• Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, China 200032.
• Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203; Geriatric, Research, Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.
• Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203.
• Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203.
• Institute for Public Health and Medicine, Northwestern University, Chicago, IL.
• Geriatric, Research, Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212; Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203.
• Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA.
• Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, China 200032; Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203.
• Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, China 200032; Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203. Electronic address: qi.dai@vanderbilt.edu.

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)].