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.

Keywords: Case-control study; Human genetics; Serotonergic receptor; Temporomandibular disorder.

Figure 1

Case-control differences in intermediate phenotypes for localized TMD and TMD with widespread pain Mean (±95% confidence interval) differences in quantitative phenotypes between n=192 TMD controls and two TMD subtypes ▭ localized TMD (n=94), and TMD with widespread pain (n=105)]. Phenotypes in Fig 1A are measures of pressure pain thresholds (PPT) and mood, where lower means in TMD subtypes relative to controls signify greater pain sensitivity and more negative mood (respectively). Phenotypes in Fig 1B are measures of pain perceptions, psychological states, and numerical ratings of thermal pain, where higher means in TMD subtypes relative to controls signify more severe pain, greater psychological distress, and greater pain sensitivity (respectively). Mood was measured using the Profile of Mood States (POMS) questionnaire. Pain perceptions were measured using the McGill Pain Questionnaire (MPQ). Psychological stress was measured using the Perceived Stress Scale (PSS). Somatization was measure using the Pennebaker Index of Limbic Languidness (PILL). All phenotypic measures were transformed to standardized z-scores with a mean of zero and standard deviation of 1.0 for the full cohort of TMD cases and controls. * indicates phenotypes where the case-control difference varies significantly (P<0.002) according to TMD subtype.

Figure 2

Cellular pathways associated with (A) localized TMD and (B) TMD with widespread pain. Genes shown in blue are significantly associated with case status with P<0.05. (A) HTR2-> ELK-SRF/GATA4 pathway. HTR2A – 5-hydroxytryptamine receptor 2A (OMIM 182135), HTR2C - 5-hydroxytryptamine receptor 2C (OMIM 312861), MAPK1 – mitogen-activated protein kinase 1 (OMIM 176948), MAP2K1 - mitogen-activated protein kinase 1 (OMIM 176872). (B) T-cell receptor -> CREBBP pathway. CAMK4 - calcium/calmodulin-dependent protein kinase IV (OMIM 114080), CALM2 - calmodulin 2 (OMIM 114182).