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

Autor: Kari E. North, Nora Franceschini, Karin Haack, Shelley A. Cole, Kevin A. Francesconi, Dhananjay Vaidya, Walter Goessler, Poojitha Balakrishnan, V. Saroja Voruganti, Jason G. Umans, Matthew O. Gribble, Lyle G. Best, Ana Navas-Acien
Rok vydání: 2018
Předmět:
Adult
Male
0301 basic medicine
Multifactorial Inheritance
medicine.medical_specialty
Beta-cell Function
chemistry.chemical_element
Apoptosis
Single-nucleotide polymorphism
Protein Serine-Threonine Kinases
Biology
Toxicology
Polymorphism
Single Nucleotide
Mass Spectrometry
Article
Arsenic
Germinal Center Kinases
Young Adult
03 medical and health sciences
Insulin resistance
Risk Factors
Insulin-Secreting Cells
Internal medicine
Diabetes mellitus
Diabetes Mellitus
medicine
Humans
Genetic Predisposition to Disease
Beta (finance)
Gene
Chromatography
High Pressure Liquid
Pharmacology
Incidence
Tumor Suppressor Proteins
Middle Aged
medicine.disease
United States
Oxidative Stress
Phenotype
030104 developmental biology
Endocrinology
Genetic epidemiology
chemistry
Indians
North American
Environmental Pollutants
Female
Insulin Resistance
Zdroj: Toxicology and Applied Pharmacology. 348:123-129
ISSN: 0041-008X
Popis: 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.
Databáze: OpenAIRE
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