Fas 670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia.
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.
Farre
L
L
LIMI-CPqGM, Rua Waldemar Falcão 121, 40296-710 Salvador-BA, Brazil.
Bittencourt
A L
AL
Silva-Santos
G
G
Almeida
A
A
Silva
A C
AC
Decanine
D
D
Soares
G M
GM
Alcantara
L C
LC
Van Dooren
S
S
Galvão-Castro
B
B
Vandamme
A M
AM
Van Weyenbergh
J
J
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
D012333:RNA, Messenger; D019014:fas Receptor; D007371:Interferon-gamma