A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density.
BACKGROUND
Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.


METHODS
The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.


RESULTS
No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).


CONCLUSIONS
The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. a.rudolph@dkfz.de.
Anja
A
Rudolph
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. peter.fasching@uk-erlangen.de.|David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA. peter.fasching@uk-erlangen.de.
Peter A
PA
Fasching
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. s.behrens@dkfz.de.
Sabine
S
Behrens
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. u.eilber@dkfz.de.
Ursula
U
Eilber
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. mkh39@medschl.cam.ac.uk.
Manjeet K
MK
Bolla
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. qw232@medschl.cam.ac.uk.
Qin
Q
Wang
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. djt25@medschl.cam.ac.uk.
Deborah
D
Thompson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Kamila.Czene@ki.se.
Kamila
K
Czene
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. judith.brand@ki.se.
Judith S
JS
Brand
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. jingmei@gmail.com.
Jingmei
J
Li
Division of Biostatistics, Mayo Clinic, Rochester, MN, USA. Scott.Christopher@mayo.edu.
Christopher
C
Scott
Division of Biostatistics, Mayo Clinic, Rochester, MN, USA. vpankratz@salud.unm.edu.
V Shane
VS
Pankratz
Department of Radiology, Mayo Clinic, Rochester, MN, USA. brandt.kathy@mayo.edu.
Kathleen
K
Brandt
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. Hallberg.emily@mayo.edu.
Emily
E
Hallberg
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. olsonj@mayo.edu.
Janet E
JE
Olson
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. lee.adam@mayo.edu.
Adam
A
Lee
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. Fk-direktion@uk-erlangen.de.
Matthias W
MW
Beckmann
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. Arif.Ekici@humgenet.uni-erlangen.de.
Arif B
AB
Ekici
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. lothar.haeberle@uk-erlangen.de.
Lothar
L
Haeberle
University of Hawaii Cancer Center, Honolulu, HI, USA. Gertraud@cc.hawaii.edu.
Gertraud
G
Maskarinec
University of Hawaii Cancer Center, Honolulu, HI, USA. loic@crch.hawaii.edu.
Loic
L
Le Marchand
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. fschumac@usc.edu.
Fredrick
F
Schumacher
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. Roger.Milne@cancervic.org.au.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. Roger.Milne@cancervic.org.au.
Roger L
RL
Milne
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada. knight@lunenfeld.ca.|Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. knight@lunenfeld.ca.
Julia A
JA
Knight
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. capic@unimelb.edu.au.
Carmel
C
Apicella
Department of Pathology, The University of Melbourne, Melbourne, Australia. msouthey@unimelb.edu.au.
Melissa C
MC
Southey
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. kmk@unimelb.edu.au.
Miroslav K
MK
Kapuscinski
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. j.hopper@unimelb.edu.au.
John L
JL
Hopper
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada. andrulis@lunenfeld.ca.|Department of Molecular Genetics, University of Toronto, Toronto, Canada. andrulis@lunenfeld.ca.
Irene L
IL
Andrulis
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. Graham.Giles@cancervic.org.au.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. Graham.Giles@cancervic.org.au.
Graham G
GG
Giles
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Christopher.Haiman@med.usc.edu.
Christopher A
CA
Haiman
MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival (CNC), University of Cambridge, Cambridge, UK. kk101@medschl.cam.ac.uk.
Kay-Tee
KT
Khaw
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Robert.luben@phpc.cam.ac.uk.
Robert
R
Luben
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Per.Hall@ki.se.
Per
P
Hall
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. pp10001@medschl.cam.ac.uk.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. pp10001@medschl.cam.ac.uk.
Paul D P
PD
Pharoah
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. couch.fergus@mayo.edu.
Fergus J
FJ
Couch
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. dfe20@medschl.cam.ac.uk.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. dfe20@medschl.cam.ac.uk.
Douglas F
DF
Easton
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. isabel.silva@lshtm.ac.uk.
Isabel
I
Dos-Santos-Silva
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. Vachon.celine@mayo.edu.
Celine
C
Vachon
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. j.chang-claude@dkfz.de.
Jenny
J
Chang-Claude
D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000473:pathology*; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities* / Q000473:pathology; D008327:Mammography / Q000379:methods; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017698:Postmenopause / Q000235:genetics*; D012307:Risk Factors