Association of body mass index with colorectal cancer risk by genome-wide variants.,Journal of the National Cancer Institute

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Association of body mass index with colorectal cancer risk by genome-wide variants.
Journal of the National Cancer Institute ( IF 9.9 ) Pub Date : 2020-09-03 , DOI: 10.1093/jnci/djaa058
Peter T Campbell ₁ , Yi Lin ₂ , Stephanie A Bien ₂ , Jane C Figueiredo _{3,

4} , Tabitha A Harrison ₂ , Mark A Guinter ₁ , Sonja I Berndt ₅ , Hermann Brenner _{6,

7,

8} , Andrew T Chan _{9,

10,

11,

12,

13,

14} , Jenny Chang-Claude _{15,

16} , Steven J Gallinger ₁₇ , Susan M Gapstur ₁ , Graham G Giles _{18,

19,

20} , Edward Giovannucci _{13,

21} , Stephen B Gruber ₂₂ , Marc Gunter ₂₃ , Michael Hoffmeister ₆ , Eric J Jacobs ₁ , Mark A Jenkins ₁₉ , Loic Le Marchand ₂₄ , Li Li ₂₅ , John R McLaughlin ₂₆ , Neil Murphy ₂₃ , Roger L Milne _{18,

19,

20} , Polly A Newcomb ₂ , Christina Newton ₁ , Shuji Ogino _{12,

13,

27,

28} , John D Potter ₂ , Gad Rennert _{29,

30,

31} , Hedy S Rennert _{29,

30,

31} , Jennifer Robinson ₃₂ , Lori C Sakoda _{2,

33} , Martha L Slattery ₃₄ , Yiqing Song ₃₅ , Emily White _{2,

36} , Michael O Woods ₃₇ , Graham Casey ₃₈ , Li Hsu ₂ , Ulrike Peters _{2,

36}

Affiliation

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Preventive Oncology, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Center for Precision Medicine and Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
University of Hawaii Cancer Center, Honolulu, HI, USA.
Department of Family Medicine and Cancer Center, University of Virginia, Charlottesville, VA, USA.
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA, USA.
Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Clalit National Cancer Control Center, Haifa, Israel.
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA.
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Abstract

Background

Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk.

Methods

We tested multiplicative statistical interactions between BMI (per 5 kg/m²) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided.

Results

Each 5 kg/m² increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10^–17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10^–24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; P_observed = .0009; P_threshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10^–10). Each 5 kg/m² increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10^–10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10^–8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes.

Conclusion

These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

中文翻译：

全基因组变异的体重指数与结直肠癌风险的关联。

抽象的

背景

体重指数 (BMI) 是一种复杂的表型，可能与遗传变异相互作用，从而影响结直肠癌风险。

方法

我们在 14 059 名结直肠癌病例（53.2% 女性）和 14 416 名对照组（53.8% 女性）参与者中测试了 BMI（每 5 kg/m ² ）和大约 270 万个单核苷酸多态性与结直肠癌风险之间的乘性统计交互作用。所有分析均按性别先验分层。统计方法包括两步（即鸡尾酒法）和单步（即病例对照逻辑回归和联合二自由度检验）程序。所有统计检验都是双面的。

结果

BMI 每增加 5 kg/m ²与结直肠癌风险升高相关，女性则较少（比值比 [OR] = 1.14，95% 置信区间 [CI] = 1.11 至 1.18； P = 9.75 × 10 ^–17 ）高于男性（OR = 1.26，95% CI = 1.20 至 1.32； P = 2.13 × 10 ^–24 ）。两步鸡尾酒法确定了女性（而非男性）BMI 与 18q21.1 处SMAD7内含子变异之间的相互作用（rs4939827；_观察到的P = .0009； P_阈值= .005）。联合 2 自由度测试与女性的这一发现一致（联合P = 2.43 × 10 ^–10 ）。与具有 rs4939827 -CC基因型的女性相比，BMI 每增加 5 kg/m ²与结直肠癌风险的相关性更强（OR = 1.24，95% CI = 1.16 至 1.32； P = 2.60 × 10 ^–10 ） CT （OR = 1.14，95% CI = 1.09 至 1.19； P = 1.04 × 10 ^–8 ）或TT （OR = 1.07，95% CI = 1.01 至 1.14； P = .02）基因型。

结论

这些结果为SMAD7变异（之前被确定为结直肠癌易感位点）和 BMI 可能影响女性结直肠癌风险的潜在机制提供了新的见解。

更新日期：2020-09-03

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