Comprehensive Prediction Analysis of Novel Noncoding Regulatory Variants Identified in the MicroRNA Binding Regions in Complement System Genes

The complement system is a central component of innate immunity that coordinates host defense, immune surveillance, and inflammatory responses through tightly regulated proteolytic cascades. Genetic variation within complement genes contributes substantially to interindividual differences in complement activity and disease susceptibility. While coding variants directly alter complement protein structure and function, the microRNA (miRNA)-mediated control and post-transcriptional regulation is not fully understood in shaping complement gene expression across immune and inflammatory mechanisms. Complement pathway genes exhibit extensive and heterogeneous 3′-untranslated regions (3′UTRs), which serve as primary platforms for miRNA binding and RNA-binding protein interactions. Both common and rare single-nucleotide polymorphisms within coding regions and 3′UTRs can influence miRNA targeting efficiency, disrupt regulatory motifs, or alter mRNA turnover, thereby fine-tuning complement activity rather than causing complete loss of function. Here, we systematically analyzed miRNA binding sites and single-nucleotide polymorphisms (SNPs) within the 3′UTRs of complement pathway genes spanning the classical, lectin, alternative, and terminal pathways. Our analysis uncovered heterogeneous patterns of miRNA-mediated regulation across the complement system. While core complement components showed relatively sparse conserved miRNA targeting, regulatory factors, receptors, and terminal pathway proteins emerged as densely regulated nodes, harboring multiple conserved binding sites. A broad repertoire of miRNAs was predicted to engage complement genes in a pathway-specific manner, implicating these interactions in inflammation, cancer progression, metabolic regulation, and immune signaling. SNPs within miRNA-binding regions are predicted to disrupt or create regulatory interactions, providing a mechanistic basis for how non-coding genetic variation can alter gene expression and modulate disease susceptibility. Our findings indicate miRNA-mediated post-transcriptional regulation as an important yet underappreciated layer of complement system control, providing a framework for understanding how regulatory genetic variation shapes complement-driven immune responses and disease risk.