Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, FIOCRUZ, Avenida Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Brazil.
Infect Genet Evol. 2013 Dec;20:197-205. doi: 10.1016/j.meegid.2013.08.017. Epub 2013 Sep 7.
Dengue is an arthropod-borne emerging viral disease with high morbidity and mortality risk in tropical countries like Brazil. Clinical manifestations are vast, ranging from asymptomatic to most severe forms of dengue such as shock. Previous data have shown that host genetics play a role in disease susceptibility and severity. Herein, we have tested the association of single nucleotide polymorphisms (SNPs) at TNF, IL10, MIF, DCSIGN, CLEC5A, NOD2, CCR5 and MRC1 as candidate genes using a matched case-control study design including 88 severe children cases of dengue patients and 335 healthy unrelated subjects that was also separated in IgG(+) and IgG(-) controls. We demonstrated that the TT genotype of CLEC5A SNP (rs1285933 C>T) is associated with dengue severity (OR=2.25; p=0.03) and that GG genotype of -336G>A DCSIGN (CD209) SNP is associated with protection to severe dengue (OR=0.12; p=0.04). Both comparisons were borderline significant when cases were compared with IgG(+) controls subgroup. Nevertheless, genotype-phenotype correlation was also assessed using serum levels of TNF from infected patients at the onset of dengue fever, and CT/TT carriers in CLEC5A secreted higher levels of TNF than CC individuals in 5-7 days of infection. No significant difference was observed in TNF levels between genotypes GG versus AG/AA at DCSIGN promoter. Next, we performed a meta-analysis retrieving results from the literature for -336G>A DCSIGN and -308G>A TNF SNPs demonstrating that the consensus estimates of these SNPs indicated no association with dengue severity (when compared to Dengue fever) in the overall analysis. But, a subgroup analysis in the -336G>A DCSIGN, the G allele was associated with severe dengue susceptibility in Asians (ORallele=2.77; p=0.0001; ORcarriers=2.99; p=0.0001) and protection in Brazilians (ORallele=0.66; p=0.013). In summary, our results suggest that genetic variations at CLEC5A increase the risk and regulate TNF secretion in dengue severity among Brazilians. Also, combined data of the literature suggest population-specific effect of the -336 DCSIGN SNP more prominent in Asians and in a different direction than Brazilians.
登革热是一种虫媒病毒病，在巴西等热带国家具有高发病率和死亡率风险。临床表现广泛，从无症状到登革热最严重的形式，如休克。先前的数据表明，宿主遗传学在疾病易感性和严重程度方面发挥作用。在此，我们使用匹配的病例对照研究设计，测试了 TNF、IL10、MIF、DCSIGN、CLEC5A、NOD2、CCR5 和 MRC1 候选基因中的单核苷酸多态性 (SNP) 的关联，该研究包括 88 例重症登革热患儿病例和 335 例健康无关对照，这些对照也分为 IgG(+)和 IgG(-)对照组。我们证明了 CLEC5A SNP(rs1285933 C>T)的 TT 基因型与登革热严重程度相关(OR=2.25;p=0.03)，-336G>A DCSIGN(CD209)SNP 的 GG 基因型与重症登革热的保护相关(OR=0.12;p=0.04)。当病例与 IgG(+)对照亚组进行比较时，这两种比较均具有边缘显著性。然而，还评估了基因型-表型相关性，方法是使用登革热发热时感染患者的 TNF 血清水平，并在感染后 5-7 天，CT/TT 携带者比 CC 个体分泌更高水平的 TNF。在 DCSIGN 启动子中，TNF 基因型 GG 与 AG/AA 之间未见 TNF 水平有显著差异。接下来，我们进行了一项荟萃分析，检索了文献中关于-336G>A DCSIGN 和-308G>A TNF SNP 的结果，结果表明，这些 SNP 的一致性估计值表明，在总体分析中，它们与登革热严重程度无关(与登革热相比)。但是，在-336G>A DCSIGN 的亚组分析中，G 等位基因与亚洲人重症登革热易感性相关(ORallele=2.77;p=0.0001;ORcarriers=2.99;p=0.0001)，并在巴西人中具有保护作用(ORallele=0.66;p=0.013)。总之，我们的结果表明，CLEC5A 上的遗传变异增加了巴西人中登革热严重程度的风险，并调节了 TNF 的分泌。此外，文献综合数据表明，-336 DCSIGN SNP 的人群特异性效应在亚洲人中更为显著，方向与巴西人不同。
