Heterozygosity for the S180L variant of MAL/TIRAP, a gene expressing an adaptor protein in the Toll-like receptor pathway, is associated with lower risk of developing chronic Chagas cardiomyopathy.
BACKGROUND
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Among T. cruzi-infected individuals, only a subgroup develops severe chronic Chagas cardiomyopathy (CCC); the majority remain asymptomatic. T. cruzi displays numerous ligands for the Toll-like receptors (TLRs), which are an important component of innate immunity that lead to the transcription of proinflammatory cytokines by nuclear factor-kappaB. Because proinflammatory cytokines play an important role in CCC, we hypothesized that single-nucleotide polymorphisms (SNPs) in the genes that encode proteins in the TLR pathway could explain differential susceptibility to CCC among T. cruzi-infected individuals.


METHODS
For 169 patients with CCC and 76 T. cruzi-infected, asymptomatic individuals, we analyzed SNPs by use of polymerase chain reaction-restriction fragment length polymorphism analysis for the genes TLR1, TLR2, TLR4, TLR5, TLR9, and MAL/TIRAP, which encodes an adaptor protein.


RESULTS
Heterozygous carriers of the MAL/TIRAP variant S180L were more prevalent in the asymptomatic group (24 [32%] of 76 subjects) than in the CCC group (21 [12%] of 169) (chi2=12.6; P=.0004 [adjusted P (Pc)=.0084]; odds ratio [OR], 0.31 [95% confidence interval {CI}, 0.16-0.60]). Subgroup analysis showed a stronger association when asymptomatic patients were compared with patients who had severe CCC (i.e., patients with left-ventricular ejection fraction<or=40%) (chi2=11.3; P=.0008 [Pc=.017]; OR, 0.22 [95% CI, 0.09-0.56]) than when asymptomatic patients were compared with patients who had mild CCC (i.e., patients with left-ventricular ejection fraction>40%) (chi2=7.7; P=.005 [Pc=.11]; OR, 0.33 [95% CI, 0.15-0.73]).


CONCLUSIONS
T. cruzi-infected individuals who are heterozygous for the MAL/TIRAP S180L variant that leads to a decrease in signal transduction upon ligation of TLR2 or TLR4 to their respective ligand may have a lower risk of developing CCC.
Ramasawmy
Rajendranath
R
Heart Institute, InCor, São Paulo, Brazil. ramasawm@usp.br
Cunha-Neto
Edecio
E
Fae
Kellen C
KC
Borba
Susan C P
SC
Teixeira
Priscila C
PC
Ferreira
Susanne C P
SC
Goldberg
Anna C
AC
Ianni
Barbara
B
Mady
Charles
C
Kalil
Jorge
J
D002598:Chagas Cardiomyopathy / Q000235:genetics*; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human