title: Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case-control study in Inuit women.
abstract: BACKGROUND
  We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case-control study aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels on BC risk in Greenlandic Inuit women.
  
  
  METHODS
  The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572); CYP19A1 (C> T; rs10046) and CYP19A1 ((TTTA)n repeats) polymorphisms and BRCA1 founder mutation using TaqMan allelic discrimination method and polymerase chain reaction based restriction fragment length polymorphism. The χ2 -test was used to compare categorical variables between cases and controls and the odds ratios were estimated by unconditional logistic regression models.
  
  
  RESULTS
  We found an independent association of CYP1A1 (Val) and CYP17 (A1) with BC risk.Furthermore, an increased BC risk was observed for women with high serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and carriers of at least: one CYP1A1 variant Val allele; one variant COMT Met allele; or the common CYP17 A1 allele. No combined effects were seen between PFAS exposure and CYP1B1 and CYP19 polymorphisms. The risk of BC was not found significantly associated with exposure to PCBs and OCPs, regardless of genotype for all investigated SNPs. The frequency of the Greenlandic founder mutation in BRCA1 was as expected higher in cases than in controls.
  
  
  CONCLUSIONS
  The BRCA1 founder mutation and polymorphisms in CYP1A1 (Val) and CYP17 (A1) can increase the BC risk among Inuit women and the risk increases with higher serum levels of PFOS and PFOA. Serum PFAS levels were a consistent risk factor of BC, but inter-individual polymorphic differences might cause variations in sensitivity to the PFAS/POP exposure.
authors.forename: Mandana
authors.initials: M
authors.lastname: Ghisari
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.forename: Manhai
authors.initials: M
authors.lastname: Long
authors.affiliation: Centre for Arctic Health & Unit of Cellular and Molecular Toxicology, Department of Public Health, Aarhus University, Bartholins Álle 2, Build 1260, 8000 Aarhus C, Denmark. ebj@mil.au.dk.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Bonefeld-Jørgensen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017738:Alkanesulfonic Acids / Q000097:blood*; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004784:Environmental Monitoring; D004785:Environmental Pollutants / Q000097:blood*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005466:Fluorocarbons / Q000097:blood*; D006116:Greenland / Q000453:epidemiology; D006801:Humans; D004930:Inuit / Q000235:genetics; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D015262:Xenobiotics / Q000097:blood; D055815:Young Adult
chemical_list: D017738:Alkanesulfonic Acids; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004785:Environmental Pollutants; D004967:Estrogens; D005466:Fluorocarbons; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase