Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women

J Nutr. 2015 Mar;145(3):418-24. doi: 10.3945/jn.114.203489. Epub 2015 Jan 7.

Abstract

Background: Prospective studies consistently link low magnesium intake to higher type 2 diabetes (T2D) risk.

Objective: We examined the association of common genetic variants [single nucleotide polymorphisms (SNPs)] in genes related to magnesium homeostasis with T2D risk and potential interactions with magnesium intake.

Methods: Using the Women's Health Initiative-SNP Health Association Resource (WHI-SHARe) study, we identified 17 magnesium-related ion channel genes (583 SNPs) and examined their associations with T2D risk in 7287 African-American (AA; n = 1949 T2D cases) and 3285 Hispanic-American (HA; n = 611 T2D cases) postmenopausal women. We performed both single- and multiple-locus haplotype analyses.

Results: Among AA women, carriers of each additional copy of SNP rs6584273 in cyclin mediator 1 (CNNM1) had 16% lower T2D risk [OR: 0.84; false discovery rate (FDR)-adjusted P = 0.02]. Among HA women, several variants were significantly associated with T2D risk, including rs10861279 in solute carrier family 41 (anion exchanger), member 2 (SLC41A2) (OR: 0.54; FDR-adjusted P = 0.04), rs7174119 in nonimprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) (OR: 1.27; FDR-adjusted P = 0.04), and 2 SNPs in mitochondrial RNA splicing 2 (MRS2) (rs7738943: OR = 1.55, FDR-adjusted P = 0.01; rs1056285: OR = 1.48, FDR-adjusted P = 0.02). Even with the most conservative Bonferroni adjustment, two 2-SNP-haplotypes in SLC41A2 and MRS2 region were significantly associated with T2D risk (rs12582312-rs10861279: P = 0.0006; rs1056285-rs7738943: P = 0.002). Among women with magnesium intake in the lowest 30% (AA: ≤0.164 g/d; HA: ≤0.185 g/d), 4 SNP signals were strengthened [rs11590362 in claudin 19 (CLDN19), rs823154 in SLC41A1, rs5929706 and rs5930817 in membra; HA: ≥0.313 g/d), rs6584273 in CNNM1 (OR: 0.71; FDR-adjusted P = 0.04) and rs1800467 in potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) (OR: 2.50; FDR-adjusted P = 0.01) were significantly associated with T2D risk.

Conclusions: Our findings suggest important associations between genetic variations in magnesium-related ion channel genes and T2D risk in AA and HA women that vary by amount of magnesium intake.

Keywords: diabetes; genes; ion channel; magnesium intake; women.

Publication types

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

MeSH terms

  • Aged
  • Black or African American / genetics*
  • Body Mass Index
  • Case-Control Studies
  • Cation Transport Proteins / genetics
  • Claudins / genetics
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Dietary Supplements
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotyping Techniques
  • Haplotypes
  • Hispanic or Latino / genetics*
  • Humans
  • Ion Channels / genetics*
  • Logistic Models
  • Magnesium / administration & dosage*
  • Magnesium / blood
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Postmenopause
  • Potassium Channels, Inwardly Rectifying / genetics
  • Prospective Studies
  • Risk Factors

Substances

  • CLDN19 protein, human
  • Cation Transport Proteins
  • Claudins
  • Ion Channels
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • SLC41A1 protein, human
  • Magnesium