Cholinergic neurotransmission in the central and autonomic nervous systems regulates immediate variations in and longer-term maintenance of cardiovascular function with acetylcholinesterase (AChE) activity being 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 re-sequencing identified 19 SNPs: 7 coding (cSNPs), of which 4 are non-synonymous. Twelve SNPs were in untranslated regions (3 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, while BChE activity was associated with features of the metabolic syndrome (especially body weight and BMI). Gene products from cDNAs with non-synonymous cSNPs were expressed and purified. Protein expression of ACHE non-synonymous 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. Certain non-synonymous ACHE SNPs impair protein expression of enzyme variants, having in turn compromised activity in the face of thermal stress or chemical perturbation.
- cardiovascular function
- metabolic syndrome
- protein stability
- Received January 27, 2011.
- Revision received April 11, 2011.
- Accepted April 12, 2011.
- The American Society for Pharmacology and Experimental Therapeutics