title: Cytokine biomarkers and chronic pain: association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness.
abstract: For reasons unknown, temporomandibular disorder (TMD) can manifest as localized pain or in conjunction with widespread pain. We evaluated relationships between cytokines and TMD without or with widespread palpation tenderness (TMD-WPT or TMD+WPT, respectively) at protein, transcription factory activity, and gene levels. Additionally, we evaluated the relationship between cytokines and intermediate phenotypes characteristic of TMD and WPT. In a case-control study of 344 females, blood samples were analyzed for levels of 22 cytokines and activity of 48 transcription factors. Intermediate phenotypes were measured by quantitative sensory testing and questionnaires asking about pain, health, and psychological status. Single nucleotide polymorphisms (SNPs) coding cytokines and transcription factors were genotyped. TMD-WPT cases had elevated protein levels of proinflammatory cytokine monocyte chemotactic protein (MCP-1) and antiinflammatory cytokine interleukin (IL)-1ra, whereas TMD+WPT cases had elevated levels of proinflammatory cytokine IL-8. MCP-1, IL-1ra, and IL-8 were differentially associated with experimental pain, self-rated pain, self-rated health, and psychological phenotypes. TMD-WPT and TMD+WPT cases had inhibited transcription activity of the antiinflammatory cytokine transforming growth factor β1 (TGFβ1). Interactions were observed between TGFβ1 and IL-8 SNPs: an additional copy of the TGFβ1 rs2241719 minor T allele was associated with twice the odds of TMD+WPT among individuals homozygous for the IL-8 rs4073 major A allele, and half the odds of TMD+WPT among individuals heterozygous for rs4073. These results demonstrate how pro- and antiinflammatory cytokines contribute to the pathophysiology of TMD and WPT in genetically susceptible people. Furthermore, they identify MCP-1, IL-1ra, IL-8, and TGFβ1 as potential diagnostic markers and therapeutic targets for pain in patients with TMD.
authors: Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA Attagene, Inc, Morrisville, NC 27560, USA.
authors: Gary D
authors: GD
authors: Slade
authors: Mathew S
authors: MS
authors: Conrad
authors: Luda
authors: L
authors: Diatchenko
authors: Naim U
authors: NU
authors: Rashid
authors: Sheng
authors: S
authors: Zhong
authors: Shad
authors: S
authors: Smith
authors: Jesse
authors: J
authors: Rhodes
authors: Alex
authors: A
authors: Medvedev
authors: Sergei
authors: S
authors: Makarov
authors: William
authors: W
authors: Maixner
authors: Andrea G
authors: AG
authors: Nackley
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D059350:Chronic Pain / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D010147:Pain Measurement / Q000379:methods; D010173:Palpation / Q000379:methods; D011795:Surveys and Questionnaires; D013705:Temporomandibular Joint Disorders / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines