Polymorphisms in the Gene for Lymphotoxin-αPredispose to Chronic Chagas Cardiomyopathy

Background. Chagas disease, caused by Trypanosoma cruzi infection, displays clinical heterogeneity and may be attributable to differential genetic susceptibility. Chronic Chagas cardiomyopathy (CCC) develops only in a subset of T.cruzi–infected individuals and may lead to heart failure that has a worse clinical course and that leads to reduced life expectancy, compared with heart failure of other etiologies. Proinflammatory cytokines play a key role in the development of CCC. Clinical, genetic, and epidemiological studies have linked lymphotoxin- (LTA), a proinflammatory cytokine, to coronary artery disease and myocardial infarction. Methods. We used polymerase chain reaction to genotype the LTA 80A3 C and LTA 252A3 G variants in 169 patients with CCC and in 76 T. cruzi–infected asymptomatic (ASY) patients. Results. Homozygosity with respect to theLTA80C andLTA252G alleles was significantly more frequent in the patients with CCC than in the ASY patients (homozygosity for LTA 80C, 47% vs. 33%; homozygosity for LTA 252G, 16% vs. 8%). Haplotype LTA 80A-252A was associated with protection against CCC, whereas haplotype LTA 80C-252G was associated with susceptibility to CCC. Furthermore, homozygosity for the LTA 80A allele correlated with the lowest levels of plasmatic tumor-necrosis factor–. Conclusions. Our results suggest that the study of genetic variations in patients with Chagas disease may help in the identification of individuals at increased risk of progressing to CCC and, by providing early treatment, reduce the morbidity and mortality associated with this disease. Chagas disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is still a major threat to human health in Latin America, despite efficient control of the transmitting vector, the triatomine. More than 18 million people are estimated to be chronically infected with T. cruzi, and 200,000 new cases are reported each year [1]. Nearly one-third of these T. cruzi–infected individuals will progress to chronic Chagas cardiomyopathy (CCC), whereas the remaining two-thirds will remain asymptomatic (ASY).