Impact of SCN10A Polymorphism on Abdominal Pain Perception and Visceral Hypoalgesia in Crohn's Disease and Ulcerative Colitis

Overview

Journal Clin Transl Gastroenterol

Specialty Gastroenterology

Date 2024 Dec 27

PMID 39729348

Authors

Matthew D Coates

Vonn Walter

August Stuart

Jeffrey Small

Shannon Dalessio

Nurgul Carkaci-Salli

Ann Ouyang

Kofi Clarke

Andrew Tinsley

Emmanuelle D Williams

Piotr Janicki

Victor Ruiz-Velasco

Kent E Vrana

Affiliations

Soon will be listed here.

Abstract

Introduction: Hypoalgesic inflammatory bowel disease (IBD) may provide critical insights into human abdominal pain. This condition was previously associated with homozygosity for a polymorphism (rs6795970, A1073V; 1073 val/val ) related to Na v 1.8, a voltage-gated sodium channel preferentially expressed on nociceptors. It was unclear whether this relationship existed for both Crohn's disease (CD) and ulcerative colitis (UC). This study evaluated a larger, carefully phenotyped IBD cohort to investigate this question.

Methods: Allelic and genotypic frequencies of rs6795970 were compared among study cohorts characterized by concomitant assessment of intestinal inflammatory status and abdominal pain experience. Visceral sensory perception was performed in healthy individuals using rectal balloon distension.

Results: We analyzed 416 patients with IBD (261CD:155UC) and 142 healthy controls. In the IBD cohort, 84 individuals (43CD:41UC) were determined to have hypoalgesic disease. The allelic frequency of rs6795970 was significantly higher in patients with hypoalgesic IBD when compared with other patients with IBD and healthy controls. Patients with hypoalgesic IBD were also more likely to be homozygous for this polymorphism when compared with other patients with IBD and healthy controls. Hypoalgesic CD (30% vs 12%, P = 0.004) and hypoalgesic UC (32% vs 15%, P = 0.036) were each significantly more likely to be associated with homozygosity for the rs6795970 polymorphism. In a cohort of healthy individuals (n = 50), rs6795970 homozygotes (n = 11) also demonstrated reduced abdominal discomfort to rectal balloon distension.

Discussion: These findings indicate that Na v 1.8 plays a key role in human visceral pain perception, and could serve as a novel diagnostic target in the management of hypoalgesic CD and UC, and potential therapeutic target for conditions associated with chronic abdominal pain.

References

Satsangi J, Silverberg M, Vermeire S, Colombel J . The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006; 55(6):749-53. PMC: 1856208. DOI: 10.1136/gut.2005.082909. View

Peyrin-Biroulet L, Reinisch W, Colombel J, Mantzaris G, Kornbluth A, Diamond R . Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut. 2013; 63(1):88-95. DOI: 10.1136/gutjnl-2013-304984. View

Park K, Ehrlich O, Allen J, Meadows P, Szigethy E, Henrichsen K . The Cost of Inflammatory Bowel Disease: An Initiative From the Crohn's & Colitis Foundation. Inflamm Bowel Dis. 2019; 26(1):1-10. PMC: 7534391. DOI: 10.1093/ibd/izz104. View

Best W, Becktel J, SINGLETON J, KERN Jr F . Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976; 70(3):439-44. View

Click B, Vargas E, Anderson A, Proksell S, Koutroubakis I, Rivers C . Silent Crohn's Disease: Asymptomatic Patients with Elevated C-reactive Protein Are at Risk for Subsequent Hospitalization. Inflamm Bowel Dis. 2015; 21(10):2254-61. DOI: 10.1097/MIB.0000000000000516. View

Duan G, Han C, Wang Q, Guo S, Zhang Y, Ying Y . A SCN10A SNP biases human pain sensitivity. Mol Pain. 2016; 12. PMC: 5011395. DOI: 10.1177/1744806916666083. View

Jones J, Correll D, Lechner S, Jazic I, Miao X, Shaw D . Selective Inhibition of Na1.8 with VX-548 for Acute Pain. N Engl J Med. 2023; 389(5):393-405. DOI: 10.1056/NEJMoa2209870. View

Dahlhamer J, Zammitti E, Ward B, Wheaton A, Croft J . Prevalence of Inflammatory Bowel Disease Among Adults Aged ≥18 Years - United States, 2015. MMWR Morb Mortal Wkly Rep. 2016; 65(42):1166-1169. DOI: 10.15585/mmwr.mm6542a3. View

Bielefeldt K, Davis B, Binion D . Pain and inflammatory bowel disease. Inflamm Bowel Dis. 2009; 15(5):778-88. PMC: 3180862. DOI: 10.1002/ibd.20848. View

10.

Norton C, Czuber-Dochan W, Artom M, Sweeney L, Hart A . Systematic review: interventions for abdominal pain management in inflammatory bowel disease. Aliment Pharmacol Ther. 2017; 46(2):115-125. DOI: 10.1111/apt.14108. View

11.

Chen G, Pedarla V, Null K, Cazzetta S, Khan Q, Schwartz D . Health Care Costs and Resource Utilization Among Patients With Crohn's Disease With and Without Perianal Fistula. Inflamm Bowel Dis. 2021; 28(6):870-877. PMC: 9165558. DOI: 10.1093/ibd/izab198. View

12.

Cohen R, Skup M, Ozbay A, Rizzo J, Yang M, Diener M . Direct and indirect healthcare resource utilization and costs associated with ulcerative colitis in a privately-insured employed population in the US. J Med Econ. 2015; 18(6):447-56. DOI: 10.3111/13696998.2015.1021353. View

13.

Louis E, Siegel C, James B, Heidenreich S, Krucien N, Ghosh S . Patients with Inflammatory Bowel Disease Have Heterogeneous Treatment Preferences That Are Largely Determined by the Avoidance of Abdominal Pain and Side Effects [P-POWER IBD Study]. J Crohns Colitis. 2022; 17(2):231-239. PMC: 10024545. DOI: 10.1093/ecco-jcc/jjac130. View

14.

Peyrin-Biroulet L, Panes J, Sandborn W, Vermeire S, Danese S, Feagan B . Defining Disease Severity in Inflammatory Bowel Diseases: Current and Future Directions. Clin Gastroenterol Hepatol. 2015; 14(3):348-354.e17. DOI: 10.1016/j.cgh.2015.06.001. View

15.

Arisawa T, Tahara T, Shiroeda H, Minato T, Matsue Y, Saito T . Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects. J Gastroenterol. 2012; 48(1):73-80. DOI: 10.1007/s00535-012-0602-3. View

16.

Coates M, Kim J, Carkaci-Salli N, Vrana K, Koltun W, Puhl H . Impact of the Na1.8 variant, A1073V, on post-sigmoidectomy pain and electrophysiological function in rat sympathetic neurons. J Neurophysiol. 2019; 122(6):2591-2600. PMC: 6957366. DOI: 10.1152/jn.00542.2019. View

17.

Coates M, Lahoti M, Binion D, Szigethy E, Regueiro M, Bielefeldt K . Abdominal pain in ulcerative colitis. Inflamm Bowel Dis. 2013; 19(10):2207-14. PMC: 3749243. DOI: 10.1097/MIB.0b013e31829614c6. View

18.

Gonzalez-Lopez E, Kawasawa Y, Walter V, Zhang L, Koltun W, Huang X . Homozygosity for the SCN10A Polymorphism rs6795970 Is Associated With Hypoalgesic Inflammatory Bowel Disease Phenotype. Front Med (Lausanne). 2018; 5:324. PMC: 6277464. DOI: 10.3389/fmed.2018.00324. View

19.

Chambers J, Zhao J, Terracciano C, Bezzina C, Zhang W, Kaba R . Genetic variation in SCN10A influences cardiac conduction. Nat Genet. 2010; 42(2):149-52. DOI: 10.1038/ng.516. View

20.

Bogale K, Maheshwari P, Kang M, Gorrepati V, Dalessio S, Walter V . Symptoms associated with healthcare resource utilization in the setting of inflammatory bowel disease. Sci Rep. 2022; 12(1):10577. PMC: 9217979. DOI: 10.1038/s41598-022-14838-y. View