Whole Genome Sequencing Identifies Crucial Diagnostic Biomarkers and Therapeutic Targets in Premature Coronary Artery Disease in South Asians: A Pilot Study

Whole genome sequencing (WGS) was conducted in a cohort comprising 12 individuals (5 cases vs 7 matched controls) to identify potential genetic variants associated with premature coronary artery disease (PCAD). High-integrity genomic DNA was sequenced with a minimum read depth of 10x, with a quality score threshold of Q30. Variant calling and stringent quality control identified over 8.8 million single-nucleotide polymorphisms (SNPs) per individual, with aggregate variant counts demonstrating comparable distributions across cases and control groups. Initial analysis identified 120 SNPs exclusively present in PCAD patients. Annotation of allele frequencies against the gnomAD database revealed that all protein-coding variants were rare (AF < 0.0001), and none were previously classified as pathogenic in the ClinVar database. Following annotation and filtration for protein-coding regions, 87 candidate genes were prioritized for further analysis (full list presented in supplementary data). Subsequent comparative analyses identified SNPs that were either uniquely present or significantly enriched in the PCAD cohort compared to controls. Several notable SNPs were localized to genes implicated in diverse pathophysiological pathways associated with atherosclerosis, including lipid metabolism (ELOVL2, ELOVL2-AS1 SUGP1, SULF2), endothelial dysfunction (DAB1, EFNA5MAP2K4), inflammatory signaling (BABAM2, CNTN5, DLEU7 TRAPPC9), immune regulation (DLEU7, IL4I1, KIR2DS4), thrombosis (MAP2K4, SULF2), vascular remodeling (ADAMTSL1, DOCK2, TBX5) and metabolic processes (GLIS3). Additional variants were identified in genes associated with other biological mechanisms, including smooth muscle proliferation, oxidative stress, and other pathways (NDOR1, PIPOX, SATB2, and TYW1). Collectively, this WGS pilot dataset delineates a comprehensive genomic landscape for elucidating molecular drivers of early-onset cardiovascular disease and constitutes a valuable resource for further functional validation and population-based genetic studies.