Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC4643630 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Zhang Ben B Shu Xiao-Ou XO Delahanty Ryan J RJ Zeng Chenjie C Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Dennis Joe J Wen Wanqing W Long Jirong J Li Chun C Dunning Alison M AM Chang-Claude Jenny J Shah Mitul M Perkins Barbara J BJ Czene Kamila K Darabi Hatef H Eriksson Mikael M Bojesen Stig E SE Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Lambrechts Diether D Neven Patrick P Wildiers Hans H Floris Giuseppe G Schmidt Marjanka K MK Rookus Matti A MA van den Hurk Katja K de Kort Wim L A M WL Couch Fergus J FJ Olson Janet E JE Hallberg Emily E Vachon Celine C Rudolph Anja A Seibold Petra P Flesch-Janys Dieter D Peto Julian J Dos-Santos-Silva Isabel I Fletcher Olivia O Johnson Nichola N Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Li Jingmei J Humphreys Keith K Brand Judith J Guénel Pascal P Truong Thérèse T Cordina-Duverger Emilie E Menegaux Florence F Burwinkel Barbara B Marme Frederik F Yang Rongxi R Surowy Harald H Benitez Javier J Zamora M Pilar MP Perez Jose I A JI Cox Angela A Cross Simon S SS Reed Malcolm W R MW Andrulis Irene L IL Knight Julia A JA Glendon Gord G Tchatchou Sandrine S Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Chenevix-Trench Georgia G Haiman Christopher A CA Henderson Brian E BE Schumacher Fredrick F Marchand Loic Le LL Lindblom Annika A Margolin Sara S Hooning Maartje J MJ Martens John W M JW Tilanus-Linthorst Madeleine M A MM Collée J Margriet JM Hopper John L JL Southey Melissa C MC Tsimiklis Helen H Apicella Carmel C Slager Susan S Toland Amanda E AE Ambrosone Christine B CB Yannoukakos Drakoulis D Giles Graham G GG Milne Roger L RL McLean Catriona C Fasching Peter A PA Haeberle Lothar L Ekici Arif B AB Beckmann Matthias W MW Brenner Hermann H Dieffenbach Aida Karina AK Arndt Volker V Stegmaier Christa C Swerdlow Anthony J AJ Ashworth Alan A Orr Nick N Jones Michael M Figueroa Jonine J Garcia-Closas Montserrat M Brinton Louise L Lissowska Jolanta J Dumont Martine M Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Brauch Hiltrud H Brüning Thomas T Ko Yon-Dschun YD Peterlongo Paolo P Manoukian Siranoush S Bonanni Bernardo B Radice Paolo P Bogdanova Natalia N Antonenkova Natalia N Dörk Thilo T Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Devilee Peter P Seynaeve Caroline C Van Asperen Christi J CJ Jakubowska Anna A Lubiński Jan J Jaworska-Bieniek Katarzyna K Durda Katarzyna K Hamann Ute U Torres Diana D Schmutzler Rita K RK Neuhausen Susan L SL Anton-Culver Hoda H Kristensen Vessela N VN Grenaker Alnæs Grethe I GI Pierce Brandon L BL Kraft Peter P Peters Ulrike U Lindstrom Sara S Seminara Daniela D Burgess Stephen S Ahsan Habibul H Whittemore Alice S AS John Esther M EM Gammon Marilie D MD Malone Kathleen E KE Tessier Daniel C DC Vincent Daniel D Bacot Francois F Luccarini Craig C Baynes Caroline C Ahmed Shahana S Maranian Mel M Healey Catherine S CS González-Neira Anna A Pita Guillermo G Alonso M Rosario MR Álvarez Nuria N Herrero Daniel D Pharoah Paul D P PD Simard Jacques J Hall Per P Hunter David J DJ Easton Douglas F DF Zheng Wei W

Journal of the National Cancer Institute 20150820 11

<h4>Background</h4>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.<h4>Methods</h4>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 ind ...[more]

PMID: 26296642

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Project description: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.

Project description:Purpose of review:In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i.e., "instrumental variables" or IVs), and these can be used to obtain an effect estimate that, under certain assumptions, is not prone to bias caused by unobserved confounding or reverse causality. This review seeks to describe how MR studies have contributed to our understanding of cancer causation. Recent findings:We searched the published literature and identified 76 MR studies of cancer risk published prior to October 31, 2017. Risk factors commonly studied included alcohol consumption, Vitamin D, anthropometric traits, telomere length, lipid traits, glycemic traits, and markers of inflammation. Risk factors showing compelling evidence of a causal association with risk for at least one cancer type include alcohol consumption (for head/neck and colorectal), adult body mass index (increases risk for multiple cancers, but decreases risk for breast), height (increases risk for breast, colorectal, and lung; decreases risk for esophageal), telomere length (increases risk for lung adenocarcinoma, melanoma, renal cell carcinoma, glioma, B-cell lymphoma subtypes, chronic lymphocytic leukemia, and neuroblastoma), and hormonal factors (affects risk for sex-steroid sensitive cancers). Summary:This review highlights alcohol consumption, body mass index, height, telomere length, and the hormonal exposures as factors likely to contribute to cancer causation. This review also highlights the need to study specific cancer types, ideally subtypes, as the effects of risk factors can be heterogeneous across cancer types. As consortia-based genome-wide association studies increase in sample size and analytical methods for MR continue to become more sophisticated, MR will become an increasingly powerful tool for understanding cancer causation.

Project description:BackgroundObservational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.Methods and findingsIn summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.ConclusionsIn this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.

Project description:The Rho GTPase family consists of 20 genes encoding intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. They are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. As a sensitivity analysis, we undertook co-localisation to examine whether findings reflected shared causal variants or genomic confounding. We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI) 1.03, 1.09; P = 5.65 × 10-5) and OR 1.22 (95% CI 1.11, 1.35; P = 5.22 × 10-5) in normal breast tissue and blood respectively). There was a consistent direction of association for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was negatively associated with overall and ER + breast cancer risk. The evidence from colocalization analyses strongly supported our MR results particularly for RHOD. Our study suggests a potential causal role of increased RHOD gene expression, and, although the evidence is weaker, a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.

Dataset Information

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

Publications

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

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