TY - JOUR
T1 - Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study
AU - Balakrishnan, Poojitha
AU - Navas-Acien, Ana
AU - Haack, Karin
AU - Vaidya, Dhananjay
AU - Umans, Jason G.
AU - Best, Lyle G.
AU - Goessler, Walter
AU - Francesconi, Kevin A.
AU - Franceschini, Nora
AU - North, Kari E.
AU - Cole, Shelley A.
AU - Voruganti, V. Saroja
AU - Gribble, Matthew O.
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
KW - Arsenicals
KW - Diabetes
KW - Environmental Epidemiology
KW - Genetic Epidemiology
KW - Pancreas
KW - Susceptibility
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U2 - 10.1016/j.taap.2018.03.034
DO - 10.1016/j.taap.2018.03.034
M3 - Article
C2 - 29621497
AN - SCOPUS:85046157769
SN - 0041-008X
VL - 348
SP - 123
EP - 129
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -