Abstract
GSTA1 encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTA1 has several functional SNPs within its promoter region that are responsible for a change in its expression by altering promoter function. This study aims to investigate distributions of GSTA1 promoter haplotypes across different human populations and to assess their impact on the expression of GSTA1. PHASE 2.1.1 was used to infer haplotypes and diplotypes of six GSTA1 promoter SNPs on 2501 individuals from 26 populations classified by the 1000 Genomes Project into five super-populations that included Africa (N = 660), America (N = 347), East Asia (N = 504), Europe (N = 502), and South Asia (N = 488). We used pairwise FST analysis to compare sub-populations and luciferase reporter assay (LRA) to evaluate the impact of each SNP on activation of transcription and interaction with other SNPs. The distributions of GSTA1 promoter haplotypes and diplotypes were significantly different among the different human populations. Three new promoter haplotypes were found in the African super-population. LRA demonstrated that SNPs at -52 and -69 has the most impact on GSTA1 expression, however other SNPs have a significant impact on transcriptional activity. Based on LRA, a new model of cis-elements interaction is presented. Due to the significant differences in GSTA1 diplotype population frequencies, future pharmacogenomics or disease-related studies would benefit from the inclusion of the complete GSTA1 promoter haplotype based on the newly proposed metabolic grouping derived from the LRA results.
Highlights
GSTA1 encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress
GSTA1 holds much importance in the field of oncology, as it is involved in the metabolic pathway of many important chemotherapeutic agents such as busulfan (Bu)13, thiotepa14,15, doxorubicin16, cyclophosphamide[17], and chlorambucil[18]
FST analysis (Fig. 1A, Supplementary Fig. 1) shows that all super-populations are homogenous except the American super-population where Peruvians from Lima were significantly different from three other American sub-populations and Mexicans were significantly different from Puerto Ricans
Summary
GSTA1 encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. Due to the significant differences in GSTA1 diplotype population frequencies, future pharmacogenomics or disease-related studies would benefit from the inclusion of the complete GSTA1 promoter haplotype based on the newly proposed metabolic grouping derived from the LRA results. Because GSTA1 is the most abundantly expressed enzyme of its group in the liver, it establishes itself as the top candidate gene for influencing drug clearance[19]. It is expressed in the breast, thought to be the reason why it influences the efficacy of Scientific Reports | (2021) 11:5038. Of great interest in onco-haematology is Bu, an alkylating agent used in the conditioning regimen before haematopoietic stem cell transplant (HSCT) as a treatment for different types of malignancies and non-malignancies[8]
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