Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making?

Abstract

Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.

Keywords: genetics; inflammatory bowel disease; molecular profiling; transcriptomics.

Figure 1

The prediction of IBD risk based on the polygenic risk score (PRS). (A) Histogram of IBD PRS distribution in controls and patients with IBD. Patients tend to have larger risk scores than controls, as seen by the shift to the right of the patient distribution (purple) compared to the control distribution (salmon), although the distributions of patients and controls tend to overlap for the most part. Also, it is equally possible to see patients with IBD but with a low IBD PRS (blue arrow on the left), as there are controls with high IBD PRS that do not develop IBD (orange arrow on the right). Thus, calculating someone’s PRS is only able to tell something about that persons’ risk to get the disease (compared to the general population), but not whether he/she will get the disease. (B) Risk gradient for IBD in the high polygenic risk score area (20% highest scores, dashed box). The ascertainment of individuals with high polygenic risk score in a population may provide an opportunity to identify the individuals with the highest genetic risk. On this figure, the increased fold-risk is indicated for individuals in the top 20%, 10%, 5%, 1%, and 0.5% of the distribution based on estimates from Khera et al. [20]. The size of the circles and the numbers inside indicate the odds ratios. The top 1% of PRS thus has 3.9-fold risk (compared with the remainder 99% of the population), which represents an increase of IBD risk to 5.1% (with a lifetime IBD risk of 1.3%). The utility of polygenic risk score-based risk estimations is thus currently limited by the relatively small effect sizes.

Figure 2

Prediction of IBD disease progression based on molecular profiling. Molecular profiling of disease prognosis using genetics, transcriptomics, and serology has been rapidly evolving. The most promising studies in the IBD filed and their general study designs are shown with references. CD: Crohn’s disease, UC: ulcerative colitis, ASCA: anti-Saccharomyces cerevisiae antibodies, Cbir1: anti-flagellin antibodies.

Figure 3

Schematic diagram of the currently most promising use of molecular profiling in inflammatory bowel disease. Some further details can be found in Table 2. VEO-IBD: very early onset IBD.