Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study

J Nutr. 2014 Nov;144(11):1734-41. doi: 10.3945/jn.114.196709. Epub 2014 Aug 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism
  • Adult
  • Aged
  • Calcium / metabolism*
  • Case-Control Studies
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genotype
  • Humans
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Genetic*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Risk Factors
  • Solute Carrier Family 12, Member 1 / genetics
  • Solute Carrier Family 12, Member 1 / metabolism*

Substances

  • KCNJ1 protein, human
  • Potassium Channels, Inwardly Rectifying
  • SLC12A1 protein, human
  • Solute Carrier Family 12, Member 1
  • Calcium