Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Published online before print October 25, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407198

Received for publication April 2, 2007.
Revised October 2, 2007.
Accepted for publication October 2, 2007.

Article

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

L. Farre *, A. L. Bittencourt {dagger}, G. Silva-Santos *, A. Almeida *, A. C. Silva *, D. Decanine *, G. M. Soares *, L. C. Alcantara Jr.{ddagger}, S. Van Dooren {sect}, B. Galvão-Castro {ddagger}, A. M. Vandamme {sect}, and J. Van Weyenbergh *||@

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

@ To whom correspondence should be addressed. 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 over-represented significantly 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-{gamma}-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 associated significantly to susceptibility, clinical manifestation, and survival in ATL.

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






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