Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Autor: Luke Devey, Lon R. Cardon, Sirui Zhou, Dawn Waterworth, Cong Guo, George Davey Smith, Robert A. Scott, Claudia Langenberg, Lauren E. Mokry, J. Brent Richards, Philippe Sanseau, Nicholas J. Wareham
Přispěvatelé: Richards, J. Brent [0000-0002-3746-9086], Apollo - University of Cambridge Repository, Richards, J Brent [0000-0002-3746-9086]
Rok vydání: 2019
Předmět:
0301 basic medicine
Oncology
Epidemiology
45/43
lcsh:Medicine
Type 2 diabetes
Severity of Illness Index
Inflammatory bowel disease
law.invention
631/208
0302 clinical medicine
Randomized controlled trial
law
Odds Ratio
692/308/174
lcsh:Science
Enterocolitis
Receptors
Interleukin-18
Multidisciplinary
Drug discovery
Anti-Inflammatory Agents
Non-Steroidal
Confounding
Interleukin-18
article
3. Good health
Drug repositioning
Treatment Outcome
692/4020/1503/257
medicine.symptom
medicine.medical_specialty
Single-nucleotide polymorphism
Polymorphism
Single Nucleotide
03 medical and health sciences
Internal medicine
Mendelian randomization
Genetics
medicine
Humans
Genetic Predisposition to Disease
Alleles
business.industry
lcsh:R
Drug Repositioning
631/154
Mendelian Randomization Analysis
Inflammatory Bowel Diseases
medicine.disease
030104 developmental biology
lcsh:Q
business
Biomarkers
030217 neurology & neurosurgery
Zdroj: Mokry, L E, Zhou, S, Guo, C, Scott, R A, Devey, L, Langenberg, C, Wareham, N, Waterworth, D M, Cardon, L, Sanseau, P, Davey Smith, G & Richards, B 2019, ' Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease : A Mendelian randomization study ', Scientific Reports, vol. 9, no. 1, 9386 (2019) . https://doi.org/10.1038/s41598-019-45747-2
Scientific Reports
Scientific Reports, Vol 9, Iss 1, Pp 1-7 (2019)
DOI: 10.1038/s41598-019-45747-2
Popis: Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.
Databáze: OpenAIRE
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