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J Natl Cancer Inst. 2015 Aug 20;107(11). pii: djv219. doi: 10.1093/jnci/djv219. Print 2015 Nov.

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

Zhang B1, Shu XO1, Delahanty RJ1, Zeng C1, Michailidou K1, Bolla MK1, Wang Q1, Dennis J1, Wen W1, Long J1, Li C1, Dunning AM1, Chang-Claude J1, Shah M1, Perkins BJ1, Czene K1, Darabi H1, Eriksson M1, Bojesen SE1, Nordestgaard BG1, Nielsen SF1, Flyger H1, Lambrechts D1, Neven P1, Wildiers H1, Floris G1, Schmidt MK1, Rookus MA1, van den Hurk K1, de Kort WL1, Couch FJ1, Olson JE1, Hallberg E1, Vachon C1, Rudolph A1, Seibold P1, Flesch-Janys D1, Peto J1, Dos-Santos-Silva I1, Fletcher O1, Johnson N1, Nevanlinna H1, Muranen TA1, Aittomäki K1, Blomqvist C1, Li J1, Humphreys K1, Brand J1, Guénel P1, Truong T1, Cordina-Duverger E1, Menegaux F1, Burwinkel B1, Marme F1, Yang R1, Surowy H1, Benitez J1, Zamora MP1, Perez JI1, Cox A1, Cross SS1, Reed MW1, Andrulis IL1, Knight JA1, Glendon G1, Tchatchou S1, Sawyer EJ1, Tomlinson I1, Kerin MJ1, Miller N1, Chenevix-Trench G1; kConFab Investigators, Australian Ovarian Study Group, Haiman CA1, Henderson BE1, Schumacher F1, Marchand LL1, Lindblom A1, Margolin S1, Hooning MJ1, Martens JW1, Tilanus-Linthorst MM1, Collée JM1, Hopper JL1, Southey MC1, Tsimiklis H1, Apicella C1, Slager S1, Toland AE1, Ambrosone CB1, Yannoukakos D1, Giles GG1, Milne RL1, McLean C1, Fasching PA1, Haeberle L1, Ekici AB1, Beckmann MW1, Brenner H1, Dieffenbach AK1, Arndt V1, Stegmaier C1, Swerdlow AJ1, Ashworth A1, Orr N1, Jones M1, Figueroa J1, Garcia-Closas M1, Brinton L1, Lissowska J1, Dumont M1, Winqvist R1, Pylkäs K1, Jukkola-Vuorinen A1, Grip M1, Brauch H1, Brüning T1, Ko YD1, Peterlongo P1, Manoukian S1, Bonanni B1, Radice P1, Bogdanova N1, Antonenkova N1, Dörk T1, Mannermaa A1, Kataja V1, Kosma VM1, Hartikainen JM1, Devilee P1, Seynaeve C1, Van Asperen CJ1, Jakubowska A1, Lubiński J1, Jaworska-Bieniek K1, Durda K1, Hamann U1, Torres D1, Schmutzler RK1, Neuhausen SL1, Anton-Culver H1, Kristensen VN1, Grenaker Alnæs GI1; DRIVE Project, Pierce BL1, Kraft P1, Peters U1, Lindstrom S1, Seminara D1, Burgess S1, Ahsan H1, Whittemore AS1, John EM1, Gammon MD1, Malone KE1, Tessier DC1, Vincent D1, Bacot F1, Luccarini C1, Baynes C1, Ahmed S1, Maranian M1, Healey CS1, González-Neira A1, Pita G1, Alonso MR1, Álvarez N1, Herrero D1, Pharoah PD1, Simard J1, Hall P1, Hunter DJ1, Easton DF1, Zheng W1.

Author information

1
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

Abstract

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.

PMID:
26296642
PMCID:
PMC4643630
DOI:
10.1093/jnci/djv219
[Indexed for MEDLINE]
Free PMC Article

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