Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study.

MedStar author(s):
Citation: Toxicology & Applied Pharmacology. 348:123-129, 2018 06 01.PMID: 29621497Institution: MedStar Health Research Instituteason GForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Arsenic/ae [Adverse Effects] | *Diabetes Mellitus/ci [Chemically Induced] | *Diabetes Mellitus/ge [Genetics] | *Environmental Pollutants/ae [Adverse Effects] | *Insulin Resistance/ge [Genetics] | *Insulin-Secreting Cells/de [Drug Effects] | *Multifactorial Inheritance | *Polymorphism, Single Nucleotide | Adult | Apoptosis/de [Drug Effects] | Apoptosis/ge [Genetics] | Arsenic/me [Metabolism] | Chromatography, High Pressure Liquid | Diabetes Mellitus/bl [Blood] | Diabetes Mellitus/eh [Ethnology] | Environmental Pollutants/me [Metabolism] | Female | Genetic Predisposition to Disease | Humans | Incidence | Indians, North American/ge [Genetics] | Insulin-Secreting Cells/me [Metabolism] | Insulin-Secreting Cells/pa [Pathology] | Male | Mass Spectrometry | Middle Aged | Oxidative Stress/de [Drug Effects] | Oxidative Stress/ge [Genetics] | Phenotype | Protein-Serine-Threonine Kinases/ge [Genetics] | Protein-Serine-Threonine Kinases/me [Metabolism] | Risk Factors | Tumor Suppressor Proteins/ge [Genetics] | Tumor Suppressor Proteins/me [Metabolism] | United States/ep [Epidemiology] | Young AdultYear: 2018ISSN:
  • 0041-008X
Name of journal: Toxicology and applied pharmacologyAbstract: Copyright (c) 2018 Elsevier Inc. All rights reserved.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 (1.16x10<sup>-3</sup>). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic beta-cell endocrine function, but were not Bonferroni-significant.All authors: Balakrishnan P, Best LG, Cole SA, Franceschini N, Francesconi KA, Goessler W, Gribble MO, Haack K, Navas-Acien A, North KE, Umans JG, Vaidya D, Voruganti VSFiscal year: FY2018Digital Object Identifier: Date added to catalog: 2018-05-08
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Journal Article MedStar Authors Catalog Article 29621497 Available 29621497

Copyright (c) 2018 Elsevier Inc. All rights reserved.

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 (1.16x10<sup>-3</sup>). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic beta-cell endocrine function, but were not Bonferroni-significant.

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