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Research ArticleMetabolism, Transport, and Pharmacogenomics

Naturally Occurring Variations in the Human Cholinesterase Genes: Heritability and Association with Cardiovascular and Metabolic Traits

Anne M. Valle, Zoran Radić, Brinda K. Rana, Vafa Mahboubi, Jennifer Wessel, Pei-an Betty Shih, Fangwen Rao, Daniel T. O'Connor and Palmer Taylor
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 125-133; DOI: https://doi.org/10.1124/jpet.111.180091
Anne M. Valle
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Zoran Radić
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Brinda K. Rana
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Vafa Mahboubi
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Jennifer Wessel
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Pei-an Betty Shih
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Fangwen Rao
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Daniel T. O'Connor
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Palmer Taylor
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Abstract

Cholinergic neurotransmission in the central and autonomic nervous systems regulates immediate variations in and longer-term maintenance of cardiovascular function with acetylcholinesterase (AChE) activity that is critical to temporal responsiveness. Butyrylcholinesterase (BChE), largely confined to the liver and plasma, subserves metabolic functions. AChE and BChE are found in hematopoietic cells and plasma, enabling one to correlate enzyme levels in whole blood with hereditary traits in twins. Using both twin and unrelated subjects, we found certain single nucleotide polymorphisms (SNPs) in the ACHE gene correlated with catalytic properties and general cardiovascular functions. SNP discovery from ACHE resequencing identified 19 SNPs: 7 coding SNPs (cSNPs), of which 4 are nonsynonymous, and 12 SNPs in untranslated regions, of which 3 are in a conserved sequence of an upstream intron. Both AChE and BChE activity traits in blood were heritable: AChE at 48.8 ± 6.1% and BChE at 81.4 ± 2.8%. Allelic and haplotype variations in the ACHE and BCHE genes were associated with changes in blood AChE and BChE activities. AChE activity was associated with BP status and SBP, whereas BChE activity was associated with features of the metabolic syndrome (especially body weight and BMI). Gene products from cDNAs with nonsynonymous cSNPs were expressed and purified. Protein expression of ACHE nonsynonymous variant D134H (SNP6) is impaired: this variant shows compromised stability and altered rates of organophosphate inhibition and oxime-assisted reactivation. A substantial fraction of the D134H instability could be reversed in the D134H/R136Q mutant. Hence, common genetic variations at ACHE and BCHE loci were associated with changes in corresponding enzymatic activities in blood.

Footnotes

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant P01-HL058120-10]; the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM018360-39, T32-GM07752]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant U01-NS58046]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grant P42-ES010337-10].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180091.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AChE
    acetylcholinesterase
    BChE
    butyrylcholinesterase
    SNP
    single-nucleotide polymorphism
    cSNP
    coding SNP
    ACh
    acetylcholine
    hAChE
    human AChE
    h2
    heritability
    2-PAM
    pyridine-2-aldoxime methyl methanesulfonate
    SOLAR
    sequential oligogenic linkage analysis
    BP
    blood pressure
    kb
    kilobase
    wtT547
    wild-type monomeric hAChE truncated at amino acid 547
    SBP
    systolic BP
    BMI
    body mass index
    UTR
    untranslated region
    HEK
    human embryonic kidney
    BSA
    bovine serum albumin
    QTL
    quantitative trait locus
    LOD
    logarithm of the odds
    CI
    confidence interval.

  • Received January 27, 2011.
  • Accepted April 12, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Naturally Occurring Variations in the Human Cholinesterase Genes: Heritability and Association with Cardiovascular and Metabolic Traits

Anne M. Valle, Zoran Radić, Brinda K. Rana, Vafa Mahboubi, Jennifer Wessel, Pei-an Betty Shih, Fangwen Rao, Daniel T. O'Connor and Palmer Taylor
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 125-133; DOI: https://doi.org/10.1124/jpet.111.180091

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Naturally Occurring Variations in the Human Cholinesterase Genes: Heritability and Association with Cardiovascular and Metabolic Traits

Anne M. Valle, Zoran Radić, Brinda K. Rana, Vafa Mahboubi, Jennifer Wessel, Pei-an Betty Shih, Fangwen Rao, Daniel T. O'Connor and Palmer Taylor
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 125-133; DOI: https://doi.org/10.1124/jpet.111.180091
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