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Tumor Necrosis Factor Polymorphism Associated with Increased Susceptibility to Development of Adult T-Cell Leukemia/Lymphoma in Human T-lymphotropic Virus Type 1 Carriers¹

Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California 90024 [K.T., C.W.M., T.K., S.T., H.P.K.]; Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Ngasaki 852, Japan [T.F., M.T.]; and Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan [S.I.]

Human T-lymphotropic virus type 1 (HTLV-1) is etiologically associated with adult T-cell leukemia/lymphoma (ATL). Nevertheless, most individuals infected with HTLV-1 do not develop ATL. To attempt to identify genetic factors promoting the progression to ATL, we investigated in HTLV-1 carriers the relationship between susceptibility to ATL and several polymorphisms: the three "decreased-detoxifying" polymorphisms in GSTM1, GSTT1, and CYP1A1, the "proapoptotic" polymorphism in BCL2, and the five "high-production" polymorphisms in tumor necrosis factor (TNF-) using PCR-based genotyping assays. ATL patients (n = 71) were younger than HTLV-1 carriers (n = 80; 57 ± 12 versus 63 ± 10 years; P = 0.0017). Male:female ratio in ATL patients was higher than in carriers (52:19 versus 19:61, respectively; P < 0.0001), probably reflecting a higher incidence of HTLV-1 infection in females and a higher incidence of development of ATL in males. We found that the frequency of the TNF--857T allele, reported to be associated with high transcriptional activity of the promoter/enhancer region of the TNF- gene, was enriched in individuals with ATL compared with healthy carriers (18.3% versus 8.8%, respectively; odds ratio, 2.34; 95% confidence interval, 1.2–4.7). None of the other four TNF- polymorphisms was a significant indicator of risk of development of ATL, although odds ratios (ATL versus carrier) of all of the TNF- polymorphisms were higher than 1.0. Furthermore, analysis of polymorphisms for GSTM1, GSTT1, CYP1A1, and BCL2 showed no significant difference between ATL patients and healthy carriers. Genetic polymorphism leading to increased TNF- production may enhance susceptibility to ATL among HTLV-1 carriers. Alternatively, but less likely, the HLA loci might be an important factor because the TNF- gene lies within the class III region of the MHC; however, the 857T allele is not in linkage disequilibrium with HLA alleles associated with ATL development.

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