Genetic variant association analysis in Inflammatory Bowel Disease using targeted NGS

Inflammatory Bowel Disease (IBD), primarily encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic disorder driven by complex interactions between immune dysregulation and polygenic susceptibility. This study aims to characterize the mutational landscape of an IBD cohort and explore genotype-phenotype correlations by evaluating the total genetic burden against clinical subtypes and objective inflammatory biomarkers. The study encompasses 48 individuals, comprising 32 IBD patients (18 CD and 14 UC) and 16 healthy controls. An NGS analysis was performed on the Illumina MiSeq sequencing platform using a targeted panel provided by Sophia Genetics: Fever and Autoinflammatory Disease (FAID_GenEra_v1), which includes the following genes: ADA2, CARD14, ELANE, IL10RA, IL10RB, IL1RN, LPIN2, MEFV, MVK, NLRP12, NLRP3, NLRP7, NOD2, PSMB8, PSTPIP1, TNFRSF11A, and TNFRSF1A. A total of 101 non-synonymous variants were identified, predominantly characterized by a heterogeneous distribution of variants of uncertain significance and benign alterations. These variants were distributed unevenly across the gene panel. Statistical analysis revealed no significant difference in the total genetic burden between IBD patients and healthy controls, nor between CD and UC subtypes. Correlation analyses and multivariate diagnostic modeling (ROC) demonstrated that aggregate genetic variability did not independently correlate with acute inflammatory biomarkers, such as C-reactive protein and faecal calprotectin. An integrated clinic-genetic model showed high discriminative performance for distinguishing IBD patients from controls in this cohort (AUC = 0.965). However, this result appeared to be mainly driven by clinical parameters rather than by the genetic burden, and should be interpreted cautiously given the limited sample size and the lack of external validation. These findings suggest that the variants captured by this targeted panel act as a shared, baseline genetic susceptibility rather than dynamic modulators of active mucosal inflammation, underscoring the dominant role of clinical and biochemical monitoring in the stratification of IBD phenotypes.