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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.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.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).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 publication

DOI

10.1093/jnci/djv219

Type

Journal article

Journal

Journal of the National Cancer Institute

Publication Date

11/2015

Volume

107

Addresses

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center (BZ, XOS, RJD, CZ, WW, JL, WZ) and Department of Biostatistics (CL), Vanderbilt University School of Medicine, Nashville, TN; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care(KM, MKB, QW, JD, PDPP, DFE) and Department of Oncology (AMD, MS, BJP, CL, CB, SA, MM, CSH, PDPP, DFE), University of Cambridge, Cambridge, UK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KC, HD, ME); Copenhagen General Population Study (SEB, BGN, SFN), Department of Clinical Biochemistry (SEB, BGN, SFN), and Department of Breast Surgery (HF), Herlev Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (SEB, BGN); Vesalius Research Center (VRC), VIB, Leuven, Belgium (DL); Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium (DL); University Hospitals Leuven and Department of Oncology, Leuven, Belgium (PN, HW, GF); Netherlands Cancer Institute, Amsterdam, the Netherlands (MKS, MAR); Division Research, Department of Donor Studies, Sanquin Blood Supply, Amsterdam, the Netherlands (KVDH, WLAMDK); Department of Laboratory Medicine and Pathology (FJC) and Department of Health Sciences Research (JEO, EH, CV, SS), Mayo Clinic, Rochester, MN; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (JCC, AR, PS); Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (DFJ); Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK (JP, IDSS); Breakthrough Breast Cancer Research Centre, the Institute of Cancer Research, London, UK (OF, NJ); Department of Obstetrics and Gynecology (HN, TAM), D

Keywords

kConFab Investigators, Australian Ovarian Study Group, DRIVE Project, Humans, Breast Neoplasms, Body Height, Odds Ratio, Risk Factors, Prospective Studies, Evidence-Based Medicine, Female, Mendelian Randomization Analysis