GSTM1 copy number variation in the context of single nucleotide polymorphisms in the human GSTM cluster

Abstract

BackgroundGSTM1 gene deletion is one of the most known copy number polymorphisms in human genome. It is most likely caused by homologous recombination between the repeats flanking the gene. However, taking into account that the deletion has no crucial effects on human well-being, and the ability of other GSTMs to compensate for the lack of GSTM1, a role for additional factors affecting GSTM1 deletion can be proposed. Our goal was to explore the relationships between GSTM1 deletion polymorphism and single nucleotide polymorphisms (SNPs) in the region of the GSTM cluster that includes GSTM2, GSTM3, GSTM4, and GSTM5 in addition to GSTM1.ResultsReal-time polymerase chain reaction was used to quantify the number of GSTM1 copies. Fourteen SNPs from the region were tested and their allelic patterns were compared in groups of Russian individuals subdivided according to their GSTM1 deletion genotypes. Linkage disequilibrium-based haplotype analysis showed substantial differences of haplotype frequencies between the groups, especially between individuals with homozygous GSTM1 −/− and +/+ genotypes. Exploration of the results of phasing of GSTM1 and SNP genotypes revealed unequal segregation of GSTM1 + and − alleles at different haplotypes.ConclusionsThe observed differences in haplotype patterns suggest the potential role of genetic context in GSTM1 deletion frequency (appearance) and in the determination of the deletion-related effects.

Complex Haplotypes of GSTM1 Gene Deletions Harbor Signatures of a Selective Sweep in East Asian Populations

“…Instead, we found multiple branches that are predominantly populated with deleted haplotypes and others with non-deleted haplotypes without notable population structuring. These observations are concordant with the recent study documenting the genetic variation in this locus in a Russian population ( Khrunin et al 2016 ). It is important to note here, however, that Neanderthal and Denisovan haplotypes, as well as the branching point for the chimpanzee reference haplotype, all cluster with the predominantly non-deleted haplotypes.…”

“…Even considering multiple single nucleotide variants within a single population, we were not able to impute the deletion accurately in any of the study populations (YRI, CHB, and CEU) ( Figure 3B ). This is concordant with the previous finding reported the difficulty to predict the copy number of the GSTM1 gene by the flanking haplotypes in CEU ( Khrunin et al 2016 ). As such, direct genotyping, rather than imputation, may be more robust approach to study GSTM1 deletion.…”

Complex haplotypes of metabolizingGSTM1gene deletion harbors signatures of a selective sweep in East Asian populations

“…3B). This is concordant with the previous finding reported the difficulty to predict the copy number of the GSTM1 gene by the flanking haplotypes in CEU (Khrunin et al 2016). As such, direct genotyping, rather than imputation, may be more robust approach to study GSTM1 deletion.…”

GSTM1 Copy Number Is Not Associated With Risk of Kidney Failure in a Large Cohort

“…Finally, other factors such as SNPs and haplotypes in the GSTM cluster, CNV of other GST genes, such as GSTT1 , and environmental factors such as diet were not examined. A recent study identified substantial differences of SNP-based haplotype in GSTM cluster among groups of individuals with different GSTM1 CNV, suggesting a role for local genetic context in the deletion frequency thus the deletion-related effects on various disease (Khrunin et al, 2016). Studies that examined the combined effect of GSTM1 and GSTT1 deletion showed increased risk for ESRD in patients with null genotype of both GSTM1 and GSTT1 (Agrawal et al, 2007; Suvakov et al, 2013; Nomani et al, 2016).…”