Toll-Like Receptors and Mannose Binding Lectin Gene Polymorphisms Associated with Cryptosporidial Diarrhea in Children in Southern India

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  • 1 The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;
  • | 2 Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts

In low-resource settings, Cryptosporidium spp. is a common cause of diarrheal disease in children under age 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.

Author Notes

Address correspondence to Sitara S. R. Ajjampur, The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India 632004, India. E-mail: sitararao@cmcvellore.ac.in

Funding support: This work was supported by the Indian Council for Medical Research grant (Immu.19/11/8/2008ECD-I) to S. S. R. A., National Institutes of Health (R03 TW07211) to H. W., and Wellcome Trust, UK (063144) to G. K. F. B. was supported by a fellowship grant from the Lady Tata Memorial Trust, India.

Authors’ addresses:Farzana Begum Liakath, Savitha Varatharajan, Chanduni Syed, Gagandeep Kang, and Sitara S. R. Ajjampur, The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Indian, E-mails: farzana.liakath@gmail.com, savitha0384@gmail.com, syedchanduni@gmail.com, gkang@cmcvellore.ac.in, and sitararao@cmcvellore.ac.in. Prasanna Samuel Premkumar, Department of Biostatistics, Christian Medical College, Vellore, India, E-mail: prasanna.samuel@cmcvellore.ac.in. Honorine Ward, Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine, Boston, MA, E-mail: hward@tuftsmedicalcenter.org.

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