Balakrishnan P1, Navas-Acien A1, Haack K2, Vaidya D3, Umans JG4, Best LG5, Goessler W6, Francesconi KA6, Franceschini N7, North KE7, Cole SA2, Voruganti VS8, Gribble MO9. 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.
1 Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, United States.
2 Texas Biomedical Research Institute, San Antonio, TX, United States.
3 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States; Clinical and Translational Research, Johns Hopkins School of Medicine, Baltimore, MD, United States.
4 MedStar Health Research Institute, Hyattsville, MD, United States.
5 Missouri Breaks Industries Research, Inc., Eagle Butte, SD, United States.
6 Institute of Chemistry, University of Graz, Graz, Austria.
7 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
8 Department of Nutrition and UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States.
9 Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, United States; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States. Electronic address: firstname.lastname@example.org.
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.
Arsenicals; Diabetes; Environmental Epidemiology; Genetic Epidemiology; Pancreas; Susceptibility