Background: We examined associations between SNPs (single-nucleotide-polymorphisms) of IFITM3, TLR3, and CD55 genes and influenza clinical outcomes in Chinese patients.

Methods: A multicenter-study was conducted on 275 adult cases of prospectively-diagnosed H7N9 and H1N1pdm09 infections. Host DNA was extracted from diagnostic respiratory samples; IFITM3 rs12252, TLR3 rs5743313, CD55 rs2564978, and TLR4 rs4986790/4986791 were targeted for genotyping by Sanger-sequencing. The primary outcome analyzed was death.

Results: IFITM3 and TLR3 SNPs were in Hardy-Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of the homozygous IFITM3 CC (54.5% vs 33.2%, P=0.02) and TLR3 CC (93.3% vs 76.9%, P=0.04) genotypes among fatal influenza cases. Recessive genetic models showed their significant associations with higher death risks (aHR 2.78, 95%CI1.29-6.02, and aHR 4.85, 95%CI1.11-21.06 respectively; confounders adjusted). Cumulative effects were found (aHR 3.53, 95%CI1.64-7.59 per risk-genotype; aHR 9.99, 95%CI1.27-78.59 with both). Results were consistent for each influenza subtype and other severity indicators. The CD55 TT genotype was linked to severity. TLR4 was non-polymorphic.

Conclusion: Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings may pose important implications on disease burden, healthcare planning, patient care, and design of clinical trials in at-risk populations.