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Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

The Pharmacogenomics Journal volume 16, pages 454–460 (2016)Cite this article

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Abstract

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene–drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine–COMT interaction effects in other conditions.

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Acknowledgements

KTH was supported by T32AT000051, K01HL130625, and the Harvard Catalyst Faculty Fellowship. JK was supported by Grant P300P1_158427 from the Swiss National Science Foundation and NLM Grant T15LM007092. TJK was supported by NIH/NCCIH Grant 2K24 AT004095. We thank Valerie Stone, Leigh Simmons and Irving Kirsch for helpful discussions, Kristin Godang for catecholamine analyses and Kari Gjersum for practical assistance.

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Author notes

  1. K T Hall and J Kossowsky: These two authors contributed equally to this workstudy.

Authors and Affiliations

  1. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    K T Hall

  2. Harvard Medical School, Boston, MA, USA

    K T Hall, J Kossowsky, T J Kaptchuk & K J Mukamal

  3. Department of Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    J Kossowsky

  4. Department of Clinical Psychology and Psychotherapy, University of Basel, Basel, Switzerland

    J Kossowsky

  5. Department of Pediatrics, Child and Family Research Institute, and School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada

    T F Oberlander

  6. Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    T J Kaptchuk & K J Mukamal

  7. Program in Placebo Studies, Beth Israel Deaconess Medical Center, Boston, MA, USA

    T J Kaptchuk

  8. Division of Cardiology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

    J P Saul

  9. Department of Paediatrics, Akershus University Hospital, Lørenskog, Norway

    V B Wyller

  10. Department of Anesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway

    E Fagermoen

  11. Department of Pediatrics, Lillehammer County Hospital, Brumunddal, Norway

    D Sulheim

  12. Department, National Institute of Occupational Health, Oslo, Norway

    J Gjerstad

  13. Department of Nursing and Health Promotion, Faculty of Health, Oslo University College of Applied Sciences, Oslo, Norway

    A Winger

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Correspondence to K T Hall.

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Hall, K., Kossowsky, J., Oberlander, T. et al. Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. Pharmacogenomics J 16, 454–460 (2016). https://doi.org/10.1038/tpj.2016.53

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