The analysis of GSTA1 promoter genetic and functional diversity of human populations

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.

Figure 1

FST analysis of human super- and sub-populations (A) and world-wide frequencies of GSTA1 metabolic category (B). (A) red—African, green—American, light brown—East Asian, blue—European, violet—South Asian sub-populations. (B) grey-blue—fast metabolisers, blue—intermediate metabolisers, dark blue—slow metabolisers.

Figure 2

Luciferase reporter assay results for each haplotype. Dark blue (*A haplotypes), dark red (*B haplotypes), faded colours (non-existent haplotypes), green (no promoter).

Figure 3

Luciferase reporter assay results grouped by position. The impact of SNPs was evaluated by pairwise comparison for each SNP site. Results of plasmid LRA were paired per site of change and identity of surrounding haplotype. The results demonstrate that surrounding haplotypes can have an impact on the functioning of the SNP, therefore, indicating an interaction between two sites (see sections "Results", "Reporter gene assay" and "Discussion").

Figure 4

Predicted GSTA1 diplotype expression levels.