Published online on April 1, 2004, 10.1073/pnas.0307659101
PNAS | April 13, 2004 | vol. 101 | no. 15 | 5512-5517
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BIOCHEMISTRY
Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study
Ella H. Sklan *,
Alexander Lowenthal *,
Mira Korner 
,
Ya'acov Ritov 
,
Daniel M. Landers 
,
Tuomo Rankinen ¶,
Claude Bouchard ¶,
Arthur S. Leon ||,
Treva Rice **,
D. C. Rao **,
Jack H. Wilmore ,
James S. Skinner , and
Hermona Soreq * 
*Department of Biological Chemistry and Laboratory of DNA Analysis, Institute of Life Sciences and Department of Statistics, Hebrew University of Jerusalem, Jerusalem 91904, Israel; Department of Kinesiology, Arizona State University, Tempe, AZ 85287; ¶Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808; ||School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, MN 55455; **Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110; Department of Health and Kinesiology, Texas A&M University, College Station, TX 78363; and Department of Kinesiology, Indiana University, Bloomington, IN 47405
Edited by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, and approved February 23, 2004
(received for review November 19, 2003)
Anxiety involves complex, incompletely understood interactions of genomic, environmental, and experience-derived factors, and is currently being measured by psychological criteria. Here, we report previously nonperceived interrelationships between expression variations and nucleotide polymorphisms of the chromosome 7q21–22 acetylcholinesterase-paraoxonase 1 (ACHE-PON1) locus with the trait- and state-anxiety measures of 461 healthy subjects from the Health, Risk Factors, Exercise Training, and Genetics Family Study. The AChE protein controls the termination of the stress-enhanced acetylcholine signaling, whereas the PON protein displays peroxidase-like activity, thus protecting blood proteins from oxidative stress damages. Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures. Moreover, the transient scores of state anxiety and the susceptibility score of trait anxiety both appeared to be linked to enzyme activities. This finding supported the notion of corresponding gene expression relationships. Parallel polymorphisms in the ACHE and PON1 genes displayed apparent associations with both trait- and state-anxiety scores. Our findings indicate that a significant source of anxiety feelings involves inherited and acquired parameters of acetylcholine regulation that can be readily quantified, which can help explaining part of the human variance for state and trait anxiety.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; AChE-R, readthrough AChE; PON, paraoxonase; BChE, butyrylcholinesterase; HERITAGE, Health, Risk Factors, Exercise Training, and Genetics; LD, linkage disequilibrium; STAI, state-trait-anxiety inventory; BMI, body mass index.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AF539592 (PON1), AF002993 (ACHE), and NM000055 (BCHE)].
To whom correspondence should be addressed. E-mail: soreq{at}cc.huji.ac.il.
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