title: Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study.
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.
  
  
  CONCLUSIONS
  These findings, if confirmed, will be critical for the development of personalized prevention strategies for colorectal cancer.
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN;
authors.forename: Xiangzhu
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Maternal and Child Health, School of Public Health, Fudan University, Shanghai, China;
authors.forename: Ji
authors.initials: J
authors.lastname: Liang
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN;
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Shrubsole
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Reid M
authors.initials: RM
authors.lastname: Ness
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and.
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and.
authors.forename: Jirong
authors.initials: J
authors.lastname: Long
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Dawn
authors.initials: D
authors.lastname: Wiese
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN; and.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 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;
authors.forename: Walter E
authors.initials: WE
authors.lastname: Smalley
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN;
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.affiliation: Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Division of Epidemiology, Vanderbilt Ingram Cancer Center, and Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center, Nashville, TN;
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Dai
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D064466:Solute Carrier Family 12, Member 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; C578714:SLC12A1 protein, human; D064466:Solute Carrier Family 12, Member 1; D002118:Calcium