Miranda J Spratlen1, Maria Grau-Perez2, Jason G Umans3, Joseph Yracheta4, Lyle G Best4, Kevin Francesconi5, Walter Goessler5, Poojitha Balakrishnan6, Shelley A Cole7, Mary V Gamble6, Barbara V Howard3, Ana Navas-Acien8. 1. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, NY, New York, United States of America; Department of Environmental Health & Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America. Electronic address: mjs2376@cumc.columbia.edu. 2. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, NY, New York, United States of America; Fundación Investigación Clínico de Valencia-INCLIVA, Area of Cardiometabolic and Renal Risk, Valencia, Spain; Department of Statistics and Operational Research, University of Valencia, Valencia, Spain. 3. MedStar Health Research Institute, Hyattsville, MD, United States of America; Department of Medicine, Georgetown University School of Medicine, Washington, DC, United States of America. 4. Missouri Breaks Industries Research, Inc., Eagle Butte, SD, United States of America. 5. Institute of Chemistry - Analytical Chemistry, University of Graz, Austria. 6. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, NY, New York, United States of America. 7. Texas Biomedical Research Institute, San Antonio, TX, United States of America. 8. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, NY, New York, United States of America; Department of Environmental Health & Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
Abstract
BACKGROUND: Inorganic arsenic exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes; however, this profile has also been associated with increased risk for diabetes-related outcomes. The mechanism behind these contrasting associations is equivocal; we hypothesized one carbon metabolism (OCM) may play a role. METHODS: We evaluated the association between OCM-related variables (nutrient intake and genetic variants) and both arsenic metabolism biomarkers (iAs%, MMA% and DMA%) and diabetes-related outcomes (metabolic syndrome, diabetes, HOMA2-IR and waist circumference) in 935 participants free of prevalent diabetes and metabolic syndrome from the Strong Heart Family Study, a family-based prospective cohort comprised of American Indian tribal members aged 14+ years. RESULTS: Of the 935 participants free of both diabetes and metabolic syndrome at baseline, 279 (29.8%) developed metabolic syndrome over a median of 5.3 years of follow-up and of the 1458 participants free of diabetes at baseline, 167 (11.3%) developed diabetes over follow-up. OCM nutrients were not associated with arsenic metabolism, however, higher vitamin B6 was associated with diabetes-related outcomes (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). A polymorphism in an OCM-related gene, methionine synthase (MTR), was associated with both higher MMA% (β = 2.57, 95% CI: 0.22, 4.92) and lower HOMA2-IR (GMR = 0.79, 95% CI = 0.66, 0.93 per 5 years of follow-up). Adjustment for OCM variables did not affect previously reported associations between arsenic metabolism and diabetes-related outcomes; however, the association between the MTR variant and diabetes-related outcomes were attenuated after adjustment for arsenic metabolism. CONCLUSIONS: Our findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Additional mediation analyses with longer follow-up period are needed to confirm this finding. Further research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.
BACKGROUND: Inorganic arsenic exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes; however, this profile has also been associated with increased risk for diabetes-related outcomes. The mechanism behind these contrasting associations is equivocal; we hypothesized one carbon metabolism (OCM) may play a role. METHODS: We evaluated the association between OCM-related variables (nutrient intake and genetic variants) and both arsenic metabolism biomarkers (iAs%, MMA% and DMA%) and diabetes-related outcomes (metabolic syndrome, diabetes, HOMA2-IR and waist circumference) in 935 participants free of prevalent diabetes and metabolic syndrome from the Strong Heart Family Study, a family-based prospective cohort comprised of American Indian tribal members aged 14+ years. RESULTS: Of the 935 participants free of both diabetes and metabolic syndrome at baseline, 279 (29.8%) developed metabolic syndrome over a median of 5.3 years of follow-up and of the 1458 participants free of diabetes at baseline, 167 (11.3%) developed diabetes over follow-up. OCM nutrients were not associated with arsenic metabolism, however, higher vitamin B6 was associated with diabetes-related outcomes (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). A polymorphism in an OCM-related gene, methionine synthase (MTR), was associated with both higher MMA% (β = 2.57, 95% CI: 0.22, 4.92) and lower HOMA2-IR (GMR = 0.79, 95% CI = 0.66, 0.93 per 5 years of follow-up). Adjustment for OCM variables did not affect previously reported associations between arsenic metabolism and diabetes-related outcomes; however, the association between the MTR variant and diabetes-related outcomes were attenuated after adjustment for arsenic metabolism. CONCLUSIONS: Our findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Additional mediation analyses with longer follow-up period are needed to confirm this finding. Further research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.
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