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Circadian genes and breast cancer susceptibility in rotating shift workers.

ABSTRACT: Rotating night shift work is associated with increased risk of breast cancer, likely via circadian disruption. We hypothesized that circadian pathway genes influence breast cancer risk, particularly in rotating night shift workers. We selected 178 common variants across 15 genes pertinent to the circadian system. Using a mixed candidate- and tag-single nucleotide polymorphism approach, we tested for associations between these variants and breast cancer risk in 1,825 women within the Nurses' Health Study II cohort and investigated potential interactions between genotype and rotating shift-work in a subset of 1,318 women. Multiple-testing-adjusted p-values were obtained by permutation (n = 10,000). None of the selected variants was significantly associated with breast cancer risk. However, when accounting for potential effect modification, rs23051560 (Ala394Thr) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2) was most strongly associated with breast cancer risk (nominal test for interaction p-value = 0.0005; 10,000-permutation-based main-effects p-value among women with < 24 months of shift-work = 0.003). The observed multiplicative association with breast cancer risk per minor allele (A) was 0.65 (95% CI = 0.51-0.82) among women with < 24 months of shift-work and 1.19 (95% CI = 0.93-1.54) with ? 24 months of shift-work. Women homozygous for the minor allele (AA) with ? 24 months of shift-work had a 2.83-times higher breast cancer risk compared to homozygous AA women with < 24 months of shift-work (95% CI = 1.47-5.56). In summary, common variation in circadian genes plays at most a small role in breast cancer risk among women of European ancestry. The impact of NPAS2 Ala394Thr in the presence of rotating shift-work requires further investigation.

SUBMITTER: Monsees GM

PROVIDER: S-EPMC3408553 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Circadian genes and breast cancer susceptibility in rotating shift workers.

Monsees Genevieve M GM Kraft Peter P Hankinson Susan E SE Hunter David J DJ Schernhammer Eva S ES

International journal of cancer 20120907 11

Rotating night shift work is associated with increased risk of breast cancer, likely via circadian disruption. We hypothesized that circadian pathway genes influence breast cancer risk, particularly in rotating night shift workers. We selected 178 common variants across 15 genes pertinent to the circadian system. Using a mixed candidate- and tag-single nucleotide polymorphism approach, we tested for associations between these variants and breast cancer risk in 1,825 women within the Nurses' Heal ...[more]

PMID: 22473669

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Project description:IntroductionPreliminary studies suggest that night shift work is associated with a desynchronization of rhythmic immune markers, possibly explaining the increased risk of infection, cardiometabolic disorders, and cancer in shift workers.MethodsThis study included 51 male rotating shift workers from a car industry in Barcelona, Spain, sampled twice toward the end of a 3-week night shift (22:00-06:00 h) and a 3-week day shift (06:00-14:00 h) rotation. We collected four blood samples per worker, at the start and end of each shift. We measured 27 cytokines, chemokines and growth factors in plasma samples by luminex using the Cytokine Human Magnetic 30-Plex Panel LHC6003M and applied linear mixed models to examine within-person associations between shift work and analytes' concentrations, comparing samples taken at 06:00 h on a day and night shift. We also conducted a factor analysis using analyte concentrations from all 4 time points for each individual to identify common factors and determine if these factors were altered by shift work.ResultsWe observed lower levels of 15 analytes in the night shift compared to the day shift including cytokines (pro-inflammatory TNF-α, IL-2R; anti-inflammatory IL1-RA; Th1 IL-2, Th2 IL-4 and Th17 Il-17), chemokines (IP-10, MIP-1α, MIP-1β, RANTES) and growth factors (EGF, G-CSF, HGF, VEGF, FGF). In a factor analysis, three factors were identified. The main factor (Factor 1), explaining 57% of the variance and including IL-1β, IL-12, IL-15, MIP-1α, MIP-1β, EGF and FGF; and another factor (Factor 3) explaining 10% of the variance and including the Th1 cytokine IL-12, were inversely associated with the night shift (coefficient: -0.17, 95%CI -0.32 to -0.01 and coefficient: -0.22, 95%CI -0.38, -0.06, for Factors 1 and 3, respectively). Our results indicate that night shift disrupts the levels of several immune markers, which could contribute to the increased risk of infections and cancer reported in night shift workers.ConclusionNight shift is associated with disruption of multiple immune response pathways.

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Circadian genes and breast cancer susceptibility in rotating shift workers.

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Circadian genes and breast cancer susceptibility in rotating shift workers.

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