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Cited by 29Pain Mechanisms and TreatmentsIon Channels and ReceptorsHereditary Neurological Disorders

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TRPA1 rare variants in chronic neuropathic and nociplastic pain patients

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Marchi, Margherita, Salvi, Erika, Andelic, Mirna, Mehmeti, Elkadia, D'Amato, Ilaria, Cazzato, Daniele, Chiappori, Federica, Lombardi, Raffaella, Cartelli, Daniele, Devigili, Grazia, Dalla Bella, Eleonora, Gerrits, Monique, Almomani, Rowida, Malik, Rayaz A., Ślęczkowska, Milena, Mazzeo, Anna, Gentile, Luca, Dib-Hajj, Sulayman, Waxman, Stephen G., Faber, Catharina G., Vecchio, Eleonora, de Tommaso, Marina, Lauria, Giuseppe·2023·Pain
DOI 10.1097/j.pain.0000000000002905PMC PMC10443199
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Abstract

Missing aspects of the heritability of chronic neuropathic pain, as a complex adult-onset trait, may be hidden within rare variants with low effect on disease risk, unlikely to be resolved by a single-variant approach. To identify new risk genes, we performed a next-generation sequencing of 107 pain genes and collapsed the rare variants through gene-wise aggregation analysis. The optimal unified sequence kernel association test was applied to 169 patients with painful neuropathy, 223 patients with nociplastic pain (82 diagnosed with chronic widespread pain and 141 with fibromyalgia), and 216 healthy controls. Frequency and features of variants in TRPA1 , which was the most significant gene, were further validated in 2 independent cohorts of 140 patients with chronic pain (90 with painful neuropathy and 50 with chronic widespread pain) and 34 with painless neuropathy. The effect of aminoacidic changes were modeled in silico according to physicochemical characteristics. TRPA1 was significantly enriched of rare variants which significantly discriminated chronic pain patients from healthy controls after Bonferroni correction ( P = 6.7 × 10 −4 , ρ = 1), giving a risk of 4.8-fold higher based on the simple burden test ( P = 0.0015, OR = 4.8). Among the 32 patients harboring TRPA1 variants, 24 (75%) were diagnosed with nociplastic pain, either fibromyalgia (12; 37.5%) or chronic widespread pain (12; 37.5%), whereas 8 (25%) with painful neuropathy. Irrespective of the clinical diagnosis, 12 patients (38%) complained of itch and 10 (31.3%) of cold-induced or cold-accentuated pain, mostly episodic. Our study widens the spectrum of channelopathy-related chronic pain disorders and contributes to bridging the gap between phenotype and targeted therapies based on patients' molecular profile.

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Metadata

Authors
Marchi, M., Salvi, E., Andelic, M., Mehmeti, E., D'Amato, I., Cazzato, D., Chiappori, F., Lombardi, R., Cartelli, D., Devigili, G., Dalla Bella, E., Gerrits, M., Almomani, R., Malik, R. A., Ślęczkowska, M., Mazzeo, A., Gentile, L., Dib-Hajj, S., Waxman, S. G., Faber, C. G., Vecchio, E., de Tommaso, M., & Lauria, G.
Affiliations
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
  • Institute of Biomedical Technologies (IT)
  • Maastricht University Medical Centre (NL)
  • Jordan University of Science and Technology (JO)
  • University of Manchester (GB)
  • Maastricht University (NL)
  • University of Messina (IT)
  • Department of Neurology, Yale University School of Medicine, New Haven, CT, United States
  • Yale University (US)
  • University of Bari Aldo Moro (IT)
  • University of Milan (IT)
Corresponding author
Lauria, Giuseppe
ORCID
Venue
Pain
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-04-19
Volume
164
Issue
9
Pages
2048-2059
ISSN
  • 0304-3959 (ISSN-L)
  • 1872-6623
DOI
10.1097/j.pain.0000000000002905
PMC
PMC10443199
OpenAlex
W4366465447
Cited by
29
References
6
Citations by year
2026: 10 · 2025: 9 · 2024: 8 · 2023: 2
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Pain (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by-nc-nd)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • CNR ExploRA (submittedVersion)
Funders
  • European Commission (721841, HORIZON2020, 602273)
  • Ministero della Salute
Topics
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
TRPA1, rare variants, chronic neuropathic pain, nociplastic pain, fibromyalgia, chronic widespread pain, channelopathies, cold pain, pruritus, amino acid substitutions
MeSH terms
TRPA1 Cation Channel, Humans, Neuralgia, Chronic Pain

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