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?
Authors: Park JooYong , Choi Ji-Yeob , Choi Jaesung , Chung Seokang , Song Nan , Park Sue K. , Han Wonshik , Noh Dong-Young , Ahn Sei-Hyun , Lee Jong Won , Kim Mi Kyung , Jee Sun Ha , Wen Wanqing , Bolla Manjeet K. , Wang Qin , Dennis Joe , Michailidou Kyriaki , Shah Mitul , Conroy Don M. , Harrington Patricia A. , Mayes Rebecca , Czene Kamila , Hall Per , Teras Lauren R. , Patel Alpa V. , Couch Fergus J. , Olson Janet E. , Sawyer Elinor J. , Roylance Rebecca , Bojesen Stig E. , Flyger Henrik , Lambrechts Diether , Baten Adinda , Matsuo Keitaro , Ito Hidemi , Guénel Pascal , Truong Thérèse , Keeman Renske , Schmidt Marjanka K. , Wu Anna H. , Tseng Chiu-Chen , Cox Angela , Cross Simon S. ,   kConFab Investigators, Andrulis Irene L. , Hopper John L. , Southey Melissa C. , Wu Pei-Ei , Shen Chen-Yang , Fasching Peter A. , Ekici Arif B. , Muir Kenneth , Lophatananon Artitaya , Brenner Hermann , Arndt Volker , Jones Michael E. , Swerdlow Anthony J. , Hoppe Reiner , Ko Yon-Dschun , Hartman Mikael , Li Jingmei , Mannermaa Arto , Hartikainen Jaana M. , Benitez Javier , González-Neira Anna , Haiman Christopher A. , Dörk Thilo , Bogdanova Natalia V. , Teo Soo Hwang , Mohd Taib Nur Aishah , Fletcher Olivia , Johnson Nichola , Grip Mervi , Winqvist Robert , Blomqvist Carl , Nevanlinna Heli , Lindblom Annika , Wendt Camilla , Kristensen Vessela N. ,   NBCS Collaborators, Tollenaar Rob A. E. M. , Heemskerk-Gerritsen Bernadette A. M. , Radice Paolo , Bonanni Bernardo , Hamann Ute , Manoochehri Mehdi , Lacey James V. , Martinez Maria Elena , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Yoo Keun-Young , Kang Daehee 
Published: May 2021

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.