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

Background/ObjectivesCoronary artery disease (CAD) remains the leading cause of mortality worldwide, with South Asia bearing a disproportionately high and rising burden, particularly at younger ages. This pilot study aimed to investigate genetic variants associated with premature coronary artery disease (PCAD) using whole genome sequencing (WGS). MethodsWGS was conducted on 12 people (5 PCAD cases, 7 matched controls) to assess feasibility and methodology for future large-scale research. High-quality genomic DNA was sequenced at a minimum read depth of 10x with a quality threshold of Q30. Variant calling with stringent quality control identified single nucleotide polymorphisms (SNPs), followed by annotation against gnomAD for allele frequencies and ClinVar for pathogenicity. Protein-coding variants were filtered, and candidate genes were prioritized for comparative analysis between cases and controls. ResultsAn average of over 8.8 million SNPs per individual was identified, with comparable overall variant distributions between cases and controls. Initial analyses revealed 120 SNPs exclusively present in PCAD cases. All protein-coding variants were rare (allele frequency <0.0001), and none were previously classified as pathogenic in ClinVar. After filtration, 87 candidate genes were prioritized. Enriched or unique variants in PCAD cases are mapped to genes involved in lipid metabolism, endothelial dysfunction, inflammatory signaling, immune regulation, thrombosis, vascular remodeling, and metabolic processes. Additional variants were identified in genes related to smooth muscle proliferation, oxidative stress, and other biological pathways. ConclusionsThis WGS pilot study provides an initial overview of the genomic landscape of PCAD in a South Asian cohort, highlighting potential rare variants across multiple biological pathways implicated in atherosclerosis that needs validation in a large-scale study. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/25342163v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1429c57org.highwire.dtl.DTLVardef@264dd8org.highwire.dtl.DTLVardef@c0c6f6org.highwire.dtl.DTLVardef@46752d_HPS_FORMAT_FIGEXP M_FIG C_FIG