Newswise — WASHINGTON, D.C. — Researchers have identified a potential explanation for inconsistent results from prior research about the association between calcium intake and risk for colorectal adenomas, which are precursors to colorectal cancers. The findings may help identify patients who would benefit from higher calcium intake or calcium supplementation, according to the researcher who presented the data at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
Previous studies suggested that a high intake of calcium was associated with a reduced risk for colorectal adenomas and cancer, but data from the Women’s Health Initiative did not support the benefit for colorectal cancer after seven years of follow-up, according to Xiangzhu Zhu, M.D., M.P.H., staff scientist in the Division of Epidemiology in the Department of Medicine at Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine in Nashville, Tenn.
Zhu and colleagues conducted a two-phase study to investigate whether the associations between risk for colorectal adenoma and intake of calcium and magnesium, as well as the calcium/magnesium ratio, were modified by common changes in 14 genes involved in controlling the amounts of calcium and magnesium in the body.
They evaluated 1,818 cases and 3,992 controls from the Tennessee Colorectal Polyp Study, a colonoscopy-based case-control study conducted in Nashville. Patients with the highest calcium intake showed no reduction in their risk for colorectal adenoma if they had no changes in either of two of the 14 genes analyzed, the KCNJ1 and SLC12A1 genes, both of which were identified and replicated in the two-phase study and are essential in calcium reabsorption in the kidney.
Fifty-two percent of the study population carried genetic changes in at least one of the two genes, and 13 percent of the population carried genetic changes in both genes. The highest calcium intake — patients in the top 33 percent — was significantly related to a 39 percent reduction in adenoma risk for patients who carried a genetic change in one gene and a 69 percent reduction in adenoma risk among those who carried genetic changes in both genes, according to Zhu. In addition, the corresponding reduction in risk for advanced or multiple adenomas was 89 percent among those with genetic changes in both genes.
According to Zhu, based on these data, a person with genetic changes in any of the two genes will see an increased risk for adenoma if they consume less than about 1,000 mg of calcium a day, especially if they carry genetic changes in both genes. The risk will increase by more than 50 percent for an adenoma and by 120 percent for advanced or multiple adenomas. “These patients should increase their calcium intake to reduce the risks,” Zhu said.
“Our results may provide one possible explanation for the inconsistency in previous studies on calcium intake and colorectal abnormalities because calcium may primarily prevent colorectal cancer in the early stage and reduce risk only among those with genetic changes in calcium reabsorption, which involves KCNJ1 and SLC12A1,” Zhu said. “If confirmed in future studies, our findings will be critical for the development of new personalized prevention strategies for colorectal cancer.”
The study was funded by National Institutes of Health (National Center for Complementary and Alternative Medicine/Office of Dietary Supplements) Grant Number 5R01AT004660-04 (PI: Qi Dai). The project was conducted using resources collected from the Tennessee Colorectal Polyp Study, a project of the Vanderbilt Gastrointestinal Cancer Specialized Program of Research Excellence.
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Abstract Number: 4832
Presenter: Xiangzhu Zhu, M.D., M.P.H.
Title: 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: Xiangzhu Zhu1, Martha J. Shrubsole1, Reid M. Ness2, Qiuyin Cai1, Jirong Long1, Zhi Chen1, Ji Liang3, Guoliang Li1, Walter E. Smalley, Jr.2, Todd L. Edwards1, Edward Giovannucci4, Wei Zheng1, Qi Dai1. 1Division of Epidemiology, Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; 2Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; 3Department of Maternal and Child Health, School of Public Health, Fudan University, Shanghai, China; 4Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA
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.
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