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Complex Multilocus Effects of Catechol-O-Methyltransferase Haplotypes Predict Pain and Pain Interference 6 Weeks After Motor Vehicle Collision

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Abstract

Catechol-O-methyltransferase, encoded by COMT gene, is the primary enzyme that metabolizes catecholamines. COMT haplotypes have been associated with vulnerability to persistent non-traumatic pain. In this prospective observational study, we investigated the influence of COMT on persistent pain and pain interference with life functions after motor vehicle collision (MVC) in 859 European American adults for whom overall pain (0–10 numeric rating scale) and pain interference (Brief Pain Inventory) were assessed at week 6 after MVC. Ten single nucleotide polymorphisms spanning the COMT gene were successfully genotyped, and nine were present in three haploblocks: block 1 (rs2020917, rs737865, rs1544325), block 2 (rs4633, rs4818, rs4680, rs165774), and block 3 (rs174697, rs165599). After adjustment for multiple comparisons, haplotype TCG from block 1 predicted decreased pain interference (p = 0.004). The pain-protective effect of the low pain sensitivity (CGGG) haplotype from block 2 was only observed if at least one TCG haplotype was present in block 1 (haplotype × haplotype interaction p = 0.002 and <0.0001 for pain and pain interference, respectively). Haplotype AG from block 3 was associated with pain and interference in males only (sex × haplotype interaction p = 0.005 and 0.0005, respectively). These results suggest that genetic variants in the distal promoter are important contributors to the development of persistent pain after MVC, directly and via the interaction with haplotypes in the coding region of the gene.

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References

  • Barbosa, F. R., Matsuda, J. B., Mazucato, M., de Castro Franca, S., Zingaretti, S. M., da Silva, L. M., et al. (2012). Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients. Rheumatology International, 32(2), 427–430.

    Article  CAS  PubMed  Google Scholar 

  • Barnett, J. H., Heron, J., Goldman, D., Jones, P. B., & Xu, K. (2009). Effects of catechol-O-methyltransferase on normal variation in the cognitive function of children. American Journal of Psychiatry, 166(8), 909–916.

    Article  PubMed Central  PubMed  Google Scholar 

  • Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2005). Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics, 21(2), 263–265.

    Article  CAS  PubMed  Google Scholar 

  • Bijur, P. E., Latimer, C. T., & Gallagher, E. J. (2003). Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Academic Emergency Medicine, 10(4), 390–392.

    Article  PubMed  Google Scholar 

  • Bray, N. J., Buckland, P. R., Williams, N. M., Williams, H. J., Norton, N., Owen, M. J., et al. (2003). A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. American Journal of Human Genetics, 73(1), 152–161.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., et al. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics, 75(5), 807–821.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cleeland, C. S., & Ryan, K. M. (1994). Pain assessment: Global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore, 23(2), 129–138.

    CAS  PubMed  Google Scholar 

  • Cohen, H., Neumann, L., Glazer, Y., Ebstein, R. P., & Buskila, D. (2009). The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia. Clinical and Experimental Rheumatology, 27(5 Suppl 56), S51–S56.

    CAS  PubMed  Google Scholar 

  • Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., et al. (2005). Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics, 14(1), 135–143.

    Article  CAS  PubMed  Google Scholar 

  • Diatchenko, L., Slade, G. D., Nackley, A. G., & Maixner, W. (2007). Responses to Drs. Kim and Dionne regarding comments on Diatchenko, et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006; 125: 216-24. Pain, 129(3), 366–370.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dworkin, R. H., Turk, D. C., Farrar, J. T., Haythornthwaite, J. A., Jensen, M. P., Katz, N. P., et al. (2005). Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain, 113(1–2), 9–19.

    Article  PubMed  Google Scholar 

  • Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., et al. (2002). The structure of haplotype blocks in the human genome. Science, 296(5576), 2225–2229.

    Article  CAS  PubMed  Google Scholar 

  • Gaysina, D., Xu, M. K., Barnett, J. H., Croudace, T. J., Wong, A., Richards, M., et al. (2013). The catechol-O-methyltransferase gene (COMT) and cognitive function from childhood through adolescence. Biological Psychology, 92(2), 359–364.

    Article  PubMed Central  PubMed  Google Scholar 

  • George, S. Z., Dover, G. C., Wallace, M. R., Sack, B. K., Herbstman, D. M., Aydog, E., et al. (2008a). Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: Pain catastrophizing and catechol-o-methyltransferase (COMT) diplotype predict pain ratings. Clinical Journal of Pain, 24(9), 793–801.

    Article  PubMed Central  PubMed  Google Scholar 

  • George, S. Z., Wallace, M. R., Wright, T. W., Moser, M. W., Greenfield, W. H, 3rd, Sack, B. K., et al. (2008b). Evidence for a biopsychosocial influence on shoulder pain: Pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain, 136(1–2), 53–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gogos, J. A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., et al. (1998). Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proceedings of the National Academy of Sciences, 95(17), 9991–9996.

    Article  CAS  Google Scholar 

  • Gursoy, S., Erdal, E., Herken, H., Madenci, E., Alasehirli, B., & Erdal, N. (2003). Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatology International, 23(3), 104–107.

    PubMed  Google Scholar 

  • Hocking, L. J., Smith, B. H., Jones, G. T., Reid, D. M., Strachan, D. P., & Macfarlane, G. J. (2010). Genetic variation in the beta2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: Results from the 1958 British Birth Cohort Study. Pain, 149(1), 143–151.

    Article  CAS  PubMed  Google Scholar 

  • Jacobsen, L. M., Schistad, E. I., Storesund, A., Pedersen, L. M., Rygh, L. J., Roe, C., et al. (2012). The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation. European Journal of Pain, 16(7), 1064–1069.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, H., Xie, T., Ramsden, D. B., & Ho, S. L. (2003). Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology, 45(7), 1011–1018.

    Article  CAS  PubMed  Google Scholar 

  • Katerberg, H., Cath, D. C., Denys, D. A., Heutink, P., Polman, A., van Nieuwerburgh, F. C., et al. (2010). The role of the COMT Val(158)Met polymorphism in the phenotypic expression of obsessive-compulsive disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153B(1), 167–176.

    CAS  Google Scholar 

  • Keller, S., Bann, C. M., Dodd, S. L., Schein, J., Mendoza, T. R., & Cleeland, C. S. (2004). Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clinical Journal of Pain, 20(5), 309–318.

    Article  PubMed  Google Scholar 

  • Kraft, P., & Stram, D. O. (2007). Re: The use of inferred haplotypes in downstream analysis. American Journal of Human Genetics, 81(4), 863–865. author reply 865–866.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lin, S., Cutler, D. J., Zwick, M. E., & Chakravarti, A. (2002). Haplotype inference in random population samples. American Journal of Human Genetics, 71(5), 1129–1137.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lotta, T., Vidgren, J., Tilgmann, C., Ulmanen, I., Melen, K., Julkunen, I., et al. (1995). Kinetics of human soluble and membrane-bound catechol O-methyltransferase: A revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry, 34(13), 4202–4210.

    Article  CAS  PubMed  Google Scholar 

  • Macrae, W. A., & Davies, D. H. O. (1999). Chronic post-surgical pain. In I. K. Crombie, P. Croft, M. Von Korff, & L. LeResche (Eds.), Epidemiology of pain (pp. 125–142). Seattle, WA: IASP Press.

    Google Scholar 

  • Meyer-Lindenberg, A., Nichols, T., Callicott, J. H., Ding, J., Kolachana, B., Buckholtz, J., et al. (2006). Impact of complex genetic variation in COMT on human brain function. Molecular Psychiatry, 11(9), 867–877, 797.

    Google Scholar 

  • Nackley, A. G., Shabalina, S. A., Tchivileva, I. E., Satterfield, K., Korchynskyi, O., Makarov, S. S., et al. (2006a). Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science, 314(5807), 1930–1933.

    Article  CAS  PubMed  Google Scholar 

  • Nackley, A. G., Tan, K. S., Fecho, K., Flood, P., Diatchenko, L., & Maixner, W. (2006b). Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta(2)- and beta(3)-adrenergic receptors. Pain, 128(3), 199–208.

    Article  PubMed  Google Scholar 

  • Nicholl, B. I., Holliday, K. L., Macfarlane, G. J., Thomson, W., Davies, K. A., O’Neill, T. W., et al. (2010). No evidence for a role of the catechol-O-methyltransferase pain sensitivity haplotypes in chronic widespread pain. Annals of the Rheumatic Diseases, 69(11), 2009–2012.

    Article  PubMed  Google Scholar 

  • Paalzow, G. H., & Paalzow, L. K. (1983). Yohimbine both increases and decreases nociceptive thresholds in rats: Evaluation of the dose–response relationship. Naunyn-Schmiedeberg’s Archives of Pharmacology, 322(3), 193–197.

    Article  CAS  PubMed  Google Scholar 

  • Palmatier, M. A., Pakstis, A. J., Speed, W., Paschou, P., Goldman, D., Odunsi, A., et al. (2004). COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Molecular Psychiatry, 9(9), 859–870.

    Article  CAS  PubMed  Google Scholar 

  • Pelissier, T., Laurido, C., Hernandez, A., Constandil, L., & Eschalier, A. (2006). Biphasic effect of apomorphine on rat nociception and effect of dopamine D2 receptor antagonists. European Journal of Pharmacology, 546(1–3), 40–47.

    Article  CAS  PubMed  Google Scholar 

  • Platts-Mills, T. F., Ballina, L., Bortsov, A. V., Soward, A., Swor, R. A., Jones, J. S., et al. (2011). Using emergency department-based inception cohorts to determine genetic characteristics associated with long term patient outcomes after motor vehicle collision: Methodology of the CRASH study. BMC Emergency Medicine, 11, 14.

    Article  PubMed Central  PubMed  Google Scholar 

  • Pooley, E. C., Fineberg, N., & Harrison, P. J. (2007). The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: Case-control study and meta-analysis. Molecular Psychiatry, 12(6), 556–561.

    Article  CAS  PubMed  Google Scholar 

  • Reuter, M., & Hennig, J. (2005). Association of the functional catechol-O-methyltransferase VAL158MET polymorphism with the personality trait of extraversion. NeuroReport, 16(10), 1135–1138.

    Article  CAS  PubMed  Google Scholar 

  • Roth, J. A. (1992). Membrane-bound catechol-O-methyltransferase: A reevaluation of its role in the O-methylation of the catecholamine neurotransmitters. Reviews of Physiology Biochemistry and Pharmacology, 120, 1–29.

    Article  CAS  Google Scholar 

  • Shibata, K., Diatchenko, L., & Zaykin, D. V. (2009). Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects. Genetic Epidemiology, 33(1), 63–78.

    Article  PubMed Central  PubMed  Google Scholar 

  • Shifman, S., Bronstein, M., Sternfeld, M., Pisante-Shalom, A., Lev-Lehman, E., Weizman, A., et al. (2002). A highly significant association between a COMT haplotype and schizophrenia. American Journal of Human Genetics, 71(6), 1296–1302.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith, S. B., Maixner, D. W., Greenspan, J. D., Dubner, R., Fillingim, R. B., Ohrbach, R., et al. (2011). Potential genetic risk factors for chronic TMD: Genetic associations from the OPPERA case control study. The Journal of Pain, 12(11 Suppl), T92–101.

    Article  PubMed Central  PubMed  Google Scholar 

  • Smolka, M. N., Buhler, M., Schumann, G., Klein, S., Hu, X. Z., Moayer, M., et al. (2007). Gene-gene effects on central processing of aversive stimuli. Molecular Psychiatry, 12(3), 307–317.

    CAS  PubMed  Google Scholar 

  • Talkowski, M. E., Kirov, G., Bamne, M., Georgieva, L., Torres, G., Mansour, H., et al. (2008). A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Human Molecular Genetics, 17(5), 747–758.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tander, B., Gunes, S., Boke, O., Alayli, G., Kara, N., Bagci, H., et al. (2008). Polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase genes: A study on fibromyalgia susceptibility. Rheumatology International, 28(7), 685–691.

    Article  CAS  PubMed  Google Scholar 

  • Tang, H., Quertermous, T., Rodriguez, B., Kardia, S. L., Zhu, X., Brown, A., et al. (2005). Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. American Journal of Human Genetics, 76(2), 268–275.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tunbridge, E. M., & Harrison, P. J. (2011). Importance of the COMT gene for sex differences in brain function and predisposition to psychiatric disorders. Current Topics in Behavioral Neurosciences, 8, 119–140.

    Article  CAS  PubMed  Google Scholar 

  • van Meurs, J. B., Uitterlinden, A. G., Stolk, L., Kerkhof, H. J., Hofman, A., Pols, H. A., et al. (2009). A functional polymorphism in the catechol-O-methyltransferase gene is associated with osteoarthritis-related pain. Arthritis and Rheumatism, 60(2), 628–629.

    Article  PubMed  Google Scholar 

  • Vargas-Alarcon, G., Fragoso, J. M., Cruz-Robles, D., Vargas, A., Lao-Villadoniga, J. I., Garcia-Fructuoso, F., et al. (2007). Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther, 9(5), R110.

    Article  PubMed Central  PubMed  Google Scholar 

  • Wolfe, F., Smythe, H. A., Yunus, M. B., Bennett, R. M., Bombardier, C., Goldenberg, D. L., et al. (1990). The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism, 33(2), 160–172.

    Article  CAS  PubMed  Google Scholar 

  • Zubieta, J. K., Heitzeg, M. M., Smith, Y. R., Bueller, J. A., Xu, K., Xu, Y., et al. (2003). COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 299(5610), 1240–1243.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number R01AR056328 to Dr. Samuel A. McLean. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Dr. Diatchenko is a co-founder and equity stock holder in Algynomics, Inc. Other authors declare no conflict of interest.

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Authors and Affiliations

  1. TRYUMPH Research Program, University of North Carolina, Chapel Hill, NC, 27599, USA

    Andrey V. Bortsov & Samuel A. McLean

  2. Department of Anesthesiology, University of North Carolina, Medical School Wing C CB#7010, Chapel Hill, NC, 27599-7010, USA

    Andrey V. Bortsov & Samuel A. McLean

  3. Center of Neurosensory Disorders, University of North Carolina, Chapel Hill, NC, 27599, USA

    Luda Diatchenko

  4. Emergency Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

    Samuel A. McLean

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  1. Andrey V. Bortsov
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  2. Luda Diatchenko
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Correspondence to Samuel A. McLean.

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Bortsov, A.V., Diatchenko, L. & McLean, S.A. Complex Multilocus Effects of Catechol-O-Methyltransferase Haplotypes Predict Pain and Pain Interference 6 Weeks After Motor Vehicle Collision. Neuromol Med 16, 83–93 (2014). https://doi.org/10.1007/s12017-013-8255-9

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