David Constant
Gene 210, Spring 2012
SNPediawriteup
rs11208534 is a polymorphism withinintron 3 of the Janus-activated kinase (JAK1) gene on human chromosome 1. This SNP is reported by dbSNP as havingA (ancestral) and G alleles, with a minor allele frequency of 19.2% (dbSNP). JAK1 is a membrane-associated protein-tyrosine kinase involved in the interferon-alpha/beta and –gamma pathways, which are important for immune responses to pathogens.
Activation of JAK-family proteins occurs after binding of interferons to cell-surface receptors, and results in tyrosine phosphorylation of members of the STAT (signal transducer and activator of transcription) protein family, inducing the expression of many other genes involved in diverse biological processes including various antiviral responses [PMID:15864272].
This SNP has been associated with increased risk of developingsevere symptoms upon infection with dengue virus. Symptoms of dengue infection vary widely in severity, andare classifiedby the WHO (listed in order of increasing severity) as undifferentiated fever, dengue fever (DF), dengue hemorrhagic fever (DHF) and severe hypovolemic shock, or dengue shock syndrome (DSS).DF commonly includes high fever, general flu-like symptoms, and sometimes severe bleeding. DHF is characterized by high fever, major hemorrhaging, circulatory failure, and extremely low blood platelet counts and if untreated can progress to DSS (
A correlation was found between rs11208534and the development of symptoms consistent with DHF in a 2010 study in Brazil of individuals seropositive for dengue virus[PMID:20588308]. The top hit out of 728 SNPs in 56 genes predicted to be involved in a cellular response to viral infection was rs11208534, for which the authors report T (major) andC (minor) alleles of rs11208534, not A and G as on dbSNP. Cases (n = 50) were recruited from patients with DHF-like symptoms by active hospital surveillance in the city of Salvador, Brazil. Controls (n = 236) who had experienced symptoms of DF, but not DHF, were recruited from families living within 1 kilometer of index cases, and were matched in age categories under and over 15 years. The association between rs11208534and DHF (P-value 2.9x10-4; OR 5.2 (95% CI 2.1-12.7) just failed to reach the Bonferroni-corrected significance threshold of 2.6x10-4 by itself, but when combined with two other highly linked SNPsin the JAK1 gene region, rs310196 and rs2780831 (D’ 0.856 and 1.0 to rs11208534 respectively),the association reached significance with a P-value of 2.1x10-4.
This study provides evidence that polymorphisms in the JAK1 gene, including this one, may provide differential susceptibility to dengue virus infection, and likely other viruses as well.
[PMID: 20588308] Dengue hemorrhagic fever is associated with polymorphisms in JAK1
[PMID:15864272]Mechanisms of type-I- and type-II-interferon-mediated signalling