The following is a summary of “Genetics of Constant and Severe Pain in the NAPS2 Cohort of Recurrent Acute and Chronic Pancreatitis Patients,” published in the December 2024 issue of Pain by Dunbar et al. 

Recurrent acute and chronic pancreatitis (RAP, CP) were complex, progressive inflammatory diseases with variable pain experiences that significantly impacted patient function and QoL, with the genetic variants and pain pathways contributing to the most severe pain still unknown.  

Researchers conducted a retrospective study to identify genetic variants and pain pathways associated with severe pain experiences in patients with RAP/CP.  

They used genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European ancestry for a nested genome-wide association study (GWAS) on pain severity, chronicity, or both. Lead variants were identified using FUMA, and loci with P <1e-5 were selected for post-hoc candidate analysis. Transcriptome-wide association studies (TWAS) examined loci in cis and trans to the lead variants. Serum from individuals with CP in the Prospective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational Studies (PROCEED) was tested for Brain Derived Neurotrophic Factor (BDNF) levels using Meso Scale Discovery Immunoassay.  

The results showed 4 pain systems defined by candidate genes: Pancreas-associated injury/stress mitigation genes, including the Regenerating Family Member gene cluster (REG) gene cluster, Chymotrypsin C (CTRC), Neuralized E3 Ubiquitin Protein Ligase 3 (NEURL3), and Heat Shock Transcription Factor 2 (HSF22), Neural development and axon guidance genes, such as SNPO, Repulsive Guidance Molecule BMP Co-Receptor A (RGMA), Mastermind Like Transcriptional Coactivator 1 (MAML1), and Docking Protein 6 (DOK6) (part of the RET complex). Genes related to psychiatric stress disorders, including Transmembrane Protein 65 (TMEM65), RNA Binding Fox-1 Homolog 1 (RBFOX1), and Zinc Finger Protein 385D (ZNF385D), Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway, such as Synaptoporin (SYNPR), Neurotrophin 3 (NTF3), and RBFOX1.  

Investigators concluded the BDNF levels were elevated in patients with constant-severe pain, suggesting that further investigation into BDNF pathways and mechanisms may lead to the development of individualized pain treatment strategies for the patients. 

Source: jpain.org/article/S1526-5900(24)00732-6/fulltext