Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. PERSPECTIVE: Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.