JAK2 Genetic Variation Associated with Susceptibility to Severe A(H1N1) Influenza

Abstract

Abstract Background JAK2 plays a key role in cytokine signaling. Genetic variation in JAK2 may affect the severity of influenza. We sought to identify single nucleotide polymorphisms (SNPs) close to JAK2 associated with the development of severe A(H1N1) influenza. Methods A pilot genome wide association study (GWAS) of A(H1N1) influenza harvested 15 highly linked SNPs of JAK2 that were differentially distributed in severe cases and mild controls. Four SNPs, including a promoter SNP rs1887429 and its high linkage disequilibrium (LD) SNP rs7034539 (R2 = 0.49 in Asian population), as well as other two high LD SNPs (rs17425819 and rs7850484; R2 = 0.88) associated with JAK2 expression in Chinese lymphoblastoid cell lines (n = 45), were validated in an extension cohort (n = 343). The mechanisms underlying these associations were determined by functional experiments. Results The four SNPs of JAK2 were significantly associated with the severe influenza in both pooled analysis (n = 463) and meta-analysis (all p-values < 0.01). A potential functional enhancer harboring one SNP rs59384377 and an indel rs527982744 (-/19T-repeat) were identified to be in high LD to rs17425819 and rs7850484, and was predicted to regulate the promoter activity of JAK2. Reporter gene luciferase assay demonstrated that rs59384377 and rs527982744 encoded regulatory polymorphisms for the enhancer activity. Furthermore, JAK2 expression was upregulated by A(H1N1) virus infection, and the inhibition of JAK2 by the inhibitor NVP-BSK805 attenuated the A(H1N1) virus-triggered induction of IP-10 and IL-8. In conclusion, the genetic association study together with molecular and cellular experiments support JAK2 as an important factor in the pathogenesis of severe A(H1N1) influenza.