title: The role of host genetics in susceptibility to influenza: a systematic review.
abstract: BACKGROUND
  The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).
  
  
  RESULTS
  PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.
  
  
  CONCLUSIONS
  The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.
authors.affiliation: Oxford University Clinical Research Unit-Wellcome Trust Major Overseas Programme, Hanoi, Vietnam. peter.horby@gmail.com
authors.forename: Peter
authors.initials: P
authors.lastname: Horby
authors.forename: Nhu Y
authors.initials: NY
authors.lastname: Nguyen
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dunstan
authors.forename: J Kenneth
authors.initials: JK
authors.lastname: Baillie
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D000818:Animals; D001717:Birds; D004195:Disease Models, Animal; D005190:Family; D019204:GTP-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D005585:Influenza in Birds / Q000235:genetics; D007251:Influenza, Human / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D064547:Myxovirus Resistance Proteins; D013045:Species Specificity
chemical_list: D000017:ABO Blood-Group System; D006680:HLA Antigens; C579071:MX1 protein, human; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D019204:GTP-Binding Proteins