Gene-environment interactions relevant to estrogen and risk of breast cancer: Can gene-environment interactions be detected only among candidate snps from genome-wide association studies?

Joo Yong Park, Ji Yeob Choi*, Jaesung Choi, Seokang Chung, Nan Song, Sue K. Park, Wonshik Han, Dong Young Noh, Sei Hyun Ahn, Jong Won Lee, Mi Kyung Kim, Sun Ha Jee, Wanqing Wen, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Mitul Shah, Don M. Conroy, Patricia A. HarringtonRebecca Mayes, Kamila Czene, Per Hall, Lauren R. Teras, Alpa V. Patel, Fergus J. Couch, Janet E. Olson, Elinor J. Sawyer, Rebecca Roylance, Stig E. Bojesen, Henrik Flyger, Diether Lambrechts, Adinda Baten, Keitaro Matsuo, Hidemi Ito, Pascal Guénel, Thérèse Truong, Renske Keeman, Marjanka K. Schmidt, Anna H. Wu, Chiu Chen Tseng, Angela Cox, Simon S. Cross, Kconfab Investigators, Irene L. Andrulis, John L. Hopper, Melissa C. Southey, Pei Ei Wu, Chen Yang Shen, Peter A. Fasching, Arif B. Ekici, Kenneth Muir, Artitaya Lophatananon, Hermann Brenner, Volker Arndt, Michael E. Jones, Anthony J. Swerdlow, Reiner Hoppe, Yon Dschun Ko, Mikael Hartman, Jingmei Li, Arto Mannermaa, Jaana M. Hartikainen, Javier Benitez, Anna González-Neira, Christopher A. Haiman, Thilo Dörk, Natalia V. Bogdanova, Soo Hwang Teo, Nur Aishah Mohd Taib, Olivia Fletcher, Nichola Johnson, Mervi Grip, Robert Winqvist, Carl Blomqvist, Heli Nevanlinna, Annika Lindblom, Camilla Wendt, Vessela N. Kristensen, N. B.C.S. Collaborators, Rob A.E.M. Tollenaar, Bernadette A.M. Heemskerk-Gerritsen, Paolo Radice, Bernardo Bonanni, Ute Hamann, Mehdi Manoochehri, James V. Lacey, Maria Elena Martinez, Alison M. Dunning, Paul D.P. Pharoah, Douglas F. Easton, Keun Young Yoo, Daehee Kang

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3 ). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4 ). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Original languageEnglish
Article number2370
Issue number10
Publication statusPublished - 14 May 2021

Bibliographical note

Funding Information:
Acknowledgments: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. The COGS study would not have been possible without the contributions of the following: Per Hall (COGS), Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC); Andrew Berchuck (OCAC); Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL); Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA); Joe Dennis, Alison M. Dunning, Andrew Lee, Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory; Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit; Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre; Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory; and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS thank Maggie Angelakos, Judi Maskiell, Gillian Dite. ABS. thanks the Blood bank Sanquin, The Netherlands. The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special thanks also go to the Thai Ministry of Public Health (MOPH), doctors, and nurses who helped with the data collection process. Finally, the study would like to thank Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Pornthep Siriwanarungsan, the former Department Director-General of Disease Control who have supported the study throughout. BBCS thanks Eileen Williams, Elaine Ryder-Mills, and Kara Sargus. CGPS thanks staff and participants of the Copenhagen General Population Study for the excellent technical assistance, Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, and Dorthe Kjeldgård Hansen. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Nuria Álvarez, Pilar Zamora, Primitiva Menendez, and the Human Genotyping CEGEN Unit (CNIO). Investigators from the CPS-II cohort thank the participants and Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. The authors would like to thank the California Teachers Study Steering Committee that is responsible for the formation and maintenance of the study within which this research was conducted. A full list of California Teachers Study team members is available at ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. The GENICA Network; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany (Hiltrud Brauch, Wing-Yee Lo, and R.H.); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Y-D. K. and Christian Baisch); Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (Ute Hamann); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz); and the Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). GLACIER thanks Kelly Kohut, Patricia Gorman, Maria Troy. HEBCS thanks Sofia Khan, Johanna Kiiski, Carl Blomqvist, Kristiina Aittomäki, Rainer Fagerholm, Kirsimari Aaltonen, Karl von Smitten, and Irja Erkkilä. HMBCS thanks Natalia Antonenkova, Peter Schürmann, Peter Hillemanns, Hans Christiansen, and Johann H. Karstens. ICICLE thanks Kelly Kohut, Michele Caneppele, and Maria Troy. KARMA and SASBAC thank the Swedish Medical Research Counsel. KBCP thanks Eija Myöhä-nen. kConFab/AOCS wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab. LAABC thanks all the study participants and the entire data collection team, especially Annie Fung and June Yashiki. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden, and Kathleen Corthouts. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers, and Stefan Nickels. MBCSG (Milan Breast Cancer Study Group): Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Erica Rosina, Daniela Zaffaroni, Irene Feroce, Mariarosaria Calvello, Aliana Guerrieri Gonzaga, Monica Marabelli, Davide Bondavalli, and the personnel of the Cogentech Cancer Genetic Test Laboratory. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. MYBRCA thanks study participants and research staff (particularly Patsy Ng, Nurhidayu Hassan, Yoon Sook-Yee, Daphne Lee, Lee Sheau Yee, Phuah Sze Yee, and Norhashimah Hassan) for their contributions and commitment to this study. The following are NBCS collaborators: Kristine K. Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, OSBREAC and Grethe I. Grenaker Alnæs. NBHS and SBCGS thank study participants and research staff for their contributions and commitment to the studies. OBCS thanks Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Meeri Otsukka, Leena Keskitalo, and Kari Mononen for their contributions to this study. The OFBCR thanks Teresa Selander, Nayana Weerasooriya, and Steve Gallinger. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of J. Molenaar. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, and Michael Stagner. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian, and Malcolm W.R. Reed. We thank the SEARCH and EPIC teams. SGBCC thanks the participants and all research coordinators for their excellent help with recruitment, data, and sample collection. SKKDKFZS. thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study.

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