Circadian Clock Period Inversely Correlates with Illness Severity in Cells from Patients with Alcohol Use Disorders
Reprint requests: Michael J. McCarthy, MD, PhD, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr MC 116A, San Diego, CA 92161; Tel.: 858-642-1520; Fax: 858-642-1281; E-mail: email@example.com
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.