linköping University, Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Nordgren
authors.affiliation: Division of Molecular Virology, Medical Faculty, Linköping University, Linköping, Sweden.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Carlsson
authors.affiliation: Division of Molecular Virology, Medical Faculty, Linköping University, Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Hagbom
authors.affiliation: Division of Molecular Virology, Medical Faculty, Linköping University, Linköping, Sweden; Department of Clinical Microbiology, Linköping University Hospital, Linköping, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.affiliation: Unit for Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lindquist
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D004675:Encephalitis, Tick-Borne / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008097:Lithuania; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D051193:Toll-Like Receptors / Q000235:genetics*
chemical_list: D019713:Receptors, CCR5; D051193:Toll-Like Receptors