Dengue fever and dengue hemorrhagic fever are mosquito-borne viral diseases. Dendritic cell–specific ICAM-3 grabbing nonintegrin (DC-SIGN1, encoded by CD209), an attachment receptor of dengue virus, is essential for productive infection of dendritic cells1,2. Here, we report strong association between a promoter variant of CD209, DCSIGN1-336, and risk of dengue fever compared with dengue hemorrhagic fever or population controls. The G allele of the variant DCSIGN1-336 was associated with strong protection against dengue fever in three independent cohorts from Thailand, with a carrier frequency of 4.7% in individuals with dengue fever compared with 22.4% in individuals with dengue hemorrhagic fever (odds ratio for risk of dengue hemorrhagic fever versus dengue fever: 5.84, P = 1.4 × 10−7) and 19.5% in controls (odds ratio for protection: 4.90, P = 2 × 10−6). This variant affects an Sp1-like binding site and transcriptional activity in vitro. These results indicate that CD209 has a crucial role in dengue pathogenesis, which discriminates between severe dengue fever and dengue hemorrhagic fever. This may have consequences for therapeutic and preventive strategies.
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We thank A. Chunharas, P. Kitpoka and A. Chairunsri for help in recruiting affected individuals and controls and L. Damrikarnlerd and S. Swasdiworn for managing the clinical database. This work was supported by the Senior Research Scholarship Program of the Thailand Research Fund (P.M.), the Thailand Tropical Disease Research Program T2 (P.M.), the Thailand National Center for Genetic Engineering and Biotechnology (P.M., P.Y. and N.T.), Mahidol University (A.S.), the Thailand SNP Discovery Program (T.L.), the Direction Générale pour l'Armement (P.D.), the Medical Scholar Program, Mahidol University and the Split Mode PhD program (S.M.K.), and the Royal Golden Jubilee Program, the Thailand Research Fund and the French Embassy of Thailand (C.T.).
The authors declare no competing financial interests.
Linkage disequilibrium between SNPs in CD209 and flanking genes CLEC4M (CD209L) and CLEC4G (LSECtin). (PDF 385 kb)
Populations studied. (PDF 53 kb)
Description of CD209 polymorphisms. (PDF 98 kb)
Haplotypes constructed from the five SNPs in LD with DCSIGN1-336 and their frequencies. (PDF 46 kb)
Description of CLEC4G (LSECtin) and CLEC4M (CD209L) polymorphisms. (PDF 90 kb)
Sequencing primers for CD209, CLEC4M (CD209L) and CLEC4G (LSECtin). (PDF 80 kb)
PCR-RFLP genotyping and PCR gel electrophoresis assays. (PDF 49 kb)
TaqMan genotyping assays. (PDF 31 kb)
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Sakuntabhai, A., Turbpaiboon, C., Casadémont, I. et al. A variant in the CD209 promoter is associated with severity of dengue disease. Nat Genet 37, 507–513 (2005). https://doi.org/10.1038/ng1550
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