Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

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Ben Zhang, Xiao-Ou Shu, Ryan J Delahanty, Chenjie Zeng, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, Wanqing Wen, Jirong Long, Chun Li, Alison M Dunning, Jenny Chang-Claude, Mitul Shah, Barbara J Perkins, Kamila Czene, Hatef Darabi, Mikael Eriksson, Stig E Bojesen, Børge G Nordestgaard & 31 others Sune F Nielsen, Henrik Flyger, Diether Lambrechts, Patrick Neven, Hans Wildiers, Giuseppe Floris, Marjanka K Schmidt, Matti A Rookus, Katja van den Hurk, Wim L A M de Kort, Fergus J Couch, Janet E Olson, Emily Hallberg, Celine Vachon, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Jingmei Li, Keith Humphreys, Judith Brand, Pascal Guénel, Thérèse Truong, kConFab Investigators, Australian Ovarian Study Group

BACKGROUND: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.

METHODS: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.

RESULTS: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).

CONCLUSIONS: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Original languageEnglish
Article numberdjv219
JournalNational Cancer Institute. Journal (Print)
Volume107
Issue number11
Pages (from-to)1-17
Number of pages17
ISSN0027-8874
DOIs
Publication statusPublished - Nov 2015

    Research areas

  • Body Height, Breast Neoplasms, Evidence-Based Medicine, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Prospective Studies, Risk Factors

ID: 161243190