DETERMINANTS OF INTERINDIVIDUAL VARIABILITY IN ARSENIC SECONDARY METHYLATION EFFICIENCY IN A POPULATION FROM NORTHWEST MEXICO

Chronic environmental exposure to inorganic arsenic is widely associated with human disease. Low human arsenic secondary methylation efficiency (SME), represented by high urinary monomethylarsonic acid (%uMMA) and low urinary dimethylarsinic acid to monomethylarsonic acid ratio (uDMA/uMMA), has been consistently associated with increased risk of arsenic-related diseases. Therefore the determination of factors modulating arsenic SME acquires particular importance. The aims of the present study are to identify novel factors of variability in arsenic secondary methylation, and to test for potential factors influencing arsenic SME for which there is equivocal literature support. A population of 808 subjects was recruited from northwest Mexico environmentally exposed to arsenic. The mean total urinary arsenic in the population was 171 μg/L. Great interindividual variability in %uMMA excretion was observed (0.85% - 40.5%). Three intronic polymorphisms in arsenic (3+ oxidation state) methyltransferase (AS3MT), the key gene in the metabolism of arsenic, were confirmed to be associated with increased arsenic SME in this study. Further analysis of this genomic region showed a large block of linkage disequilibrium (LD) comprising these three genetic variants and other 43 intronic polymorphisms within AS3MT and four additional genes. Genetic association analysis showed that all linked polymorphisms in this region except one were significantly associated with higher arsenic SME. The existence of this long region of LD associated with arsenic SME underscores the complexity of association studies involving any of these linked polymorphisms since there is no certainty of which polymorphism or gene is the causative of the association. In addition, a strong positive association between body mass index (BMI) and arsenic SME was observed in females but not in males. This association was replicated in two independently recruited populations of adult women. Moreover a unique finding of this study is the association between higher genetically estimated indigenous American (AME) ancestry and increased arsenic SME in this ancestrally admixed Mexican population. These results establish the importance of genetic and phenotypic factors in the efficiency of arsenic secondary methylation. Furthermore this study has identified several arsenic-associated risk factors that should be carefully considered in future studies seeking to better understand disease susceptibility in arsenic-exposed populations