Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization.
Zhang B., Shu X-O., Delahanty RJ., Zeng C., Michailidou K., Bolla MK., Wang Q., Dennis J., Wen W., Long J., Li C., Dunning AM., Chang-Claude J., Shah M., Perkins BJ., Czene K., Darabi H., Eriksson M., Bojesen SE., Nordestgaard BG., Nielsen SF., Flyger H., Lambrechts D., Neven P., Wildiers H., Floris G., Schmidt MK., Rookus MA., van den Hurk K., de Kort WLAM., Couch FJ., Olson JE., Hallberg E., Vachon C., Rudolph A., Seibold P., Flesch-Janys D., Peto J., Dos-Santos-Silva I., Fletcher O., Johnson N., Nevanlinna H., Muranen TA., Aittomäki K., Blomqvist C., Li J., Humphreys K., Brand J., Guénel P., Truong T., Cordina-Duverger E., Menegaux F., Burwinkel B., Marme F., Yang R., Surowy H., Benitez J., Zamora MP., Perez JIA., Cox A., Cross SS., Reed MWR., Andrulis IL., Knight JA., Glendon G., Tchatchou S., Sawyer EJ., Tomlinson I., Kerin MJ., Miller N., Chenevix-Trench G., kConFab Investigators, Australian Ovarian Study Group None., Haiman CA., Henderson BE., Schumacher F., Marchand LL., Lindblom A., Margolin S., Hooning MJ., Martens JWM., Tilanus-Linthorst MMA., Collée JM., Hopper JL., Southey MC., Tsimiklis H., Apicella C., Slager S., Toland AE., Ambrosone CB., Yannoukakos D., Giles GG., Milne RL., McLean C., Fasching PA., Haeberle L., Ekici AB., Beckmann MW., Brenner H., Dieffenbach AK., Arndt V., Stegmaier C., Swerdlow AJ., Ashworth A., Orr N., Jones M., Figueroa J., Garcia-Closas M., Brinton L., Lissowska J., Dumont M., Winqvist R., Pylkäs K., Jukkola-Vuorinen A., Grip M., Brauch H., Brüning T., Ko Y-D., Peterlongo P., Manoukian S., Bonanni B., Radice P., Bogdanova N., Antonenkova N., Dörk T., Mannermaa A., Kataja V., Kosma V-M., Hartikainen JM., Devilee P., Seynaeve C., Van Asperen CJ., Jakubowska A., Lubiński J., Jaworska-Bieniek K., Durda K., Hamann U., Torres D., Schmutzler RK., Neuhausen SL., Anton-Culver H., Kristensen VN., Grenaker Alnæs GI., DRIVE Project None., Pierce BL., Kraft P., Peters U., Lindstrom S., Seminara D., Burgess S., Ahsan H., Whittemore AS., John EM., Gammon MD., Malone KE., Tessier DC., Vincent D., Bacot F., Luccarini C., Baynes C., Ahmed S., Maranian M., Healey CS., González-Neira A., Pita G., Alonso MR., Álvarez N., Herrero D., Pharoah PDP., Simard J., Hall P., Hunter DJ., Easton DF., Zheng W.
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.