Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects

Abstract

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR=2.75 and p-value=0.01, OR=2.11 and p-value=0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r=0.55, p=0.008) and TNF production in culture supernatants (Spearman r=0.72, p=0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r=0.67, p=0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.

CLEC5A: A Promiscuous Pattern Recognition Receptor to Microbes and Beyond

“…However, there was no difference in dengue viral load or TNF expression among the different genotypes. Moreover, the authors observed only borderline significance for the association between CLEC5A mRNA levels in patients with mild dengue infection and the CC genotype; TNF mRNA expression showed no variation among mild dengue patients with different genotypes (Xavier-Carvalho et al 2017).…”

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil

“… 14 The association was replicated later in patients from another Brazilian region. 15 In the current study, we have increased gene coverage by including additional SNPs as a way to better understand the influence of CLEC5A genetic structure in dengue severity. Since no associations were found, the data available to date suggest that the 3’ near gene variation rs1285933 may be the functional variant of this gene.…”

“… 13 We have recently demonstrated an association between the polymorphism rs1285933, located at CLEC5A 3’UTR region, and severe dengue in two Brazilian cohorts. 14 , 15 …”

Human host genetics and susceptibility to ZIKV infection

“…Therefore, GWAS studies performed on other flaviviruses could help to identify potential polymorphisms associated with susceptibility to ZIKV infection. GWAS studies of DENV infection have identified several human genetic factors associated with the severity of infection (Khor et al, 2011;Sierra et al, 2017;Xavier-Carvalho et al, 2017a, 2017b, which may also affect ZIKV infection. For example, SNPs have been identified in the promoter sequence of the DC-SIGN gene (CD209) that have been shown to be associated with a predisposition to Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) (Wang et al, 2011).…”