title: Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.
abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Thérèse
authors.initials: T
authors.lastname: Truong
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.forename: Petra
authors.initials: P
authors.lastname: Seibold
authors.forename: Dieter
authors.initials: D
authors.lastname: Flesch-Janys
authors.forename: Sabine
authors.initials: S
authors.lastname: Behrens
authors.forename: Ursula
authors.initials: U
authors.lastname: Eilber
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Bolla
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Munday
authors.forename: Hatef
authors.initials: H
authors.lastname: Darabi
authors.forename: Mikael
authors.initials: M
authors.lastname: Eriksson
authors.forename: Judith S
authors.initials: JS
authors.lastname: Brand
authors.forename: Janet
authors.initials: J
authors.lastname: Olson
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.forename: Emily
authors.initials: E
authors.lastname: Hallberg
authors.forename: J Esteban
authors.initials: JE
authors.lastname: Castelao
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Maria
authors.initials: M
authors.lastname: Torres
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.forename: Keith
authors.initials: K
authors.lastname: Humphreys
authors.forename: Emilie
authors.initials: E
authors.lastname: Cordina-Duverger
authors.forename: Florence
authors.initials: F
authors.lastname: Menegaux
authors.forename: Henrik
authors.initials: H
authors.lastname: Flyger
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Sune F
authors.initials: SF
authors.lastname: Nielsen
authors.forename: Betul T
authors.initials: BT
authors.lastname: Yesilyurt
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Engelhardt
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Emiel J
authors.initials: EJ
authors.lastname: Rutgers
authors.forename: Gord
authors.initials: G
authors.lastname: Glendon
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: Simon
authors.initials: S
authors.lastname: Cross
authors.forename: Malcolm
authors.initials: M
authors.lastname: Reed
authors.forename: Anna
authors.initials: A
authors.lastname: Gonzalez-Neira
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Arias Perez
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Amanda
authors.initials: A
authors.lastname: Spurdle
authors.forename: Lothar
authors.initials: L
authors.lastname: Häberle
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Aida Karina
authors.initials: AK
authors.lastname: Dieffenbach
authors.forename: Volker
authors.initials: V
authors.lastname: Arndt
authors.forename: Christa
authors.initials: C
authors.lastname: Stegmaier
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.forename: Nick
authors.initials: N
authors.lastname: Orr
authors.forename: Minouk
authors.initials: M
authors.lastname: Schoemaker
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Vesa
authors.initials: V
authors.lastname: Kataja
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.forename: Anthony
authors.initials: A
authors.lastname: Swerdlow
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: John
authors.initials: J
authors.lastname: Hopper
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Manuela
authors.initials: M
authors.lastname: Gago-Dominguez
authors.forename: Fergus
authors.initials: F
authors.lastname: Couch
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.forename: Doug F
authors.initials: DF
authors.lastname: Easton
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Pascal
authors.initials: P
authors.lastname: Guénel
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000209:etiology / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000032:analysis; D012307:Risk Factors
chemical_list: D011960:Receptors, Estrogen
keywords: breast cancer; gene-environment interaction; genetic susceptibility; risk factor