Analysis of Genetic Association of Intestinal Permeability in Healthy First-degree Relatives of Patients with Crohn’s Disease
Authors: Turpin Williams , Espin-Garcia Osvaldo , Bedrani Larbi , Madsen Karen , Meddings Jonathan B , Raygoza Garay Juan Antonio , Silverberg Mark S , Smith Michelle I , Griffiths Anne M , Moayyedi Paul , Marshall John K , Mack David , Seidman Ernest G , Ropeleski Mark , Feagan Brian G , Jacobson Kevan , Turner Dan , Walters Thomas , Paterson Andrew D ,   CCC GEM Project Research Consortium, Abreu Maria , Beck Paul , Bernstein Charles , Croitoru Kenneth , Dieleman Leo , Feagan Brian , Griffiths Anne , Guttman David , Jacobson Kevan , Kaplan Gilaad , Krause Denis O , Madsen Karen , Marshall John , Moayyedi Paul , Ropeleski Mark , Seidman Ernest , Silverberg Mark , Snapper Scott , Stadnyk Andy , Steinhart Hilary , Surette Michael , Turner Dan , Walters Tom , Vallance Bruce , Aumais Guy , Bitton Alain , Cino Maria , Critch Jeff , Denson Lee , Deslandres Colette , El-Matary Wael , Herfarth Hans , Higgins Peter , Huynh Hien , Hyams Jeff , Mack David , McGrath Jerry , Cvitkovitch Dennis , Otley Anthony , Panancionne Remo , Bernstein Charles , Deslandres Colette , Leddin Desmond , Daly Donald , Saibil Fred , Aumais Guy , Huynh Hein , Brill Herbert , Steinhart Hillary , Wrobel Iwona , Critch Jeff , Hyams Jeff , Jones Jennifer , McGrath Jerry , Dieleman Leo , Cino Maria , Dirks Martha , Leleiko Neal , Pare Pierre , Panancionne Remo , Silverberg Mark S , Griffiths Anne M , Marshall John K , Mack David , Seidman Ernest G , Ropeleski Mark , Feagan Brian G , Jacobson Kevan , Walters Thomas , Xu Wei , Croitoru Kenneth 
Published: June 2019

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.