title: A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication.
abstract: Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
authors: Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
authors: Rebecca
authors: R
authors: Hein
authors: Department of Cancer Epidemiology, Clinical Cancer Registry, University Cancer Center and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
authors: Dieter
authors: D
authors: Flesch-Janys
authors: Congenics AG, Hamburg, Germany.
authors: Norbert
authors: N
authors: Dahmen
authors: Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany.
authors: Lars
authors: L
authors: Beckmann
authors: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard, School Of Public Health, Boston, MA 02138, USA; Department of Biostatistics, Harvard School Of Public Health, Boston, MA 02138, USA.
authors: Sara
authors: S
authors: Lindström
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Nils
authors: N
authors: Schoof
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Kamila
authors: K
authors: Czene
authors: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany.
authors: Kirstin
authors: K
authors: Mittelstraß
authors: Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
authors: Thomas
authors: T
authors: Illig
authors: Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors: Petra
authors: P
authors: Seibold
authors: Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors: Sabine
authors: S
authors: Behrens
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Keith
authors: K
authors: Humphreys
authors: Human,Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore.
authors: Jingmei
authors: J
authors: Li
authors: Human,Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore.
authors: Jianjun
authors: J
authors: Liu
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Janet E
authors: JE
authors: Olson
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Xianshu
authors: X
authors: Wang
authors: Department of Epidemiology, Harvard, School Of Public Health, Boston, MA 02138, USA.
authors: Susan E
authors: SE
authors: Hankinson
authors: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France; University Paris-Sud, UMRS 1018, Villejuif, France.
authors: Thérèse
authors: T
authors: Truong
authors: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France; University Paris-Sud, UMRS 1018, Villejuif, France.
authors: Florence
authors: F
authors: Menegaux
authors: Department of Non-Communicable, Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors: Isabel
authors: I
authors: Dos Santos Silva
authors: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors: Nichola
authors: N
authors: Johnson
authors: Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
authors: Shou-Tung
authors: ST
authors: Chen
authors: Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
authors: Jyh-Cherng
authors: JC
authors: Yu
authors: Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA.
authors: Argyrios
authors: A
authors: Ziogas
authors: School of Medicine, Institute of Clinical Medicine, Oncology, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors: Vesa
authors: V
authors: Kataja
authors: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Veli-Matti
authors: VM
authors: Kosma
authors: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Arto
authors: A
authors: Mannermaa
authors: Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
authors: Hoda
authors: H
authors: Anton-Culver
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Taiwan Biobank, Taipei, Taiwan.
authors: Chen-Yang
authors: CY
authors: Shen
authors: Dr. Margarete Fischer-Bosch-Institute, of Clinical Pharmacology, Stuttgart, University of Tübingen, Tübingen, Germany.
authors: Hiltrud
authors: H
authors: Brauch
authors: Department of Non-Communicable, Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors: Julian
authors: J
authors: Peto
authors: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France; University Paris-Sud, UMRS 1018, Villejuif, France.
authors: Pascal
authors: P
authors: Guénel
authors: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard School Of Public Health, Boston, MA 02138, USA; Department of Biostatistics, Harvard School Of Public Health, Boston, MA 02138, USA.
authors: Peter
authors: P
authors: Kraft
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Fergus J
authors: FJ
authors: Couch
authors: Centre for Cancer Genetic Epidemiology, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Cambridge, UK.
authors: Douglas F
authors: DF
authors: Easton
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Hall
authors: Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors: Jenny
authors: J
authors: Chang-Claude
mesh_terms: D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000139:chemically induced / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000139:chemically induced / Q000235:genetics*; D016022:Case-Control Studies; D002877:Chromosomes, Human; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000009:adverse effects; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011372:Progestins / Q000009:adverse effects; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D004967:Estrogens; D011372:Progestins