Colorectal cancer (CRC) remains the third most common cancer in men and the second in women worldwide; thus, preventive strategies for CRC are critically needed. 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 CRC pathogenesis. Furthermore, previous studies found both calcium (Ca) and magnesium (Mg) inhibit the transport of arginine. Thus, Ca, Mg or Ca:Mg intake ratio may interact with polymorphisms in the SLC7A2 gene in risk of CRC. To test this hypothesis, we conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study (TCPS) among participants who completed a semi-quantitative 108-item food frequency questionnaire. In the first phase, 23 tagging single-nucleotide polymorphisms (SNPs) in the SLC7A2 gene were analyzed for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we evaluated for replicationthe significant findings from the first phase. We observed that no SNPs in SLC7A2 were significantly associated with the risk of colorectal adenoma at P < 0.05. However, rs2720574 significantly interacted with Ca:Mg intake ratio in association with adenoma risk, particularly multiple/advanced adenoma in both the first and second phases. In the combined analysis, among those with a Ca:Mg intake ratio below 2.78, individuals who carried GC/CC genotypes were at a higher risk of adenoma [odds ratio (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. Among those with the GG genotype, a high Ca:Mg ratio was associated with increased risks 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 Ca:Mg ratio was related to reduced risks of colorectal adenoma (0.64(0.42-0.99))and advanced/multiple adenomas (0.55(0.31-1.00)); p(interactions) = 0.002 and 0.0001 for total and advanced/multiple adenomas, respectively. These findings indicate the Ca:Mg ratio, instead of Mg or Ca alone, interacted with SLC7A2 polymorphism in risk of colorectal neoplasia.

Citation Format: Xiangzhu Zhu, Pin Sun, Martha J. Shrubsole, Reid M. Ness, Elizabeth A. Hibler, Qiuyin Cai, Jirong Long, Zhi Chen, Guoliang Li, Lifang Hou, Walter E. Smalley, Todd L. Edwards, Edward Giovannucci, Wei Zheng, Qi Dai. Genetic polymorphism in SLC7A2 interacts with calcium:magnesium intake ratio in risk of colorectal neoplasia in a two-phase study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 802.