Abstract 4832: High calcium reduces multiple or advanced colorectal adenoma risk by nearly 90% among those with variant alleles in two critical genes in calcium reabsorption.
Authors: Zhu Xiangzhu , Shrubsole Martha J. , Ness Reid M. , Cai Qiuyin , Long Jirong , Chen Zhi , Liang Ji , Li Guoliang , Smalley Walter E. , Edwards Todd L. , Giovannucci Edward , Zheng Wei , Dai Qi 
Published: August 2014

Abstract
Despite the rapidly increasing use of colonoscopy, colorectal cancer still remains the 2nd most common cause of cancer death in the United States. Most of these colorectal cancers arise from adenomas. High calcium consumption has been linked to reduced risks of colorectal adenoma and cancer. However, results from a large clinical trial conducted in the general population were not consistent from those conducted among colorectal adenoma patients. Adenoma patients have a lower intake of calcium than general population. Furthermore, previous studies indicate there is substantial inter-individual variation in the ability to (re)absorb calcium, which is mostly attributed to genetic variation. Thus, we hypothesized that some of the inconsistency in previous studies was due to interactions between calcium and genetic polymorphisms involved in calcium homeostasis. In an NIH R01 project, we conducted a two- phase study to evaluate whether polymorphisms in KCNJ1 and 13 other genes modified the associations between calcium intake and risk of colorectal adenoma. Included in the study were 1818 cases and 3992 controls identified from the Tennessee Colorectal Polyp Study (TCPS), a colonoscopy-based case control study conducted in Nashville, TN. We identified in Phase 1 and replicated in Phase 2 that two polymorphisms in two genes (i.e. one SNP in each gene) significantly modified the associations between calcium intake and colorectal adenoma risk. One gene is potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), which etiologically leads to hereditary familial diseases with impairments in reabsorption for calcium. The p for interaction with the SNP in the KCNJ1 gene remained statistically significant after Bonferroni correction for multiple comparisons (all SNPs in 14 genes). In the combined analysis of these two genes, we found 52% of the study population carry at least one variant allele in one of two genes while 13% of the population carry variant alleles in both genes. We found among those with zero variant alleles in two genes, the highest tertile of calcium intake was not associated with adenoma risk with an OR (95% CI) of 1.06(0.65-1.72). Highest calcium intake tertile was significantly associated with a 39% reduced adenoma risk among those who carry variant allele in one gene (p for trend, 0.046), and with a 69% reduced risk among those with alleles in both genes (p for trend, 0.039). The corresponding reduction in risk with advanced or multiple adenomas increased to 89% (95%CI: 41%-98%) among those with variant alleles in both genes (p for interaction, 5.5×10−5). In summary, high intake of calcium may only protect against colorectal carcinogenesis among those who carry variant alleles in two genes, particularly for those who carry variant alleles in both genes.
Citation Format: Xiangzhu Zhu, Martha J. Shrubsole, Reid M. Ness, Qiuyin Cai, Jirong Long, Zhi Chen, Ji Liang, Guoliang Li, Walter E. Smalley, Todd L. Edwards, Edward Giovannucci, Wei Zheng, Qi Dai. High calcium reduces multiple or advanced colorectal adenoma risk by nearly 90% among those with variant alleles in two critical genes in calcium reabsorption. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4832. doi:10.1158/1538-7445.AM2013-4832