Xiangzhu Zhu1, Ji Liang2, Martha J Shrubsole1, Reid M Ness3, Qiuyin Cai4, Jirong Long4, Zhi Chen4, Guoliang Li4, Dawn Wiese3, Bing Zhang5, Walter E Smalley6, Todd L Edwards1, Edward Giovannucci7, Wei Zheng1, Qi Dai8. 1. Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN; 2. Department of Maternal and Child Health, School of Public Health, Fudan University, Shanghai, China; 3. Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; 4. Division of Epidemiology, Vanderbilt Ingram Cancer Center, and. 5. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN; and. 6. Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN; 7. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA. 8. Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN; qi.dai@vanderbilt.edu.
Abstract
BACKGROUND: The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney. OBJECTIVE: We hypothesized that polymorphisms in KCNJ1, SLC12A1, and 7 other genes may modify the association between calcium intake and colorectal neoplasia risk. METHODS: We conducted a 2-phase study in 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. RESULTS: In phase I, we identified 5 single-nucleotide polymorphisms (SNPs) that significantly interacted with calcium intake in adenoma risk. In phase II, rs2855798 in KCNJ1 was replicated. In combined analysis of phases I and II, the P values for interactions between calcium intake and rs2855798 were 1 × 10(-4) for all adenoma and 5 × 10(-3) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with no variant allele but was significantly associated with a 41% reduced adenoma risk among those who carried at least 1 variant allele in KCNJ1. The corresponding reduction in risk of multiple or advanced adenomas was 52% among those with at least 1 variant allele. The P values for interactions between calcium intake and combined SNPs from the KCNJ1 and SLC12A1 genes were 7.5 × 10(-5) for adenoma and 9.9 × 10(-5) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with nonvariant alleles in 2 genes but was significantly associated with a 34% reduced adenoma risk among those who carried a variant allele in 1 of the genes. The corresponding reduction in risk of multiple or advanced adenomas was 64% among those with variant alleles in both genes. CONCLUSION: These findings, if confirmed, will be critical for the development of personalized prevention strategies for colorectal cancer.
BACKGROUND: The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney. OBJECTIVE: We hypothesized that polymorphisms in KCNJ1, SLC12A1, and 7 other genes may modify the association between calcium intake and colorectal neoplasia risk. METHODS: We conducted a 2-phase study in 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. RESULTS: In phase I, we identified 5 single-nucleotide polymorphisms (SNPs) that significantly interacted with calcium intake in adenoma risk. In phase II, rs2855798 in KCNJ1 was replicated. In combined analysis of phases I and II, the P values for interactions between calcium intake and rs2855798 were 1 × 10(-4) for all adenoma and 5 × 10(-3) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with no variant allele but was significantly associated with a 41% reduced adenoma risk among those who carried at least 1 variant allele in KCNJ1. The corresponding reduction in risk of multiple or advanced adenomas was 52% among those with at least 1 variant allele. The P values for interactions between calcium intake and combined SNPs from the KCNJ1 and SLC12A1 genes were 7.5 × 10(-5) for adenoma and 9.9 × 10(-5) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with nonvariant alleles in 2 genes but was significantly associated with a 34% reduced adenoma risk among those who carried a variant allele in 1 of the genes. The corresponding reduction in risk of multiple or advanced adenomas was 64% among those with variant alleles in both genes. CONCLUSION: These findings, if confirmed, will be critical for the development of personalized prevention strategies for colorectal cancer.
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