title: Fas 670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia.
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-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 significantly associated to susceptibility, clinical manifestation, and survival in ATL.
authors.affiliation: LIMI-CPqGM, Rua Waldemar Falcão 121, 40296-710 Salvador-BA, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Farre
authors.forename: A L
authors.initials: AL
authors.lastname: Bittencourt
authors.forename: G
authors.initials: G
authors.lastname: Silva-Santos
authors.forename: A
authors.initials: A
authors.lastname: Almeida
authors.forename: A C
authors.initials: AC
authors.lastname: Silva
authors.forename: D
authors.initials: D
authors.lastname: Decanine
authors.forename: G M
authors.initials: GM
authors.lastname: Soares
authors.forename: L C
authors.initials: LC
authors.lastname: Alcantara
authors.forename: S
authors.initials: S
authors.lastname: Van Dooren
authors.forename: B
authors.initials: B
authors.lastname: Galvão-Castro
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: J
authors.initials: J
authors.lastname: Van Weyenbergh
mesh_terms: D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015490:HTLV-I Infections / Q000276:immunology / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015458:Leukemia, T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D015996:Survival Rate; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D019014:fas Receptor; D007371:Interferon-gamma