In mouse models the severity of influenza infection is clearly associated with both the pathogen and host genome. The observation that similar patterns of susceptibility or resistance of specific mouse strains are observed for a wide range of influenza viruses suggests that some of the host genetic determinants of susceptibility may be common across influenza subtypes. Susceptibility in mice is polygenic, and a number of candidate genes, including MxA, have been proposed. To date none of these candidate genes have been tested in studies of humans. Animal experiments will continue to be important for refining understanding of host-pathogen genetic interactions and for testing hypotheses about the pathogenesis of severe influenza.
In humans the best available evidence, relying on a single study of 4855 deaths, suggests a heritable component of susceptibility to death from seasonal and pandemic influenza. Given the numerous confounding factors, replication of this finding will require a similarly large study. Although heritability has not been quantified for H5N1, the marked familial aggregation and other epidemiological features suggest a stronger heritable predisposition. To date only one study of human host genetics and susceptibility to severe influenza has been published and no human genetic polymorphisms associated with susceptibility to seasonal, pandemic or avian influenza have been convincingly demonstrated.
Susceptibility to severe seasonal or pandemic influenza in humans is likely to be polygenic and is also likely to be co-determined by pathogen characteristics, prior infection history, co-morbidities, and environmental factors. In addition, the lack of evidence implicating any specific genes in humans suggests a hypothesis-free genome-wide approach should be taken. As such, very large studies will be required to identify genetic effects on susceptibility to severe influenza.
Pandemic H1N1 offers a rare opportunity to study genetic susceptibility to severe influenza in a context that, compared to seasonal influenza, is less confounded by infection history and pathogen diversity. However, large sample sizes will still be required to detect polygenic traits and case selection will need to consider confounding by cross-protective immunity and co-morbidity. Several groups have compiled series of severe H1N1/09 cases but it seems very unlikely that any single group will have sufficient cases to conduct an adequately powered genome-wide association study 
. To have a realistic prospect of identifying susceptibility loci for H1N1/09, groups will need to form a consortium, as has been successful for other diseases 
. The chances of identifying susceptibility loci in H1N1/09 can be enhanced by adopting an ‘extreme-trait’ study design e.g. where cases are previously healthy young adults who develop very severe disease with high viral loads and no evidence of bacterial co-infection. Influenza encephalitis is another ‘extreme-trait’ where case cohorts should be assembled for comparison with other influenza disease cohorts. There may still be possibilities to study susceptibility to 1918 pandemic influenza through linkage studies within large genealogical cohorts, where pedigree and cause of death data stretch back to the early 1900’s 
Susceptibility to H5N1 may be less complex than ‘human influenza’, since the phenotype appears to be more dichotomous than continuous, immunity probably plays a lesser role, co-morbidity seems less important, and familial aggregation is more marked. The importance of understanding the pathogenesis of highly pathogenic influenza and the possibility that a rare genetic variant with a moderate to large effect underlies H5N1 susceptibility makes efforts to assemble DNA from H5N1 cases worthwhile. Given the small number of H5N1 cases and the possibility of a rare variant with a moderate to large effect, genome-wide association studies may not be the optimal design and alternative approaches to identifying causal loci may be needed, such as sequencing candidate genes, the whole exome, or the even whole genome 
. Purely epidemiological studies may contribute to understanding the genetic component of familial aggregation of H5N1 by quantifying heritability.
High viral replication efficiency, or from a host perspective a failure to control virus replication, is emerging as a key factor in severe influenza disease and is determined by both host and virus factors 
. Thus studies of the determinants of influenza severity may benefit from a combined host-pathogen genetics approach, where the analysis of host genetic associations is conditioned upon the pathogen genotype in order to identify genotype-genotype interactions.
The fundamental question ‘Is susceptibility to severe influenza in humans heritable?’remains unanswered. It is 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.