Genetically Determined MBL Deficiency Is Associated with Protection against Chronic Cardiomyopathy in Chagas Disease.

Paola Rosa Luz,Iara J Messias-Reason,Nelson Chiminacio Neto,Márcia I Miyazaki,Ana Cláudia M Barros,Angelica B W Boldt,Marcela C Padeski,Herbert B Tanowitz

doi:10.1371/journal.pntd.0004257

Abstract

Chagas disease (CD) is caused by Trypanosoma cruzi, whose sugar moieties are recognized by mannan binding lectin (MBL), a soluble pattern-recognition molecule that activates the lectin pathway of complement. MBL levels and protein activity are affected by polymorphisms in the MBL2 gene. We sequenced the MBL2 promoter and exon 1 in 196 chronic CD patients and 202 controls. The MBL2*C allele, which causes MBL deficiency, was associated with protection against CD (P = 0.007, OR = 0.32). Compared with controls, genotypes with this allele were completely absent in patients with the cardiac form of the disease (P = 0.003). Furthermore, cardiac patients with genotypes causing MBL deficiency presented less heart damage (P = 0.003, OR = 0.23), compared with cardiac patients having the XA haplotype causing low MBL levels, but fully capable of activating complement (P = 0.005, OR = 7.07). Among the patients, those with alleles causing MBL deficiency presented lower levels of cytokines and chemokines possibly implicated in symptom development (IL9, p = 0.013; PDGFB, p = 0.036 and RANTES, p = 0.031). These findings suggest a protective effect of genetically determined MBL deficiency against the development and progression of chronic CD cardiomyopathy.

Highlights

Chagas disease (CD) is considered the most important neglected tropical disease worldwide, affecting approximately ten million people in Latin America [1,2,3]
mannan binding lectin (MBL) Deficiency Protects against Chronic Chagasic Cardiomyopathy
We identified eight MBL2 haplotypes comprehending the -221 (H/L) and -550 (X/Y) promoter single nucleotide polymorphisms (SNPs), +4 (P/Q) SNP in the 5’ untranslated region, codon 52 (A/D), codon 54 (A/B) and codon 57 (A/C) SNPs in exon 1 (Table 2)

Summary

Introduction

Chagas disease (CD) is considered the most important neglected tropical disease worldwide, affecting approximately ten million people in Latin America [1,2,3]. 50% of the individuals infected by T. cruzi remain in the indeterminate or asymptomatic clinical form of CD for their whole lives. Asymptomatic patients present in general a good prognosis, each year about 2–5% of them progress to symptomatic forms of the disease, developing cardiac, digestive and/or neurological clinical manifestations [5]. Sudden death is a constant risk at any clinical stage, occurring in one to two thirds of patients who die due to CD. Most of these patients presented prior CI, about one third to one fifth of sudden deaths occur in asymptomatic CD patients [6,7]

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Discussion

Conclusion