Published online before print October 25, 2007

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(Journal of Leukocyte Biology. 2008;83:220-222.)
© 2008 by Society for Leukocyte Biology

Fas–670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia

L. Farre^*, A. L. Bittencourt, G. Silva-Santos^*, A. Almeida^*, A. C. Silva^*, D. Decanine^*, G. M. Soares^*, L. C. Alcantara, Jr., S. Van Dooren, B. Galvão-Castro, A. M. Vandamme and J. Van Weyenbergh^*,||,1

Laboratórios de
^* Imunorregulação e Microbiologia (LIMI) and
Saúde Pública (LASP) CPqGM, FIOCRUZ, Salvador-BA, Brazil;
Hospital Universitário Professor Edgard Santos (HUPES), Salvador-BA, Brazil;
^|| Instituto de Investigação em Imunologia (iii–Millenium Institute), SP, Brazil; and
Clinical and Epidemiological Virology, Rega Institute, Leuven, Belgium

¹ Correspondence: FIOCRUZ, LIMI-CPqGM, Rua Waldemar Falcão 121, 40296-710 Salvador-BA, Brazil. E-mail: johan{at}bahia.fiocruz.br

ABSTRACT

Fas (TNFRSF6/Apo-1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the –670 FAS promoter A/G polymorphism (STAT1-binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty-one patients with ATL, 33 healthy, human T lymphotropic virus type 1-infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS –670 polymorphism by PCR-restriction fragment-length polymorphism. The AA genotype was significantly over-represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28–11.41)] and 4.58 [95% CI (1.13–20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60–44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN--induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN-dependent functionality of the –670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.

Key Words: TNFRSF6 • ATL • STAT1 • HTLV-1 • apoptosis

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