title: Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk.
abstract: 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. gaudetm@mail.nih.gov
authors.forename: Mia M
authors.initials: MM
authors.lastname: Gaudet
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Egan
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.forename: Linda
authors.initials: L
authors.lastname: Titus-Ernstoff
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Beata
authors.initials: B
authors.lastname: Peplonska
authors.forename: Amy
authors.initials: A
authors.lastname: Trentham-Dietz
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha