Background: Knowledge of the human genetic contribution to the risk of complications from influenza is limited. This study assessed the association between human single-nucleotide polymorphisms (SNPs) and disease progression in individuals with influenza.

Methods: A targeted analysis of 10 SNPs with prior evidence in COVID-19 and a genome-wide association study (GWAS) were used to assess associations between SNPs and disease progression in two multinational cohorts with suspected or laboratory-confirmed influenza: a hospitalized cohort (n = 1634) and a pooled cohort of hospitalized and outpatients (n = 3469). Disease progression was defined as prolonged hospitalization (> 28 days), progression to mechanical ventilation, admittance to intensive care unit, or death (for hospitalized individuals) or progression to hospitalization or death (for outpatients).

Results: Disease progression was observed in 9.1% of hospitalized patients and 2.2% of outpatients. Age was a significant risk factor for disease progression, with 20% increased odds of disease progression per 10-year increase in age (OR: 1.20, 95%CI: 1.08-1.33, p < 0.001). Disease progression rates also differed by continent (p < 0.0001). Targeted SNP analyses did not identify significant associations with disease progression; however, the strength of associations was most pronounced in sensitivity analyses for the pooled cohort in individuals < 65 years old. GWAS analyses did not identify significant common SNP associations in either the hospitalized or pooled cohorts, nor in sensitivity analysis of (1) individuals with laboratory-confirmed influenza and (2) those aged < 65 years.

Conclusion: In a geographically diverse cohort of individuals with influenza, the genetic links to disease progression only started to become evident in the sensitivity analyses, mainly when looking at younger individuals. The power to detect associations was limited by the rate of disease progression and heterogeneity in phenotypes of the individuals studied, and therefore, additional studies focused on the role of genetics in influenza disease progression are needed.