Pain · 23 authors, 15 centres
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This study found that rare variants in the TRPA1 gene are significantly enriched in patients with nociplastic pain (chronic widespread pain and fibromyalgia), with a 4.8-fold higher risk compared to healthy controls. These variants were associated with cold-induced pain and itch, suggesting a genetic basis for a subgroup of chronic pain patients. The findings support the use of gene-based aggregation analysis to identify new therapeutic targets for personalized pain treatment.
**Background:** Chronic pain is a complex condition with overlapping phenotypes, including neuropathic and nociplastic pain (e.g., fibromyalgia, chronic widespread pain). While variants in voltage-gated sodium channel (VGSC) genes have been linked to pain disorders, the missing heritability for common chronic pain may involve rare variants in other genes. This study aimed to identify rare genetic variants associated with chronic pain using a gene-wise aggregation analysis approach.
**Methods:** The study included 392 patients with chronic pain (169 with length-dependent painful neuropathy, 82 with chronic widespread pain, and 141 with fibromyalgia) and 216 healthy controls, all of Anglo-American ancestry recruited in Italy between 2016 and 2022. Patients underwent clinical examination, nerve conduction studies, skin biopsy for intraepidermal nerve fiber density (IENFD), and pain assessment using the Pain Intensity Numeric Rating Scale (PI-NRS). Next-generation sequencing was performed on a targeted panel of 107 pain-related genes. Gene-wise aggregation analysis using the optimal unified sequence kernel association test (SKAT-O) was applied to compare rare variant burden between patients and controls, corrected for sex and age. A validation cohort of 90 painful neuropathy, 50 chronic widespread pain, and 34 painless neuropathy patients was used to confirm single variants. Variants were classified according to ACMG guidelines.
**Key Results:** The TRPA1 gene showed a Bonferroni-adjusted significant enrichment of rare variants in nociplastic pain patients (chronic widespread pain and fibromyalgia) compared to healthy controls (P = 6.7e-04), with a 4.8-fold higher risk based on the burden test (P = 0.0015, OR = 4.8). No significant enrichment was found for VGSC genes (SCN9A, SCN10A, SCN11A). Among 32 patients harboring TRPA1 variants, 24 (75%) had nociplastic pain (12 fibromyalgia, 12 chronic widespread pain) and 8 (25%) had painful neuropathy. Clinically, 12 (37.5%) patients complained of itch and 10 (31.3%) of cold-induced or cold-accentuated pain. The variants exclusively found in patients had lower population frequencies (max 0.35% in gnomAD-NFE) and higher pathogenicity scores. In silico modeling predicted damaging effects on protein structure, including loss of hydrogen bonds in ankyrin domains and potential impact on channel permeability. Notably, the Neanderthal SCN9A haplotype (M932L, V991L, D1908G) was not enriched in patients, but the W1538R variant was significantly more frequent in patients compared to the general population (OR = 8.6, P = 2.08E-9).
**Clinical Implications:** This study identifies TRPA1 as a key gene associated with nociplastic pain, particularly in patients with cold-induced pain and itch. The findings suggest that a subgroup of chronic pain patients may have a genetic basis involving TRPA1, which could guide personalized therapeutic strategies. TRPA1 inhibitors, which have shown mixed results in clinical trials, may be more effective in patients with specific TRPA1 variants. The gene-wise aggregation approach overcomes limitations of single-variant analysis and highlights the importance of rare variants in complex pain disorders. Future clinical trials should consider molecular profiling to select patients who may benefit from TRPA1-targeted therapies.