Genome-Wide Association Study to Identify Novel Genetic Variants Associated With Primary Budd-Chiari Syndrome

Primary Budd-Chiari syndrome (BCS) is a rare hepatic vascular disorder characterized by hepatic venous outflow obstruction involving the hepatic veins and/or inferior vena cava. Marked geographic variation in vascular anatomy and prothrombotic profile suggests an underlying genetic predisposition. This study aimed to identify genetic variants associated with primary BCS using genome-wide association study (GWAS) and to characterize implicated biological pathways.

In a case-control study (June 2020-May 2022), 310 adults with primary BCS and 312 age- and sex-matched healthy controls were recruited; after quality control, 262 cases and 265 controls were included. Whole-blood DNA underwent high-density single-nucleotide polymorphism (SNP) genotyping on an Illumina bead-array platform. SNPs were mapped to genes and assessed using gene ontology, pathway, and tissue-expression analyses.

Overall, 7,78,783 high-quality SNPs were analyzed; 1549 were associated with BCS at P < 0·05 and 340 lead SNPs at P < 0·001. Fifteen top SNPs (P < 5 × 10^-5) were predominantly intronic, intergenic, or regulatory and mapped to loci including rs13164180, rs6883351, rs1558294, rs2656107, rs1413229, rs2903138, rs4919217, rs11948339, rs6936121, rs62218439, rs12966305, rs1609245, rs965428, rs697957, and rs34176204. Functional enrichment implicated extracellular matrix constitution and remodeling, cell-cell junctions, focal adhesion, and vasoconstriction pathways, with no overlap between lead SNPs and canonical hypercoagulable genes (protein C/S, antithrombin III, Factor V, JAK2, and calreticulin).

This GWAS study in primary BCS identifies novel germline loci predominantly in noncoding and regulatory regions, implicating extracellular matrix remodeling, vascular tone, and cell-adhesion pathways rather than classical thrombophilia genes, and supports further functional studies to refine genetic risk stratification.