天生越胖，乳腺癌风险越低？

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　　编者按：肥胖主要通过实际测量的体重指数判断，但是肥胖如同癌症一样，既有先天原发的遗传因素，又有后天继发的环境因素，因此实际测量的体重指数并非一成不变。如果先天性原发性肥胖，通过改变后天继发的环境因素，减少体重指数，那么乳腺癌风险是否也会减少？西方学者通过基因预测的体重指数（而非实际测量的体重指数）对大样本欧洲血统女性人群进行了研究。

　　既往流行病学观察研究表明，体重指数高，与绝经前妇女的乳腺癌风险减少、绝经后妇女的乳腺癌风险增加有相关性。尚不清楚该相关性通过基因共享还是环境因素所致。

　　2016年8月23日，美国《公共科学图书馆·医学》在线发表美国、英国、澳大利亚、荷兰、德国、丹麦、芬兰、加拿大、西班牙、意大利、挪威、瑞典、希腊、法国、波兰、比利时的人群研究报告，对14.5万欧洲血统女性的基因预测体重指数与乳腺癌风险进行了分析。

　　该研究采用孟德尔随机，根据两大乳腺癌研究组织（BCAC、DRIVE）的数据，评估了体重指数与乳腺癌风险之间的相关性。研究者创建了包括84项体重指数相关基因变异的加权体重指数基因评分以预测体重指数，使用BCAC的个体数据（患者46325例，对照42482例）和DRIVE的汇总统计（患者16003例，对照41335例）评估了基因预测体重指数与乳腺癌风险的相关性。由于大多数研究在癌症诊断后实测体重指数，故无法进行前瞻性平行分析以充分评估实测体重指数与乳腺癌风险的相关性。

　　结果发现：

• 在BCAC的数据中，基因预测体重指数每增加5kg/m²，乳腺癌风险减少35%（P=3.32×10-8），绝经前、后的乳腺癌风险减少相似，分别为56%（P=9.91×10-8）、43%（P=1.88×10-8）。

• 在DRIVE的数据数据中，基因预测体重指数每增加5kg/m²，乳腺癌风险减少28%（P=1.64×10-7）。

• 通过单标志物分析，从84项体重指数相关单核苷酸多态性（SNP）中，确定17项与乳腺癌风险有相关性（P＜0.05），其中16项等位基因相关体重指数增加与乳腺癌风险减少有相关性。

　　因此，通过全基因组相关性研究确定变异预测的体重指数，与绝经前、后的乳腺癌风险均有负相关性。该研究所见绝经后乳腺癌风险减少，与基因预测体重指数增加有相关性，不同于既往采用实测成人体重指数研究报告的相关性。探索该差异的原因，可能揭示体重遗传因素与乳腺癌病因的复杂关系。

PLoS Med. 2016 Aug 23;13(8):e1002105.

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Guo Y, Warren Andersen S, Shu XO, Michailidou K, Bolla MK, Wang Q, Garcia-Closas M, Milne RL, Schmidt MK, Chang-Claude J, Dunning A, Bojesen SE, Ahsan H, Aittomaki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bogdanova NV, Bonanni B, Borresen-Dale AL, Brand J, Brauch H, Brenner H, Brüning T, Burwinkel B, Casey G, Chenevix-Trench G, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dork T, Dumont M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fostira F, Gammon M, Giles GG, Guénel P, Haiman CA, Hamann U, Hooning MJ, Hopper JL, Jakubowska A, Jasmine F, Jenkins M, John EM, Johnson N, Jones ME, Kabisch M, Kibriya M, Knight JA, Koppert LB, Kosma VM, Kristensen V, Le Marchand L, Lee E, Li J, Lindblom A, Luben R, Lubinski J, Malone KE, Mannermaa A, Margolin S, Marme F, McLean C, Meijers-Heijboer H, Meindl A, Neuhausen SL, Nevanlinna H, Neven P, Olson JE, Perez JI, Perkins B, Peterlongo P, Phillips KA, Pylkas K, Rudolph A, Santella R, Sawyer EJ, Schmutzler RK, Seynaeve C, Shah M, Shrubsole MJ, Southey MC, Swerdlow AJ, Toland AE, Tomlinson I, Torres D, Truong T, Ursin G, Van Der Luijt RB, Verhoef S, Whittemore AS, Winqvist R, Zhao H, Zhao S, Hall P, Simard J, Kraft P, Pharoah P, Hunter D, Easton DF, Zheng W.

Vanderbilt University, Nashville, Tennessee, USA; University of Cambridge, Cambridge, UK; The Institute of Cancer Research, London, UK; Cancer Council Victoria, Melbourne, Australia; The University of Melbourne, Melbourne, Australia; Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands; German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Ulm, Ulm, Germany; University of Sheffield, Sheffield, UK; University of Copenhagen, Copenhagen, Denmark; Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; The University of Chicago, Chicago, Illinois, USA; University of Helsinki, Helsinki, Finland; Mount Sinai Hospital, Toronto, Canada; University of Toronto, Toronto, Canada; University of California Irvine, Irvine, California, USA; Spanish National Cancer Research Centre, Madrid, Spain; Centro de Investigacion en Red de Enfermedades Raras, Valencia, Spain; Hannover Medical School, Hannover, Germany; Istituto Europeo di Oncologia, Milan, Italy; University of Oslo, Oslo, Norway; Karolinska Institutet, Stockholm, Sweden; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; Ruhr University Bochum, Bochum, Germany; University of Southern California, Los Angeles, California, USA; QIMR Berghofer Medical Research Institute, Brisbane, Australia; Mayo Clinic, Rochester, Minnesota, USA; Leiden University Medical Center, Leiden, The Netherlands; Laval University, Québec City, Canada; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; University of California at Los Angeles, Los Angeles, California, USA; National Cancer Institute, Rockville, Maryland, USA; University Medical Center Hamburg-Eppendorf, Hamburg, Germany; National Centre for Scientific Research "Demokritos", Athens, Greece; University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, USA; Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France; University Paris-Sud, Villejuif, France; Erasmus University Medical Center, Rotterdam, The Netherlands; Pomeranian Medical University, Szczecin, Poland; Cancer Prevention Institute of California, Fremont, California, USA; Stanford University School of Medicine, Stanford, California, USA; Kuopio University Hospital, Kuopio, Finland; University of Eastern Finland, Kuopio, Finland; University of Hawaii Cancer Center, Honolulu, Hawaii, USA; Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; University of Heidelberg, Heidelberg, Germany; The Alfred Hospital, Melbourne, Australia; VU University Medical Center, Amsterdam, The Netherlands; Technische Universitat München, Munich, Germany; Beckman Research Institute of City of Hope, Duarte, California, USA; University Hospital Gasthuisberg, Leuven, Belgium; Hospital Monte Naranco, Oviedo, Spain; Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy; The University of Melbourne, Fitzroy, Australia; University of Oulu, Oulu, Finland; Columbia University Medical Center, New York, New York, USA; Mailman School of Public Health of Columbia University, New York, New York, USA; King's College London, London, UK; University Hospital of Cologne, Cologne, Germany; The Ohio State University, Columbus, Ohio, USA; University of Oxford, Oxford, UK; University Medical Center Utrecht, Utrecht, The Netherlands; Northern Finland Laboratory Centre NordLab, Oulu, Finland; Vesalius Research Center, Leuven, Belgium; University of Leuven, Leuven, Belgium; Harvard School of Public Health, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.

METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.

RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32×10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91×10-8) and postmenopausal breast cancer (OR = 0.57, 95%CI: 0.46-0.71, p = 1.88×10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95%CI: 0.60-0.84, p = 1.64×10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p<0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.

CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

PMID: 27551723

PMCID: PMC4995025

DOI: 10.1371/journal.pmed.1002105