TY - JOUR

T1 - Height and Breast Cancer Risk

T2 - Evidence From Prospective Studies and Mendelian Randomization

AU - Zhang, Ben

AU - Shu, Xiao-Ou

AU - Delahanty, Ryan J

AU - Zeng, Chenjie

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Wen, Wanqing

AU - Long, Jirong

AU - Li, Chun

AU - Dunning, Alison M

AU - Chang-Claude, Jenny

AU - Shah, Mitul

AU - Perkins, Barbara J

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Lambrechts, Diether

AU - Neven, Patrick

AU - Wildiers, Hans

AU - Floris, Giuseppe

AU - Schmidt, Marjanka K

AU - Rookus, Matti A

AU - van den Hurk, Katja

AU - de Kort, Wim L A M

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Hallberg, Emily

AU - Vachon, Celine

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Nevanlinna, Heli

AU - Muranen, Taru A

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Li, Jingmei

AU - Humphreys, Keith

AU - Brand, Judith

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - kConFab Investigators, Australian Ovarian Study Group

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Body Height

KW - Breast Neoplasms

KW - Evidence-Based Medicine

KW - Female

KW - Humans

KW - Mendelian Randomization Analysis

KW - Odds Ratio

KW - Prospective Studies

KW - Risk Factors

U2 - 10.1093/jnci/djv219

DO - 10.1093/jnci/djv219

M3 - Journal article

C2 - 26296642

VL - 107

SP - 1

EP - 17

JO - National Cancer Institute. Journal (Print)

JF - National Cancer Institute. Journal (Print)

SN - 0027-8874

IS - 11

M1 - djv219

ER -