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Toll-Like Receptors and Mannose Binding Lectin Gene Polymorphisms Associated with Cryptosporidial Diarrhea in
Farzana Begum Liakath1, Savitha Varatharajan1, Prasanna Samuel Premkumar1
1The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
Insights
Genetic variations in mannose binding lectin 2 (MBL2) and toll-like receptor (TLR) genes may influence susceptibility to Cryptosporidium diarrhea in young children. MBL2 variant B increased risk, while TLR4 and TIRAP variants offered protection.
Area of Science:
- Immunogenetics
- Pediatric Infectious Diseases
- Molecular Epidemiology
Background:
- Cryptosporidium spp. causes significant diarrheal disease in children under 3 in low-resource settings.
- Subclinical (asymptomatic) cryptosporidiosis negatively impacts child growth and cognitive development.
- Genetic factors may modulate susceptibility and severity of cryptosporidial infections.
Purpose of the Study:
- To investigate the association between polymorphisms in mannose binding lectin 2 (MBL2) and toll-like receptor (TLR) genes with symptomatic cryptosporidial diarrhea.
- To compare MBL2 gene polymorphisms and plasma MBL levels between children with symptomatic and asymptomatic cryptosporidiosis.
- To identify genetic variants that confer susceptibility or protection against cryptosporidial diarrhea.
Main Methods:
- Screened MBL2 gene promoter and exon1 polymorphisms, and single nucleotide polymorphisms (SNPs) in TLR1, TLR2, TLR4, TLR9, and TIRAP genes.
- Compared genotypes and plasma mannose binding lectin (MBL) levels between cryptosporidial diarrhea cases and asymptomatic controls.
- Utilized multivariate analysis to assess the association of genetic polymorphisms with disease susceptibility.
Main Results:
- The MBL2 variant allele B (rs1800450) was associated with increased susceptibility to cryptosporidial diarrhea (OR=2.2).
- MBL deficiency was significantly higher in cases (72%) compared to controls (32%) (OR=5.09).
- Heterozygous genotypes of TLR4 896A/G (rs4986790) and TIRAP 539 C/T (rs8177374) SNPs were associated with protection (OR=0.33 and OR=0.19, respectively).
Conclusions:
- Polymorphisms in MBL2 and TLR genes may influence susceptibility to symptomatic cryptosporidial diarrhea, even with high exposure.
- MBL2 variant B and MBL deficiency are linked to increased risk, while specific TLR4 and TIRAP variants appear protective.
- Further validation in larger cohorts is needed to confirm these findings and elucidate the role in immune responses to Cryptosporidium.
Abstract:
In low-resource settings, Cryptosporidium spp. is a common cause of diarrheal disease in children under the age of 3 years. In addition to diarrhea, these children also experience subclinical episodes that have been shown to affect growth and cognitive function. In this study, we screened polymorphisms in the promoter and exon1 regions of the mannose binding lectin 2 (MBL2) gene, as well as single nucleotide polymorphisms (SNPs) described in toll-like receptors (TLR) TLR1, TLR2, TLR4, and TLR9 and TIR domain-containing adaptor protein (TIRAP) genes among children with cryptosporidial diarrhea (cases) and children who only experienced asymptomatic (subclinical) cryptosporidiosis (controls). Among the polymorphisms screened, the variant allele B at codon 54 (rs1800450) of the MBL2 gene was associated with susceptibility to cryptosporidial diarrhea (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.1-4.5). When plasma MBL levels were compared, 72% of cases were found to be deficient compared with 32% among controls (OR = 5.09). Among TLR polymorphisms screened, multivariate analysis showed that heterozygous genotypes of TLR4 896A/G (rs4986790, OR = 0.33, 95% CI: 0.11-0.98) and TIRAP 539 C/T (rs8177374, OR = 0.19, 95% CI: 0.06-0.64) SNPs were associated with protection from cryptosporidial diarrhea. Although not statistically significant, these findings suggest that polymorphisms of MBL2 and TLR genes influence susceptibility to symptomatic cryptosporidial diarrhea even in settings with high exposure levels. Further studies to validate these findings in a larger cohort and to understand the role of these polymorphisms in mediating innate and adaptive immune responses to cryptosporidial infection are necessary.
