title: Polymorphisms in circadian genes, night work and breast cancer: results from the GENICA study.
abstract: OBJECTIVE
  The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer.
  
  
  METHODS
  GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR).
  
  
  RESULTS
  For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL.
  
  
  CONCLUSIONS
  In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed.
authors.affiliation: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA) , Bochum , Germany .
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rabstein
authors.forename: Volker
authors.initials: V
authors.lastname: Harth
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Beate
authors.initials: B
authors.lastname: Pesch
authors.forename: Sabine
authors.initials: S
authors.lastname: Plöttner
authors.forename: Evelyn
authors.initials: E
authors.lastname: Heinze
authors.forename: Anne
authors.initials: A
authors.lastname: Lotz
authors.forename: Christian
authors.initials: C
authors.lastname: Baisch
authors.forename: Markus
authors.initials: M
authors.lastname: Schiffermann
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Yon
authors.initials: Y
authors.lastname: Ko
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics; D016022:Case-Control Studies; D057906:Circadian Clocks / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D015999:Multivariate Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044123:Receptor, Melatonin, MT2 / Q000235:genetics; D014940:Work Schedule Tolerance; D055815:Young Adult
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D009419:Nerve Tissue Proteins; D044123:Receptor, Melatonin, MT2; C538960:BMAL1 protein, human; C573871:MTNR1B protein, human; C104264:NPAS2 protein, human; C538943:CLOCK protein, human
keywords: Case-control study; genetic variants; shift work