Computational Investigation of Harmful Single-nucleotide Polymorphisms in the ABCB4 Gene and their Potential Links to Liver Disease

Introduction: Single-Nucleotide Polymorphisms (SNPs) are one of the common genetic variants that can affect disease risk and other phenotypes. ABCB4 encodes a phosphatidylcholine translocator important for liver function, and ABCB4 mutations can be linked to both liver disorders and breast cancer. Objective: This study aims to identify the deleterious SNPs within the ABCB4 gene using in silico methodologies. Methods: The ABCB4 amino acid sequence was acquired from the UniProt database, and gene interactions were examined by GeneMANIA. A summary of the 135 SNP IDs of the ABCB4 gene was gathered from the UCSC genome browser. Deleterious SNPs were screened by SIFT and PolyPhen and validated by PROVEAN, SNAP, PhD-SNP, and SNPs and GO. Effects on protein stability were assessed using I-Mutant, MuPRO, and DynaMut. Results: Out of 135 SNPs, 4 non-synonymous SNPs, which are C433W, K435E, R788P, and R788Q, were predicted as deleterious. We showed that these variants decrease protein stability and may profoundly impact ABCB4 activity. Three SNPs (rs8187801, rs20129202, and rs201168284) were identified as high-confidence candidates with likely pathogenic clinical relevance. Conclusion: This work identifies putative liver disease- and cancer-predisposing nsSNPs in the ABCB4 gene with functional importance. These associations have only limited direct medical application at the moment, apart from risk prediction and genetic counseling, but will be a major driver for the identification of targeted therapeutic strategies.