TY  - JOUR
AB  - We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10-8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the "irritable" nociceptor profile to those with a "nonirritable" nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10-8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.
AU  - Åkerlund, M.*
AU  - Baskozos, G.*
AU  - Li, W.*
AU  - Themistocleous, A.C.*
AU  - Pascal, M.M.V.*
AU  - Rayner, N.W.
AU  - Attal, N.*
AU  - Baron, R.*
AU  - Baudic, S.*
AU  - Bennedsgaard, K.*
AU  - Bouhassira, D.*
AU  - Comini, M.*
AU  - Crombez, G.*
AU  - Faber, C.G.*
AU  - Finnerup, N.B.*
AU  - Gierthmühlen, J.*
AU  - Granovsky, Y.*
AU  - Gylfadottir, S.S.*
AU  - Hébert, H.L.*
AU  - Jensen, T.S.*
AU  - John, J.*
AU  - Kemp, H.I.*
AU  - Lauria, G.*
AU  - Laycock, H.*
AU  - Meng, W.*
AU  - Nilsen, K.B.*
AU  - Palmer, C.*
AU  - Rice, A.S.C.*
AU  - Serra, J.*
AU  - Smith, B.H.*
AU  - Tesfaye, S.*
AU  - Topaz, L.S.*
AU  - Veluchamy, A.*
AU  - Vollert, J.*
AU  - Yarnitsky, D.*
AU  - van Zuydam, N.*
AU  - Zwart, J.A.*
AU  - McCarthy, M.I.*
AU  - Lyssenko, V.*
AU  - Bennett, D.L.*
C1  - 72182
C2  - 56446
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1354-1368
TI  - Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort.
JO  - Pain
VL  - 166
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 0304-3959
ER  - 

TY  - JOUR
AB  - Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n=2,444) from the TwinsUK registry who had extensive clinical, anthropometric, and "omic" data were included. Non-targeted metabolomics screening including 324 metabolites was carried out for CWP and body composition, assessed by DXA. The biological basis of these associations were explored through GWAS and replicated in an independent population sample (KORA study, n=2,483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height was the body composition variable most strongly associated with CWP (TwinsUK p=2.4x10 and KORA p=1.59x10). Of 324 metabolites examined, epiandrosterone sulphate (EAS) was highly associated with both CWP (p=1.05 x 10 in TwinsUK and p=3.70x10 in KORA) and fat mass/height. GWAS of EAS identified imputed SNP rs1581492 at 7q22.1 to be strikingly associated with EAS levels (p ≤2.49 x10) and this result was replicated in KORA (p=2.12x10). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with BMI, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker which identifies subgroups at risk of CWP.
AU  - Livshits, G.*
AU  - Macgregor, A.J.*
AU  - Gieger, C.
AU  - Malkin, I.*
AU  - Moayyeri, A.*
AU  - Grallert, H.
AU  - Emeny, R.T.
AU  - Spector, T.*
AU  - Kastenmüller, G.
AU  - Williams, F.M.*
C1  - 44555
C2  - 36940
SP  - 1845-1851
TI  - An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker.
JO  - Pain
VL  - 156
IS  - 10
PY  - 2015
SN  - 0304-3959
ER  - 

TY  - JOUR
AB  - Growth factors such as nerve growth factor and glial cell line-derived neurotrophic factor are known to induce pain sensitization. However, a plethora of other growth factors is released during inflammation and tissue regeneration, and many of them are essential for wound healing. Which wound-healing factors also alter the sensitivity of nociceptive neurons is not well known. We studied the wound-healing factor, basic fibroblast growth factor (bFGF), for its role in pain sensitization. Reverse transcription polymerase chain reaction showed that the receptor of bFGF, FGFR1, is expressed in lumbar rat dorsal root ganglia (DRG). We demonstrated presence of FGFR1 protein in DRG neurons by a recently introduced quantitative automated immunofluorescent microscopic technique. FGFR1 was expressed in all lumbar DRG neurons as quantified by mixture modeling. Corroborating the mRNA and protein expression data, bFGF induced Erk1/2 phosphorylation in nociceptive neurons, which could be blocked by inhibition of FGF receptors. Furthermore, bFGF activated Erk1/2 in a dose- and time-dependent manner. Using single-cell electrophysiological recordings, we found that bFGF treatment of DRG neurons increased the current-density of NaV1.8 channels. Erk1/2 inhibitors abrogated this increase. Importantly, intradermal injection of bFGF in rats induced Erk1/2-dependent mechanical hyperalgesia. Perspective: Analyzing intracellular signaling dynamics in nociceptive neurons has proven to be a powerful approach to identify novel modulators of pain. In addition to describing a new sensitizing factor, our findings indicate the potential to investigate wound-healing factors for their role in nociception.
AU  - Andres, C.*
AU  - Hasenauer, J.
AU  - Ahn, H.S.*
AU  - Joseph, E.K.*
AU  - Isensee, J.*
AU  - Theis, F.J.
AU  - Allgöwer, F.*
AU  - Levine, J.D.*
AU  - Dib-Hajj, S.D.*
AU  - Waxman, S.G.*
AU  - Hucho, T.*
C1  - 27385
C2  - 32643
SP  - 2216-2226
TI  - Wound-healing growth factor, basic FGF, induces Erk1/2-dependent mechanical hyperalgesia.
JO  - Pain
VL  - 154
IS  - 10
PB  - Elsevier Science
PY  - 2013
SN  - 0304-3959
ER  - 

TY  - JOUR
AB  - The perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms that orchestrate the expression and function of ion channels relevant for pain processing are poorly understood. We demonstrate here a central role of the transcription factor Smad-interacting protein 1 (Sip1/Zfhx1b/Zeb2), a 2-handed zinc finger DNA-binding protein with essential functions in neural crest and forebrain development, in controlling nociceptive neuron excitability and pain sensitivity. Mutant mice lacking 1 Zfhx1b allele displayed decreased thermal pain responses, whereas mechanical pain was unaffected. In parallel, repetitive firing of capsaicin/heat-sensitive nociceptive DRG neurons was markedly impaired. Analysis of the voltage-gated currents underlying repetitive firing revealed a significant increase in persistent sodium currents and a reduction in delayed rectifier potassium currents. Modeling experiments in conjunction with experimental results suggest that these changes cause a depolarization-induced block of action potential propagation past the DRG axon T-junction. These data suggest that Sip1 controls the transduction properties of heat-sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in DRG-neuron voltage-gated ion channels.
AU  - Jeub, M.*
AU  - Emrich, M.*
AU  - Pradier, B.*
AU  - Taha, O.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Huylebroeck, D.*
AU  - Zimmer, A.
AU  - Beck, H.*
AU  - Rácz, I.
C1  - 3762
C2  - 28926
SP  - 2384-2398
TI  - The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability.
JO  - Pain
VL  - 152
IS  - 10
PB  - Elsevier
PY  - 2011
SN  - 0304-3959
ER  -