Abstract
The glutathione S-transferase (GST) family is essential for detoxification and protection against oxidative stress. Genetic polymorphisms in GST genes, especially non-synonymous single nucleotide polymorphisms (nsSNPs), can influence enzymatic activity and disease susceptibility. This study examines GST nsSNP diversity and functional implications in two Malaysian populations: Malays and the indigenous Orang Asli. Whole genome sequences from 105 Orang Asli and 96 Malays were analyzed using GATK HaplotypeCaller, with functional annotation from Variant Effect Predictor (VEP), SIFT, and PolyPhen-2. Population-specific allele frequencies were compared with global datasets. The structural and functional impacts of deleterious nsSNPs were assessed using I-Mutant, Jalview, I-TASSER, MutPred2, and molecular docking simulations (PyRx and Discovery Studio Visualizer). A total of 3406 SNPs (22 nsSNPs) were identified in Orang Asli and 3291 SNPs (49 nsSNPs) in Malays. Functional predictions indicated that 9 nsSNPs in Malays and 4 in Orang Asli were likely deleterious. The Orang Asli-specific rs147931601 (GSTA1; 3.8%) and Malay-specific rs368356556 (GSTA2; 2.1%) variants were absent in other populations, indicating population-specific adaptations. Stability and conservation analyses revealed that variants such as R155Q (GSTA1), P110S (GSTA2), G144R (GSTA2), D147Y (GSTP1), and E32K (GSTZ1) have high predicted structural or functional damage. Molecular docking showed altered ligand-binding affinities in mutant proteins, potentially affecting detoxification efficacy. This study highlights the genetic uniqueness and functional consequences of GST polymorphisms in Malays and Orang Asli. Population-specific and potentially deleterious variants underscore the need for inclusive genomic research in underrepresented ethnic groups, informing future studies on health disparities and advancing precision medicine in Southeast Asia.