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ADRA1A polymorphisms associated with multiple psychological and nociceptive phenotypes predict vulnerability to an idiopathic pain condition
Shad B. Smith, PhD1, Gary D. Slade, PhD2, Inna Belfer, MD, PhD3, David Goldman, MD3, Mitchell B. Max, MD4, Roger B. Fillingim, PhD5, Tomas J. Higgins, BS1, Swetha Sama1, William Maixner, DDS, PhD1, and Luda Diatchenko, MD, PhD1. (1) UNC School of Dentistry, Center for Neurosensory Disorders, CB# 7450, Chapel Hill, NC 27599, (2) University of Adelaide, 122 Frome St, 1st Floor, Adelaide, Australia, (3) NIAAA, Laboratory of Neurogenetics, 5625 Fishers Lane, Rockville, MD 20852, (4) NIDCR, Pain & Neurosensory Mechanisms Branch, 10 Center Dr. MSC 1258, Bethesda, MD 20892, (5) Department of Community Dentistry and Behavioral Science, University of Florida, P.O. Box 103628, Gainesville, FL 32610-3628
The causes of chronic pain conditions such as fibromyalgia and temporomandibular joint disorder (TMJD) are poorly understood. Recent evidence suggests that biopsychosocial and associated genetic factors contribute to the etiology of these diseases. Individual variability in adrenergic system genes may be a common determinant of both psychological and nociceptive phenotypes, as adrenergic pathways are known to mediate the response to environmental stress. We have performed a prospective study of 183 initially healthy Caucasian volunteers in order to find predictors of TMJD. Each subject was assessed for numerous psychosocial traits and underwent a battery of experimental pain measures. Blood samples were drawn for genotyping adrenergic receptor and other candidate genes. Subjects were then monitored over 3 years for the development of TMJD. We observed strong associations between polymorphisms of the alpha-1a adrenergic receptor gene (ADRA1A) and measures of alertness, anxiety, depression, and somatization, as well as sensitivity to noxious thermal and mechanical stimulation. Additionally, several alleles were associated with up to a 9-fold increase in relative risk to develop TMJD. Our findings indicate that ADRA1A variants may contribute to the vulnerability to develop an idiopathic pain condition, via increasing pain sensitivity and predisposition to psychological phenotypes that are associated with TMJD and related conditions.