The Unsolved Link of Genetic Markers and Crohn’s Disease Progression: A North American Cohort Experience

Abstract

Background While progress has been made in the identification of Crohn’s disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD. Methods Crohn’s disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used. Results A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05). Conclusion Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.

Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study

“…ATPBD4 (or DPH6) is a proteincoding gene that regulates adenosine triphosphate (ATP) binding and diphthamide synthase activity, within the protein metabolism pathway (Chertow 1981;Young et al 2004). Polymorphisms in this gene were associated-in various genome-wide association studies (GWAS)-with adiposity (Kichaev et al 2019;Pulit et al 2019), cognitive function (Lee et al 2018;Li et al 2015), and Crohn's disease progression (O'Donnell et al 2019). FARS2 is a protein-coding gene that regulates the translation of mitochondrial proteins and gene expression (Bullard et al 1999).…”

Metabolic Influences of Gut Microbiota Dysbiosis on Inflammatory Bowel Disease

“…Epidemiological studies showed that IBD is spreading widely throughout the world leading to a public health challenge worldwide ( Zheng H. et al, 2017 ; Windsor and Kaplan, 2019 ; Kaplan and Windsor, 2021 ). It is widely accepted that the IBD pathogenesis results from an interplay between gut microbiota and the host immune system with the predisposition of genetic susceptibility and environmental factors ( Ma et al, 2019 ; O’Donnell et al, 2019 ; Ramos and Papadakis, 2019 ; Pang et al, 2021 ). The microbiome-immune system interaction leads to improper immune activation responsible for the clinical and endoscopic observations in IBD patients ( Ramos and Papadakis, 2019 ; Zheng et al, 2020 ).…”

Genotype–phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients

“…So far, it is not clear whether polymorphisms that affect IBD risk also contribute to disease course and severity. While O’Donnell et al [ 37 ] report association of 8 SNPs with time to-abdominal surgery, Lee et al [ 38 ] could not identify any associations of disease susceptibility loci with disease prognosis, but identified four loci with significant association to the course of CD without any association to disease susceptibility. In addition, TLR SNPs that do not affect disease susceptibility, were found to be associated with extensive colonic disease in both CD and UC patients [ 39 ], and polymorphisms associated with smoking behavior could predict the number of surgeries and the time to first intestinal surgery in smoking Crohn’s disease patients [ 40 ].…”