Analysis of Genetic Association of Intestinal Permeability in Healthy First-degree Relatives of Patients with Crohn's Disease

Williams Turpin, Osvaldo Espin-Garcia, Larbi Bedrani, Karen Madsen, Jonathan B. Meddings, Juan Antonio Raygoza Garay, Mark S. Silverberg, Michelle I. Smith, Anne M. Griffiths, Paul Moayyedi, John K. Marshall, David Mack, Ernest G. Seidman, Mark Ropeleski, Brian G. Feagan, Kevan Jacobson, Dan Turner, Thomas Walters, Andrew D. Paterson, Wei XuKenneth Croitoru*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn's disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10-7 - 1.4 × 10-5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.

Original languageAmerican English
Pages (from-to)1796-1804
Number of pages9
JournalInflammatory Bowel Diseases
Volume25
Issue number11
DOIs
StatePublished - 18 Oct 2019

Bibliographical note

Publisher Copyright:
© 2019 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved.

Keywords

  • GWAS
  • LacMan
  • biomarker
  • intestinal barrier
  • leaky gut

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