DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation.
BACKGROUND
the C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells, and a single nucleotide polymorphism (SNP) in the promoter region of CD209 (-336 A/G; rs4804803) is susceptible to many infectious diseases. We reason that variations in the DC-SIGN gene might have a broad influence on viral replication and host immune responses.


RESULTS
we studied whether the rs4804803 SNP was associated with a susceptibility to dengue fever (DF) and/or dengue hemorrhagic fever (DHF) through genotyping analysis in a Taiwanese cohort. We generated monocyte-derived dendritic cells (MDDCs) from individuals with AA or AG genotype of rs4804803 to study the viral replication and immune responses for functional validation. A total of 574 DNA samples were genotyped, including 176 DF, 135 DHF, 143 other non-dengue febrile illnesses (OFI) and 120 population controls. A strong association between GG/AG genotypes of rs4804803 and risk of DHF was found when compared among DF, OFI and controls (p = 0.004, 3×10(-5) and 0.001, respectively). The AA genotype was associated with protection against dengue infection compared with OFI and controls (p = 0.002 and 0.020, respectively). Moreover, MDDCs from individuals with AG genotype with a higher cell surface DC-SIGN expression had a significantly higher TNFα, IL-12p40, and IP-10 production than those with AA genotype in response to dengue infection. However, the viral replication in MDDCs with AG genotype was significantly lower than those with AA genotype. With both genotypes, MDDCs revealed an increase in viral replication following the addition of anti-IP-10 neutralizing antibody.


CONCLUSIONS
the rs4804803 SNP in the CD209 promoter contributed to susceptibility to dengue infection and complication of DHF. This SNP with AG genotype affects the cell surface DC-SIGN expression related to immune augmentation and less viral replication.
Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center (CGMH-KMC), Kaohsiung, Taiwan.
Lin
L
Wang
Rong-Fu
RF
Chen
Jien-Wei
JW
Liu
Ing-Kit
IK
Lee
Chiu-Ping
CP
Lee
Ho-Chang
HC
Kuo
Shau-Ku
SK
Huang
Kuender D
KD
Yang
D000328:Adult; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000821:virology; D003716:Dengue Virus / Q000472:pathogenicity; D004198:Disease Susceptibility; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D019595:Severe Dengue / Q000276:immunology* / Q000473:pathology*; D013624:Taiwan; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014779:Virus Replication; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D054357:Chemokine CXCL10; D053762:Interleukin-12 Subunit p40; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C114753:CXCL10 protein, human
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