Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study

Anja Rudolph, Rebecca Hein, Sara Lindström, Lars Beckmann, Sabine Behrens, Jianjun Liu, Hugues Aschard, Manjeet K. Bolla, Jean S Wang, Therese Truong, Emilie Cordina-Duverger, Florence Menegaux, Thomas Brüning, Volker Harth, Wing-Yee So, Gianluca Severi, Laura Baglietto, Melissa Southey, Stephen J Chanock, Jolanta LissowskaJonine D Figueroa, Mikael Eriksson, Keith Humpreys, Hatef Darabi, Janet E Olson, Kristen N. Stevens, Celine M Vachon, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Penny M. Webb, A. Green, Peter Parsons, N Hayward, Penelope M Webb, David C Whiteman, Pascal Guenel, Hiltrud Brauch, Graham Giles, Montserrat Garca-Closas, Kamila Czene, Georgia Chenevix-Trench, Fergus J Couch, Irene L Andrulis, Anthony J Swerdlow, David J. Hunter, Dieter Flesch-Janys, Douglas F Easton, Per Hall, Heli Nevanlinna, Peter Kraft, Jenny Chang-Claude

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23 Citations (Scopus)


Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-Analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) !3.0!10K3 were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-Analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint%8.9!10K6), two SNPs in SLC25A21 (combined Pint%4.8!10K5), and three SNPs in PLCG2 (combined Pint%4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint%2.7!10K5), one SNP in CD80 (combined Pint%8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint%2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint%4.6!10K5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

Original languageEnglish
Pages (from-to)875-887
Number of pages13
JournalEndocrine-Related Cancer
Issue number6
Publication statusPublished - Dec 2013
Externally publishedYes


  • Breast cancer
  • Genetic variation
  • Genome-wide
  • Menopausal hormone therapy

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