Genetic Polymorphisms Influencing Arsenic Metabolism: Evidence from Argentina

• Published in: Environmental health perspectives Vol. 115; no. 4; pp. 599 - 605
• Main Authors: Karin Schläwicke Engström, Karin Broberg, Concha, Gabriela, Nermell, Barbro, Warholm, Margareta, Vahter, Marie
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare 01-04-2007; National Institute of Environmental Health Sciences
• Subjects: Adolescent; Adult; Aged; Alleles; Ancestry; Arbetsmedicin och miljömedicin; Argentina; Arsenic; Arsenic - metabolism; AS3MT; Cancer; Contamination; Drinking water; Environmental Exposure; Environmental Health and Occupational Health; Environmental Pollutants - metabolism; Enzymes - genetics; Enzymes - metabolism; Evaluation; Female; Genetic aspects; Genetic polymorphisms; Genetic Predisposition to Disease; Genotypes; GSTM1; GSTO1; GSTT1; Health Sciences; Homozygotes; Humans; Hälsovetenskap; Influence; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolic diseases; Metabolism; Metabolites; Methylation; Middle Aged; MTHFR; MTR; P values; Physiological aspects; Polymorphism, Genetic; polymorphisms; Potable water; Risk factors; Urine; Water Supply; Argentina
• ISSN: 0091-6765; 1552-9924; 1552-9924
• DOI: 10.1289/ehp.9734

The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 µg/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+III)methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFR. In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.