Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

TY - JOUR

T1 - Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

AU - Wang, Xiaoliang

AU - Kapoor, Pooja Middha

AU - Auer, Paul L

AU - Dennis, Joe

AU - Dunning, Alison M

AU - Wang, Qin

AU - Lush, Michael

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K

AU - Aronson, Kristan J

AU - Murphy, Rachel A

AU - Brooks-Wilson, Angela

AU - Lee, Derrick G

AU - Cordina-Duverger, Emilie

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Mulot, Claire

AU - Teras, Lauren R

AU - Patel, Alpa V

AU - Dossus, Laure

AU - Kaaks, Rudolf

AU - Hoppe, Reiner

AU - Lo, Wing-Yee

AU - Brüning, Thomas

AU - Hamann, Ute

AU - Czene, Kamila

AU - Gabrielson, Marike

AU - Hall, Per

AU - Eriksson, Mikael

AU - Jung, Audrey

AU - Becher, Heiko

AU - Couch, Fergus J

AU - Larson, Nicole L

AU - Olson, Janet E

AU - Ruddy, Kathryn J

AU - Giles, Graham G

AU - MacInnis, Robert J

AU - Southey, Melissa C

AU - Le Marchand, Loic

AU - Wilkens, Lynne R

AU - Haiman, Christopher A

AU - Olsson, Håkan

AU - Augustinsson, Annelie

AU - Krüger, Ute

AU - Wagner, Philippe

AU - Scott, Christopher

AU - Winham, Stacey J

AU - Vachon, Celine M

AU - Perou, Charles M

AU - Olshan, Andrew F

AU - Troester, Melissa A

AU - Hunter, David J

AU - Eliassen, Heather A

AU - Tamimi, Rulla M

AU - Brantley, Kristen

AU - Andrulis, Irene L

AU - Figueroa, Jonine

AU - Chanock, Stephen J

AU - Ahearn, Thomas U

AU - García-Closas, Montserrat

AU - Evans, Gareth D

AU - Newman, William G

AU - van Veen, Elke M

AU - Howell, Anthony

AU - Wolk, Alicja

AU - Håkansson, Niclas

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Jones, Michael E

AU - Orr, Nick

AU - Schoemaker, Minouk J

AU - Swerdlow, Anthony J

AU - Kitahara, Cari M

AU - Linet, Martha

AU - Prentice, Ross L

AU - Easton, Douglas F

AU - Milne, Roger L

AU - Kraft, Peter

AU - Chang-Claude, Jenny

AU - Lindström, Sara

N1 - © 2022. The Author(s).

PY - 2022/4/13

Y1 - 2022/4/13

N2 - Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

AB - Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

KW - Breast

KW - Breast Neoplasms/chemically induced

KW - Estrogen Replacement Therapy/adverse effects

KW - Female

KW - Hormone Replacement Therapy/adverse effects

KW - Humans

KW - Male

KW - Menopause

KW - Risk Factors

U2 - 10.1038/s41598-022-10121-2

DO - 10.1038/s41598-022-10121-2

M3 - SCORING: Journal article

C2 - 35418701

VL - 12

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

M1 - 6199

ER -