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

Zhang, Ben; Shu, Xiao‐Ou; Delahanty, Ryan; Zeng, Chenjie; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Wen, Wanqing; Long, Jirong; Li, Chun; Dunning, Alison M.; Chang‐Claude, Jenny; Shah, Mitul; Perkins, Barbara; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; Floris, Giuseppe; Schmidt, Marjanka K.; Rookus, Matti A.; Hurk, Katja van den; Kort, Wim de; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine M.; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; dos‐Santos‐Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Nevanlinna, Heli; Muranen, Taru; Aittomäki, Kristiina; Blomqvist, Carl; Li, Jingmei; Humphreys, Keith; Brand, Judith S.; Guénel, Pascal; Truong, Thérèse; Cordina‐Duverger, Emilie; Ménégaux, Florence; Burwinkel, Barbara; Marmé, Frederik; Yang, Rongxi; Surowy, Harald; Benı́tez, Javier; Zamora, M. Pilar; Peŕez, José Ignacio Arias; Cox, Angela; Cross, Simon S.; Reed, Malcolm; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Chenevix-Trench, Georgia; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Marchand, Loı̈c Le; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J.; Martens, John W.M.; Tilanus-Linthorst, Madeleine M.A.; Collée, J. Margriet; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Slager, Susan L.; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael E.; Figueroa, Jonine D.; García-Closas, Montserrat; Brinton, Louise A.; Lissowska, Jolanta; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon‐Dschun; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Radice, Paolo; Bogdanova, Natalia; Antonenkova, Natalia; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli‐Matti; Hartikainen, Jaana M.; Devilee, Peter; Seynaeve, C.; Asperen, Christi J. van; Jakubowska, Anna; Lubiński, Jan; Jaworska–Bieniek, Katarzyna; Durda, Katarzyna; Hamann, Ute; Torres, Diana; Schmutzler, Rita K.; Neuhausen, Susan L.; Anton‐Culver, Hoda; Kristensen, Vessela N.; Alnæs, Grethe I.G.; Pierce, Brandon L.; Kraft, Peter; Peters, Ulrike; Lindström, Sara; Seminara, Daniela; Burgess, Stephen; Ahsan, Habibul; Whittemore, Alice S.; John, Esther M.; Gammon, Marilie D.; Malone, Kathleen E.; Tessier, Daniel C.; Denis, Vincent; Bertucci, François; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; González‐Neira, Anna; Pita, Guillermo; Alonso, María R.; Álvarez, Núria; Herrero, Daniel; Pharoah, Paul D.P.; Simard, Jacques; Hall, Per; Hunter, David J.; Easton, Douglas F.; Wang, Zheng

doi:10.1093/jnci/djv219

Cited by 108 publications

(106 citation statements)

References 72 publications

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“…Our finding confirms and extends the results from observational studies that have shown that taller height is associated with improved cognitive performance [6–8], lower rates of death from dementia [9], and reduced risk of AD [10]. The association between genetically predicted height and AD is in the same direction as the genetic association between height and risk of cardiovascular disease [12, 13] but opposed the direction for certain cancers [14–16]. …”

Section: Discussionsupporting

confidence: 87%

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Genetically-Predicted Adult Height and Alzheimer’s Disease

Larsson

Traylor

Burgess

et al. 2017

JAD

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Background Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer’s disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. Objective To use a genetic approach to investigate the association between adult height and AD. Methods We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5 × 10−8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer’s Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. Results The odds ratio of AD was 0.91 (95% confidence interval, 0.86–0.95; p = 9.8 × 10−5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86–0.97; p = 4.8 × 10−3). Conclusion This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

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Section: Discussionsupporting

confidence: 87%

“…This genetic approach has been utilized to explore the association between adult height and risk of cardiovascular disease [12, 13] and cancer [14–16], but has not yet been used to investigate the association between height and AD. The aim of this study was to examine whether genetically predicted height is associated with AD.…”

Section: Introductionmentioning

confidence: 99%

Genetically-Predicted Adult Height and Alzheimer’s Disease

Larsson

Traylor

Burgess

et al. 2017

JAD

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“… a Summary sample sizes of studies included in the GAME-ON consortium. b The total number of SNPs used to construct the instrumental variable. c OR and RR represent the risk associated with a 10-cm increase in adult height. d Meta-analysis summary OR and 95% CI previously reported [53]. …”

Section: Resultsmentioning

confidence: 99%

Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses

et al. 2016

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BackgroundObservational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.Methods and FindingsA systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.ConclusionsOur study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.

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“…The authors do not draw conclusions regarding the association of height with breast cancer risk according to ER/PR status. Instead, they conclude that their results demonstrate that height is causally implicated in breast cancer etiology and that height and breast cancer share genetic risk variants (33). …”

Section: Discussionmentioning

confidence: 99%

“…A recent meta-analysis of 159 prospective cohorts that included 5,216,302 women and 9,732 breast cancer cases with known ER status, found a positive association between height and risk of ER+ tumors (HR: 1.18, 95% CI: 1.13-1.23 per 10cm increase), but no association with ER− tumors (HR: 1.00, 95% CI: 0.86-1.14). Interestingly, when tumors were classified jointly by ER and progesterone receptor (PR) status, there was a borderline significant association with ER−/PR− tumors (HR: 1.08, 95% CI: 0.99-1.18) (33). They also conducted a Mendelian randomization analysis using a genetic risk score derived from 168 height-associated variants and found strong positive associations with ER+ and ER+/PR+ tumors and no association with ER− or ER−/PR− tumors.…”

Section: Discussionmentioning

confidence: 99%

Height and Body Size in Childhood, Adolescence, and Young Adulthood and Breast Cancer Risk According to Molecular Subtype in the Nurses' Health Studies

Warner

Collins

et al. 2016

Cancer Prevention Research

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Height and body size in childhood and young adulthood have been consistently associated with breast cancer risk; whether associations differ across molecular subtypes is unclear. In a pooled analysis of the Nurses’ Health Studies we prospectively examined the association of four exposures: height, body mass index (BMI) at age 18, childhood and adolescent somatotypes, with breast cancer risk according to molecular subtypes defined by immunohistochemical markers. We used multivariable-adjusted Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI).We identified 2983 luminal A, 1281 luminal B, 318 HER2-enriched, 408 basal-like and 128 unclassified tumors. Height was positively associated with all subtypes (p-heterogeneity=0.78). BMI at age 18 (p-heterogeneity=0.001), childhood (p-heterogeneity=0.51) and adolescent somatotype (p-heterogeneity=0.046) were inversely associated, but with differences in magnitude of association. BMI at age 18 of ≥25 kg/m2 (compared to 20-21.9 kg/m2) was associated with a 52% decreased risk of HER2-enriched (HR: 0.48, 95%CI: 0.26-0.91; p-trend <0.0001) and 39% reduced risk of basal-like tumors (HR: 0.61, 95% CI: 0.36-1.02; p-trend=0.008). Compared to the lowest category, women in the highest adolescent body size category were 71% less likely to develop HER2-enriched (HR: 0.29, 95%CI: 0.10-0.85; p-trend=0.0005) and 60% less likely to develop basal-like (HR: 0.40, 95%CI: 0.17-0.95; p-trend=0.0008). Height was positively associated with risk of all breast cancer molecular subtypes. BMI at age 18 and childhood and adolescent were inversely associated with risk of most breast cancer molecular subtypes with somewhat stronger associations with HER2-enriched and basal-like subtypes.

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

Abstract: 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.

Cited by 108 publications

References 72 publications

Genetically-Predicted Adult Height and Alzheimer’s Disease

Genetically-Predicted Adult Height and Alzheimer’s Disease

Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses

Height and Body Size in Childhood, Adolescence, and Young Adulthood and Breast Cancer Risk According to Molecular Subtype in the Nurses' Health Studies

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