Arsenic-gene Interactions and Beta-Cell Function in the Strong Heart Family Study

Toxicol Appl Pharmacol. 2018 Jun 1;348:123-129. doi: 10.1016/j.taap.2018.03.034. Epub 2018 Apr 3.

Abstract

We explored arsenic-gene interactions influencing pancreatic beta-cell activity in the Strong Heart Family Study (SHFS). We considered 42 variants selected for associations with either beta-cell function (31 variants) or arsenic metabolism (11 variants) in the SHFS. Beta-cell function was calculated as homeostatic model - beta corrected for insulin resistance (cHOMA-B) by regressing homeostatic model - insulin resistance (HOMA-IR) on HOMA-B and adding mean HOMA-B. Arsenic exposure was dichotomized at the median of the sum of creatinine-corrected inorganic and organic arsenic species measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). Additive GxE models for cHOMA-B were adjusted for age and ancestry, and accounted for family relationships. Models were stratified by center (Arizona, Oklahoma, North Dakota and South Dakota) and meta-analyzed. The two interactions between higher vs. lower arsenic and SNPs for cHOMA-B that were nominally significant at P < 0.05 were with rs10738708 (SNP overall effect -3.91, P = 0.56; interaction effect with arsenic -31.14, P = 0.02) and rs4607517 (SNP overall effect +16.61, P = 0.03; interaction effect with arsenic +27.02, P = 0.03). The corresponding genes GCK and TUSC1 suggest oxidative stress and apoptosis as possible mechanisms for arsenic impacts on beta-cell function. No interactions were Bonferroni-significant (1.16 × 10-3). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic β-cell endocrine function, but were not Bonferroni-significant.

Keywords: Arsenicals; Diabetes; Environmental Epidemiology; Genetic Epidemiology; Pancreas; Susceptibility.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Arsenic / adverse effects*
  • Arsenic / metabolism
  • Chromatography, High Pressure Liquid
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / chemically induced*
  • Diabetes Mellitus / ethnology
  • Diabetes Mellitus / genetics*
  • Environmental Pollutants / adverse effects*
  • Environmental Pollutants / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Germinal Center Kinases
  • Humans
  • Incidence
  • Indians, North American / genetics
  • Insulin Resistance / genetics*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Multifactorial Inheritance*
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Risk Factors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • United States / epidemiology
  • Young Adult

Substances

  • Environmental Pollutants
  • Germinal Center Kinases
  • TUSC1 protein, human
  • Tumor Suppressor Proteins
  • Protein-Serine-Threonine Kinases
  • Arsenic