A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom.
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte California.
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
- Department of Genetics, Stanford University, Stanford, California.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- University of Hawaii Cancer Center, Honolulu, Hawaii.
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
- Huntsman Cancer Institute, Salt Lake City, Utah.
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
- Department of Medicine, Boston University School of Medicine, Slone Epidemiology Center, Boston University, Boston, Massachusetts.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.
SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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