• Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
• Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
• Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, United States of America.
• Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, United States of America.
• Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
• Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
• Cancer Care Ontario, Toronto, Ontario, Canada.
• Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
• Department of Surgery, University Health Network Toronto General Hospital, Toronto, Ontario, Canada.

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.