Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.

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Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina. / Engström, Karin; Broberg Palmgren, Karin; Concha, Gabriela; Nermell, Barbro; Warholm, Margareta; Vahter, Marie.

In: Environmental Health Perspectives, Vol. 115, No. 4, 2007, p. 599-605.

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Engström, Karin ; Broberg Palmgren, Karin ; Concha, Gabriela ; Nermell, Barbro ; Warholm, Margareta ; Vahter, Marie. / Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina. In: Environmental Health Perspectives. 2007 ; Vol. 115, No. 4. pp. 599-605.

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TY - JOUR

T1 - Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.

AU - Engström, Karin

AU - Broberg Palmgren, Karin

AU - Concha, Gabriela

AU - Nermell, Barbro

AU - Warholm, Margareta

AU - Vahter, Marie

PY - 2007

Y1 - 2007

N2 - 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 mu g/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(+ 111) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu I (GSTM1) and theta I (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 MTHFA 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.

AB - 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 mu g/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(+ 111) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu I (GSTM1) and theta I (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 MTHFA 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.

KW - polymorphisms

KW - metabolism

KW - methylation

KW - GSTT1

KW - GSTM1

KW - arsenic

KW - MTR

KW - AS3MT

KW - GSTO1

KW - MTHFR

U2 - 10.1289/ehp.9734

DO - 10.1289/ehp.9734

M3 - Article

VL - 115

SP - 599

EP - 605

JO - EHP Toxicogenomics

T2 - EHP Toxicogenomics

JF - EHP Toxicogenomics

SN - 1552-9924

IS - 4

ER -