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

2019; Oxford University Press; Volume: 25; Issue: 11 Linguagem: Inglês

10.1093/ibd/izz116

1536-4844

Williams Turpin, Osvaldo Espin‐Garcia, Larbi Bedrani, Karen Madsen, Jonathan B. Meddings, Juan A. Raygoza Garay, Mark S. Silverberg, Michelle I. Smith, Anne M. Griffiths, Paul Moayyedi, John K. Marshall, David R. Mack, Ernest G. Seidman, Mark J. Ropeleski, Brian G. Feagan, Kevan Jacobson, Dan Turner, Thomas D. Walters, Andrew D. Paterson, Maria Abreu, Paul L. Beck, Çharles N. Bernstein, Kenneth Croitoru, Leo Dieleman, Brian G. Feagan, Anne M. Griffiths, David Guttman, Kevan Jacobson, Gilaad G. Kaplan, Denis O. Krause, Karen Madsen, John K. Marshall, Paul Moayyedi, Mark J. Ropeleski, Ernest G. Seidman, Mark S. Silverberg, Scott B. Snapper, Andy Stadnyk, Hilary Steinhart, Michael G. Surette, Dan Turner, Tom Walters, Bruce A. Vallance, Guy Aumais, Alain Bitton, Maria Cino, Jeff Critch, Lee A. Denson, Colette Deslandres, Wael El‐Matary, Hans Herfarth, Peter Higgins, Hien Q. Huynh, Jeff Hyams, David R. Mack, Jerry McGrath, Dennis G. Cvitkovitch, Anthony Otley, Remo Panancionne, Çharles N. Bernstein, Colette Deslandres, Desmond Leddin, Donald S. Daly, Fred Saibil, Guy Aumais, Hein Huynh, Herbert Brill, Hillary Steinhart, Iwona Wrobel, Jeff Critch, Jeff Hyams, Jennifer Jones, Jerry McGrath, Leo Dieleman, Maria Cino, Martha H. Dirks, Neal S. LeLeiko, Pierre Paré, Remo Panancionne, Mark S. Silverberg, Anne M. Griffiths, John K. Marshall, David R. Mack, Ernest G. Seidman, Mark J. Ropeleski, Brian G. Feagan, Kevan Jacobson, Thomas D. Walters, Wei Xu, Kenneth Croitoru,

Digestive system and related health

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.