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Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides: association of single nucleotide polymorphisms in BCHE.

Howard TD, Hsu FC, Grzywacz JG, Chen H, Quandt SA, Vallejos QM, Whalley LE, Cui W, Padilla S, Arcury TA - Environ. Health Perspect. (2010)

Bottom Line: Organophosphate pesticides act as cholinesterase inhibitors.A false discovery rate (FDR) p-value was used to account for multiple testing.Thirty-five SNPs were associated (unadjusted p < 0.05) based on at least one of the genetic models tested (general, additive, dominant, and recessive).

View Article: PubMed Central - PubMed

Affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. tdhoward@wfubmc.edu

ABSTRACT

Background: Organophosphate pesticides act as cholinesterase inhibitors. For those with agricultural exposure to these chemicals, risk of potential exposure-related health effects may be modified by genetic variability in cholinesterase metabolism. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To understand fully the links between pesticide exposure and potential human disease, analyses must be able to consider genetic variability in pesticide metabolism.

Objectives: We studied participants in the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study to determine whether cholinesterase levels are associated with single-nucleotide polymorphisms (SNPs) involved in pesticide metabolism.

Methods: Cholinesterase levels were measured from blood samples taken from 287 PACE3 participants at up to four time points during the 2007 growing season. We performed association tests of cholinesterase levels and 256 SNPs in 30 candidate genes potentially involved in pesticide metabolism. A false discovery rate (FDR) p-value was used to account for multiple testing.

Results: Thirty-five SNPs were associated (unadjusted p < 0.05) based on at least one of the genetic models tested (general, additive, dominant, and recessive). The strongest evidence of association with cholinesterase levels was observed with two SNPs, rs2668207 and rs2048493, in the butyrylcholinesterase (BCHE) gene (FDR adjusted p = 0.15 for both; unadjusted p = 0.00098 and 0.00068, respectively). In participants with at least one minor allele, cholinesterase levels were lower by 4.3-9.5% at all time points, consistent with an effect that is independent of pesticide exposure.

Conclusions: Common genetic variation in the BCHE gene may contribute to subtle changes in cholinesterase levels.

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Related in: MedlinePlus

Cholinesterase activity of individuals with rs2668207 (A) and rs2048493 (B) genotypes. ls, least-squares mean. The four time periods when cholinesterase levels were collected were 1 May to 8 June 2007 (1); 9 June to 7 July 2007 (2); 8 July to 5 August 2007 (3); and 6 August to 4 September 2007 (4).
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f3-ehp-118-1395: Cholinesterase activity of individuals with rs2668207 (A) and rs2048493 (B) genotypes. ls, least-squares mean. The four time periods when cholinesterase levels were collected were 1 May to 8 June 2007 (1); 9 June to 7 July 2007 (2); 8 July to 5 August 2007 (3); and 6 August to 4 September 2007 (4).

Mentions: Twenty-six SNPs were significant at the 0.05 level (unadjusted p-values) in at least one of the models tested [general, additive, dominant, and recessive; see Supplemental Material, Table 1 (doi:10.1289/ehp.0901764)]. The top five SNPs associated with the general test of association were located in the BCHE gene, and the dominant model seemed most appropriate based on the phenotype and genotype data (Table 3, Figure 2). We observed the strongest evidence of association with two SNPs, rs2668207 and rs2048493 (Table 3; unadjusted p = 0.00098 and 0.00068, respectively; FDR adjusted p = 0.15 for both SNPs), which were in strong linkage disequilibrium (LD; r2 = 0.81). A dominant effect was consistent with the pattern of cholinesterase levels over time, where individuals carrying one or more minor alleles had lower cholinesterase activity than did individuals homozygous for the major allele, even over multiple time points (Figure 3). The results for all SNPs analyzed are provided in Supplemental Material, Table 1 (doi:10.1289/ehp.0901764).


Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides: association of single nucleotide polymorphisms in BCHE.

Howard TD, Hsu FC, Grzywacz JG, Chen H, Quandt SA, Vallejos QM, Whalley LE, Cui W, Padilla S, Arcury TA - Environ. Health Perspect. (2010)

Cholinesterase activity of individuals with rs2668207 (A) and rs2048493 (B) genotypes. ls, least-squares mean. The four time periods when cholinesterase levels were collected were 1 May to 8 June 2007 (1); 9 June to 7 July 2007 (2); 8 July to 5 August 2007 (3); and 6 August to 4 September 2007 (4).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957918&req=5

f3-ehp-118-1395: Cholinesterase activity of individuals with rs2668207 (A) and rs2048493 (B) genotypes. ls, least-squares mean. The four time periods when cholinesterase levels were collected were 1 May to 8 June 2007 (1); 9 June to 7 July 2007 (2); 8 July to 5 August 2007 (3); and 6 August to 4 September 2007 (4).
Mentions: Twenty-six SNPs were significant at the 0.05 level (unadjusted p-values) in at least one of the models tested [general, additive, dominant, and recessive; see Supplemental Material, Table 1 (doi:10.1289/ehp.0901764)]. The top five SNPs associated with the general test of association were located in the BCHE gene, and the dominant model seemed most appropriate based on the phenotype and genotype data (Table 3, Figure 2). We observed the strongest evidence of association with two SNPs, rs2668207 and rs2048493 (Table 3; unadjusted p = 0.00098 and 0.00068, respectively; FDR adjusted p = 0.15 for both SNPs), which were in strong linkage disequilibrium (LD; r2 = 0.81). A dominant effect was consistent with the pattern of cholinesterase levels over time, where individuals carrying one or more minor alleles had lower cholinesterase activity than did individuals homozygous for the major allele, even over multiple time points (Figure 3). The results for all SNPs analyzed are provided in Supplemental Material, Table 1 (doi:10.1289/ehp.0901764).

Bottom Line: Organophosphate pesticides act as cholinesterase inhibitors.A false discovery rate (FDR) p-value was used to account for multiple testing.Thirty-five SNPs were associated (unadjusted p < 0.05) based on at least one of the genetic models tested (general, additive, dominant, and recessive).

View Article: PubMed Central - PubMed

Affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. tdhoward@wfubmc.edu

ABSTRACT

Background: Organophosphate pesticides act as cholinesterase inhibitors. For those with agricultural exposure to these chemicals, risk of potential exposure-related health effects may be modified by genetic variability in cholinesterase metabolism. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To understand fully the links between pesticide exposure and potential human disease, analyses must be able to consider genetic variability in pesticide metabolism.

Objectives: We studied participants in the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study to determine whether cholinesterase levels are associated with single-nucleotide polymorphisms (SNPs) involved in pesticide metabolism.

Methods: Cholinesterase levels were measured from blood samples taken from 287 PACE3 participants at up to four time points during the 2007 growing season. We performed association tests of cholinesterase levels and 256 SNPs in 30 candidate genes potentially involved in pesticide metabolism. A false discovery rate (FDR) p-value was used to account for multiple testing.

Results: Thirty-five SNPs were associated (unadjusted p < 0.05) based on at least one of the genetic models tested (general, additive, dominant, and recessive). The strongest evidence of association with cholinesterase levels was observed with two SNPs, rs2668207 and rs2048493, in the butyrylcholinesterase (BCHE) gene (FDR adjusted p = 0.15 for both; unadjusted p = 0.00098 and 0.00068, respectively). In participants with at least one minor allele, cholinesterase levels were lower by 4.3-9.5% at all time points, consistent with an effect that is independent of pesticide exposure.

Conclusions: Common genetic variation in the BCHE gene may contribute to subtle changes in cholinesterase levels.

Show MeSH
Related in: MedlinePlus