David Constant
Gene 210, Spring 2012
SNPedia writeup
rs11208534 is a polymorphism within intron 3 of the Janus-activated kinase (JAK1) gene
on human chromosome 1. This SNP is reported by dbSNP as having A (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 developing severe symptoms upon
infection with dengue virus. Symptoms of dengue infection vary widely in severity, and
are classified by 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 flulike 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 (http://www.who.int/csr/disease/dengue/en/index.html).
A correlation was found between rs11208534 and 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) and C (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 rs11208534 and 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 SNPs in 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