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

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.
Author Summary Chagas disease is considered an important neglected tropical disease, affecting approximately ten million people in Latin America. Although most infected individuals remain asymptomatic, one third of patients develop a chronic heart disease, with progressive inflammation, increase of myocardium, arrhythmia, cardiac insufficiency and heart failure. To date, there is no available marker to indicate the progression neither to determinate the severity of heart damage. Mannan binding lectin (MBL) is an important protein of the immune system able to recognize specific regions on the microorganism surfaces (including Trypanosoma cruzi, the causal agent of Chagas disease) which activate the complement system, a crucial mechanism of the effector immunity. MBL levels and protein activity are affected by genetic differences, named polymorphisms, in the MBL2 gene. This is the first Brazilian study with MBL2 polymorphisms in chronic Chagas disease. We sequenced two regions of MBL2 gene in 196 patients and 202 controls. We found that a polymorphism associated with deficient complement activation protects against Chagas disease and patients with deficiency-associated genotypes presented less echocardiographic alterations. 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 lead us to suggest that genetically determined MBL deficiency plays a protective role against the development and progression of chronic Chagas disease.