Back to Search Start Over

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

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

Authors :
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
Richards, J. Brent [0000-0002-3746-9086]
Apollo - University of Cambridge Repository
Richards, J Brent [0000-0002-3746-9086]
Source :
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)
Publication Year :
2019
Publisher :
Nature Publishing Group UK, 2019.

Abstract

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.

Details

Database :
OpenAIRE
Journal :
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)
Accession number :
edsair.doi.dedup.....4f510183360e555079dd02158bc2a5c4
Full Text :
https://doi.org/10.1038/s41598-019-45747-2