Inherited genetic effects on arsenic metabolism: A comparison of effects on arsenic species measured in urine and in blood.

ABSTRACT

Inorganic arsenic (iAs) is a carcinogen, and chronic exposure is associated with adverse health outcomes, including cancer and cardiovascular disease. Consumed iAs can undergo two methylation reactions catalyzed by arsenic methyltransferase (AS3MT), producing monomethylated and dimethylated forms of arsenic (MMA and DMA). Methylation of iAs helps facilitate excretion of arsenic in urine, with DMA composing the majority of arsenic species excreted. Past studies have identified genetic variation in the AS3MT (10q24.32) and FTCD (21q22.3) regions associated with arsenic metabolism efficiency (AME), measured as the proportion of each species present in urine (iAs%, MMA%, and DMA%), but their association with arsenic species present in blood has not been examined. We use data from three studies nested within the Health Effects and Longitudinal Study (HEALS)-the Nutritional Influences on Arsenic Toxicity Study, the Folate and Oxidative Stress study, and the Folic Acid and Creatine Trial-to examine the association of previously identified genetic variants with arsenic species in both urine and blood of 334 individuals. We confirm that the genetic variants in AS3MT and FTCD known to effect arsenic species composition in urine (an excreted byproduct of metabolism) have similar effects on arsenic species in blood (a tissue type that directly interacts with many organs, including those prone to arsenic toxicity). This consistency we observe provides further support for the hypothesis the AME SNPs identified to date impact the efficiency of arsenic metabolism and elimination, thereby influencing internal dose of arsenic and the dose delivered to toxicity-prone organs and tissues.