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BAT1, a putative anti-inflammatory gene, is associated with chronic Chagas cardiomyopathy
Rajendranath Ramasawmy1, Edecio Cunha-Neto, Kellen C Faé
1Heart Institute (InCor), University of São Paulo, Brazil. ramasawm@usp.br
Insights
Genetic variants in the BAT1 gene are linked to chronic Chagas cardiomyopathy (CCC). These variants may impair the down-regulation of inflammatory responses, increasing CCC risk in Trypanosoma cruzi-infected individuals.
Area of Science:
- Genetics
- Immunology
- Infectious Diseases
Background:
- Chronic Chagas cardiomyopathy (CCC) development in Trypanosoma cruzi-infected individuals remains poorly understood.
- Patients with CCC exhibit elevated circulating proinflammatory cytokines, with heart-infiltrating lymphocytes expressing TNF-α and IFN-γ.
- The anti-inflammatory gene BAT1 has promoter polymorphisms affecting its expression.
Purpose of the Study:
- To investigate the association between BAT1 promoter variants and the development of chronic Chagas cardiomyopathy (CCC).
Main Methods:
- Polymerase chain reaction restriction fragment-length polymorphism analysis was used to assess BAT1 promoter variants (-22C/G and -348C/T).
- The study included 154 patients with CCC and 76 Trypanosoma cruzi-infected asymptomatic patients.
Main Results:
- Homozygosity for the -22C allele was significantly higher in CCC patients (16%) compared to asymptomatic patients (4%) (P=.004).
- A similar trend was observed for -348C homozygotes (P=.01).
- The C variants at both -22 and -348 positions in BAT1 conferred susceptibility to CCC.
Conclusions:
- Specific BAT1 variants, associated with reduced HLA-B-associated transcript 1 expression, predict CCC development.
- These BAT1 variants may be less effective at suppressing inflammatory responses.
- The findings suggest a role for these variants in the elevated proinflammatory cytokine production observed in CCC patients.
Background:
It is not understood why only a subset of individuals infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC). Patients with CCC display high levels of circulating proinflammatory cytokines. Heart-infiltrating lymphocytes from patients with CCC also express proinflammatory cytokines (tumor necrosis factor- alpha and interferon- gamma ) that are detectable in biopsy samples and surgical heart-tissue samples. BAT1, a putative anti-inflammatory gene, presents functional polymorphisms in its promoter region that influence its transcriptional level.
Methods:
We assessed, by polymerase chain reaction restriction fragment-length polymorphism analysis, BAT1 variants in the promoter region at positions -22C/G and -348C/T in 154 patients with CCC and in 76 T. cruzi-infected but asymptomatic (ASY) patients.
Results:
Of the patients with CCC, 16% were homozygous for the -22C allele, compared with 4% of the ASY patients (P=.004; odds ratio [OR], 4.7 [95% confidence interval {CI}, 1.4-16]). A similar trend was observed for the -348C homozygotes (P=.01; OR, 1.9 [95% CI, 1.0-3.5]). Susceptibility to CCC was conferred by the C variants at nt -22 (P=.003; OR, 1.8 [95% CI, 1.2-2.8]) and at nt -348 (P=.02; OR, 1.7 [95% CI, 1.0-2.8]).
Conclusions:
BAT1 variants previously associated with reduced expression of HLA-B-associated transcript 1 are predictive of the development of CCC. These variants may be less efficient in down-regulating inflammatory responses and may contribute to the elevated production of proinflammatory cytokines in patients with CCC.
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