Circadian Clock Period Inversely Correlates with Illness Severity in Cells from Patients with Alcohol Use Disorders
Article first published online: 29 MAR 2013
Copyright © 2013 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 37, Issue 8, pages 1304–1310, August 2013
How to Cite
McCarthy, M. J., Fernandes, M., Kranzler, H. R., Covault, J. M. and Welsh, D. K. (2013), Circadian Clock Period Inversely Correlates with Illness Severity in Cells from Patients with Alcohol Use Disorders. Alcoholism: Clinical and Experimental Research, 37: 1304–1310. doi: 10.1111/acer.12106
- Issue published online: 26 JUL 2013
- Article first published online: 29 MAR 2013
- Manuscript Accepted: 20 DEC 2012
- Manuscript Received: 19 OCT 2012
- Veterans Affairs Career Development Award. Grant Number: 1IK2BX001275
- NIH. Grant Numbers: R21AA017584, R01AA021164
- Veterans Affairs Merit Award. Grant Number: 1I01BX001146
- NIMH. Grant Number: R01 MH082945
- NARSAD Young Investigator Award
- Circadian Rhythm;
Clinical and genetic studies suggest circadian clock genes may contribute to biological mechanisms underlying alcohol use disorders (AUD). In particular, the Per2 gene regulates alcohol consumption in mutant animals, and in humans with AUD, the 10870 variant in PER2 has been associated with alcohol consumption. However, with respect to function, the molecular clock remains largely uncharacterized in AUD patients.
In skin fibroblast cultures from well-characterized human AUD patients (n = 19) and controls (n = 13), we used a bioluminescent reporter gene (Per2::luc) to measure circadian rhythms in gene expression at high sampling density for 5 days. Cells were genotyped for the PER2 10870 variant. The rhythm parameters period and amplitude were then analyzed using a case–control design and by genetic and clinical characteristics of the AUD subjects.
There were no differences between AUD cases and controls in rhythm parameters. However, period was inversely correlated with illness severity (defined as the number of alcohol dependence criteria met). The PER2 variant 10870 was not associated with differences in rhythm parameters.
Our data suggest that differences in the cellular circadian clock are not pronounced in fibroblasts from AUD cases and controls. However, we found evidence that the circadian clock may be associated with an altered trajectory of AUD, possibly related to illness severity. Future work will be required to determine the mechanistic basis of this association.