Polymorphisms in the gene for lymphotoxin-alpha predispose 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-alpha (LTA), a proinflammatory cytokine, to coronary artery disease and myocardial infarction.


METHODS
We used polymerase chain reaction to genotype the LTA +80A-->C and LTA +252A-->G variants in 169 patients with CCC and in 76 T. cruzi-infected asymptomatic (ASY) patients.


RESULTS
Homozygosity with respect to the LTA +80C and LTA +252G 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-alpha.


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.
Ramasawmy
Rajendranath
R
Heart Institute (InCor), Department of Clinical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil. ramasawm@usp.br
Fae
Kellen C
KC
Cunha-Neto
Edecio
E
Müller
Natalie G
NG
Cavalcanti
Vanessa L
VL
Ferreira
Renata C
RC
Drigo
Sandra A
SA
Ianni
Barbara
B
Mady
Charles
C
Goldberg
Anna C
AC
Kalil
Jorge
J
D000818:Animals; D002598:Chagas Cardiomyopathy / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008233:Lymphotoxin-alpha / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014349:Trypanosoma cruzi / Q000254:growth & development* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha