A variant in the CD209 promoter is associated with severity of dengue disease - PubMed (original) (raw)

doi: 10.1038/ng1550. Epub 2005 Apr 17.

Chairat Turbpaiboon, Isabelle Casadémont, Ampaiwan Chuansumrit, Tassanee Lowhnoo, Anna Kajaste-Rudnitski, Sita Mint Kalayanarooj, Kanchana Tangnararatchakit, Nattaya Tangthawornchaikul, Sirijit Vasanawathana, Wathanee Chaiyaratana, Pa-Thai Yenchitsomanus, Prapat Suriyaphol, Panisadee Avirutnan, Kulkanya Chokephaibulkit, Fumihiko Matsuda, Sutee Yoksan, Yves Jacob, G Mark Lathrop, Prida Malasit, Philippe Desprès, Cécile Julier

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A variant in the CD209 promoter is associated with severity of dengue disease

Anavaj Sakuntabhai et al. Nat Genet. 2005 May.

Abstract

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 cells. 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 x 10(-7)) and 19.5% in controls (odds ratio for protection: 4.90, P = 2 x 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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. LD between CD209 polymorphisms in the Thai population.

Δ values for SNPs with rare allele frequency ≥0.02.

Figure 2

Figure 2. Effects of the DCSIGN1-336 polymorphism on transcriptional activity.

(a) EMSAs with 32P-labeled probes containing the −336G variant, the −336A variant, the Sp1 consensus site or the AP2 consensus site and HeLa cell nuclear extract. Competition experiments were done in the presence of a tenfold excess of unlabeled Sp1 or AP2 probe. (b) Quantification of the major oligonucleotide-nuclear protein complex (filled arrowhead in panel a). Competition with unlabeled Sp1 consensus probe showed a threefold decrease in binding to the −336G probe, but no significant decrease in binding to the −336A probe. The AP2 consensus probe showed slight and similar competition to both probes. (c,d) Luciferase expression of reporter gene constructs expressing sequence from −472 to −1 in transfected HeLa cells. (c) Schematic representation of reporter gene constructs containing the CD209 promoter region with the DCSIGN1-336 polymorphism. (d) Relative luciferase expression from pGL3-Basic, the parental vector without promoter. Luciferase expression from the CD209 reporters relative to this value is shown.

References

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