title: Facial pain with localized and widespread manifestations: separate pathways of vulnerability.
abstract: Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P=0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P=0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P=1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P=0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P=1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background.
authors.affiliation: Regional Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Ariadne Diagnostics LLC, Rockville, MD, USA Department of Community Dentistry & Behavioral Science, University of Florida, Gainesville, FL, USA Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, NY, USA University of Maryland School of Dentistry, Baltimore, MD, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Slade
authors.forename: Shad B
authors.initials: SB
authors.lastname: Smith
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.forename: Inna E
authors.initials: IE
authors.lastname: Tchivileva
authors.forename: Dustin G
authors.initials: DG
authors.lastname: Gibson
authors.forename: Anton
authors.initials: A
authors.lastname: Yuryev
authors.forename: Ilya
authors.initials: I
authors.lastname: Mazo
authors.forename: Eric
authors.initials: E
authors.lastname: Bair
authors.forename: Roger
authors.initials: R
authors.lastname: Fillingim
authors.forename: Richard
authors.initials: R
authors.lastname: Ohrbach
authors.forename: Joel
authors.initials: J
authors.lastname: Greenspan
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005157:Facial Pain / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012306:Risk; D012701:Serotonin / Q000502:physiology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D013705:Temporomandibular Joint Disorders / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: D011948:Receptors, Antigen, T-Cell; D012701:Serotonin; D004247:DNA
keywords: Case-control study; Human genetics; Serotonergic receptor; Temporomandibular disorder