Integrative genomic analysis of missense mutations and target genes in hemorrhoid pathogenesis

Introduction : Hemorrhoids are a prevalent anorectal condition characterized by the enlargement and displacement of anal cushions. While environmental and lifestyle factors are well-established contributors, emerging evidence suggests a genetic predisposition involving connective tissue integrity and smooth muscle dysfunction. However, the specific genetic variants contributing to hemorrhoid pathogenesis remain largely undefined. Aim : This study aimed to identify and characterize potentially pathogenic single-nucleotide polymorphisms (SNPs) associated with hemorrhoids to better understand their molecular and functional implications. Materials and methods : SNPs associated with hemorrhoids were retrieved from the Genome-Wide Association Studies (GWAS) Catalog. Functional annotations and pathogenicity predictions were performed using PolyPhen-2, SIFT, SNPnexus, and GTEx to assess structural and regulatory impacts of the variants on gene function and expression in relevant tissues. Results : Functional annotation of hemorrhoid (HEM)-associated SNPs revealed that rs2186797 ( ANO1 ) and rs35318931 ( SRPX ) may impact protein structure and function, as predicted by PolyPhen-2 (possibly damaging). In contrast, rs8176746 ( ABO ) was predicted to be benign. SIFT analysis identified rs2186797 as deleterious across multiple amino acid positions, indicating potential disruption of ANO1 function. Pathway enrichment analysis linked rs2186797 to key biological processes, including stimuli-sensing channels and ion channel transport, suggesting a role for ANO1 in ion transport mechanisms relevant to HEM pathogenesis. Conclusions : These findings highlight the potential functional impact of ANO1 -related genetic variation in HEM and underscore its involvement in ion transport pathways, providing insight into the molecular mechanisms underlying HEM pathogenesis.