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Title: Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function.

Authors: Eum, Ki-Do; Wang, Florence T; Schwartz, Joel; Hersh, Craig P; Kelsey, Karl; Wright, Robert O; Spiro, Avron; Sparrow, David; Hu, Howard; Weisskopf, Marc G

Published In Neurotoxicology, (2013 Dec)

Abstract: BACKGROUND: Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association. METHODS: We used repeated measures analysis to compare the association between cumulative lead biomarkers-bone lead measured using K-shell X-Ray Fluorescence-and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses. RESULTS: A 15μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead. CONCLUSION: Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.

PubMed ID: 23958642 Exiting the NIEHS site

MeSH Terms: Aged; Aged, 80 and over; Cognition Disorders/blood; Cognition Disorders/epidemiology; Cognition Disorders/genetics*; Cohort Studies; Gene-Environment Interaction; Genetic Predisposition to Disease/epidemiology; Genetic Predisposition to Disease/genetics; Genotype; Glutathione S-Transferase pi/genetics*; Glutathione Transferase/genetics*; Humans; Lead/analysis*; Lead/blood; Male; Mental Status Schedule; Middle Aged; Polymorphism, Genetic/genetics*; Spectrometry, X-Ray Emission; Valine/genetics; Veterans

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