Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF–LTA) and breast cancer risk
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Tumor necrosis factor (TNF) is critical to regulation of inflammation. Genetic variation in the promoter region of TNF has been associated with expression differences, and a range of auto-immune, infectious, and oncologic diseases. We analyzed eight common single nucleotide polymorphisms (SNPs) (rs746868, rs909253, rs1799964, rs1800630, rs1800750, rs1800629, rs361525, and rs1800610) to capture most of the genetic variation in TNF in addition to SNPs in lymphotoxin-alpha (LTA), a pro-inflammatory cytokine in linkage disequilibrium with the TNF promoter region. SNPs were genotyped in a USA population-based case-control study (3,318 cases, 2,841 controls). Promising results were followed-up in an independent population-based case-control study in Poland (2,228 cases, 2,378 controls). In both studies, women carrying the variant allele of rs361525 were at elevated breast cancer risk compared to the GG genotype (per allele OR = 1.18, 95% CI 1.04–1.35; P for trend = 0.008). Other SNPs were not significantly associated with breast cancer risk. Haplotype analyses did not reveal any additional associations between TNF and breast cancer risk. Data from 5,269 cases and 4,982 controls suggested that the rs361525 A allele, located in the TNF promoter region, was associated with a modest increase in breast cancer risk. Additional studies are required to replicate these findings and to determine whether rs361525 is a causative SNP or is a marker of a causative SNP.
This research was funded by Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the Center for Cancer Research, and by R01 CA67264, CA47147 (P. Newcomb), by R01 CA67338, CA69664 (L. Titus-Ernstoff), and R01 CA47305 (K. Egan). We would like to thank John Hampton (University of Wisconsin, Comprehensive Cancer Center, Madison, WI, USA) for his work in data management of the USA study; Neonila Szeszenia-Dabrowska (Nofer Institute of Occupational Medicine, Lodz, Poland), Witold Zatonski, and Alicja Bardin-Mikolajczak (M. Sklodowska-Curie Institute of Oncology and Cancer Center, Warsaw, Poland) for their contribution to the Polish study, Anita Soni (Westat, Rockville, MD, USA) for her work on study management for the Polish study; Pei Chao (IMS, Silver Spring, MD, USA) for her work on data and sample management for both the USA and Poland studies; and the physicians, nurses, interviewers, and study participants for their efforts during the field work portion of this study.
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