| Genetic Polymorphisms Influencing Arsenic Metabolism: Evidence from Argentina Karin Schläwicke Engström,1 Karin Broberg,1 Gabriela Concha,2 Barbro Nermell,3 Margareta Warholm,4 and Marie Vahter3 1Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; 2Toxicology Division, National Food Administration, Uppsala, Sweden; 3Section for Metals and Health, and 4Division of Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Abstract
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. Key words: arsenic, AS3MT, GSTM1, GSTO1, GSTT1, metabolism, methylation, MTHFR, MTR, polymorphisms. Environ Health Perspect 115:599–605 (2007) . doi:10.1289/ehp.9734 available via http://dx.doi.org/ [Online 8 January 2007]
Address correspondence to K. Schläwicke Engström, Division of Occupational and Environmental Medicine, Lund University Hospital, 22185 Lund, Sweden. Telephone: +46 (0) 46 173148. Fax: +46 (0) 46 143702. E-mail: karin.engstrom@med.lu.se We thank U. Strömberg for statistical advice and A. Cohen for language editing. This research was supported by grants from the Swedish Council for Working Life and Social Research ; the European Union within the Sixth Framework Programme for Research and Technological Development ("PHIME" contract FOOD-CT-2006-016253) ; The Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning ; and the Karolinska Institutet. The authors declare they have no competing financial interests. Received 18 September 2006 ; accepted 8 January 2007.
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