Phenotype versus Genotype Methods for Copy Number Variant Analysis of Glutathione S-Transferases M1

Abstract

SummarySeveral variants have been identified for genes encoding Glutathione S-transferase (GST) enzymes; some are associated with significant alteration of protein function. One of the most extensively studied is a copy number variant (CNV) in the GSTM1 gene. In this study, we compared phenotype (positive, null) and genotype (1/1, 1/0, 0/0) methods in order to assess dissimilarities obtained using these two different approaches to evaluate possible methodology-related bias. We analyzed a sample of 1947 individuals belonging to 18 human populations with different ethnic origins. We also evaluated whether the presence of missense substitutions in the GSTM1 gene might influence the association of the CNV with phenotype distribution.Through the comparison of GSTM1 CNV frequencies in phenotype and genotype among human populations, we observed that differences increase in high heterogeneous populations. Furthermore, we identified two missense variants (rs199816990 and rs202002774) that may distort the outcome of genetic association studies on Asian populations.These results indicate that the phenotype analysis may strongly alter the genetic association. Therefore, genotype discrimination analysis should be used to analyze GSTM1 CNV. To understand the role of GSTM1 in human health, the analysis of CNV should be combined with the investigation of single nucleotide polymorphisms with functional effect.

GSTM1, GSTP1, and GSTT1 genetic variability in Turkish and worldwide populations

“…GSTM1 , GSTP1 , and GSTT1 have been deeply investigated as candidate genes involved in the predisposition to pathologic conditions. In particular, a number of studies have analyzed GSTM1 and GSTT1 deletion polymorphisms that are associated with null phenotypes (i.e., GSTM1 positive/null, GSTT1 positive/null), and two GSTP1 nonsynonymous changes (i.e., GSTP1*I105V and GSTP1*A114V), as these genetic variants may affect drug response and metabolic processes (Bolt and Thier, ; Higgins and Hayes, ; Piacentini et al, ). Besides the putative role those variants play with respect to health‐related traits, some studies have investigated their distribution among human populations (Piacentini et al, ; Polimanti et al, ) in order to provide information about the global distribution of these markers and to furnish reference data for genetic association studies.…”

The mercapturic acid pathway

“…The most studied hGSTM1 polymorphism is a gene deletion whose frequency ranges from 50 to 78% among ethnic groups (Moyer et al 2007). Other studies show functionally significant polymorphisms in hGSTM1 that may be associated with responses to chemotherapy (Moyer et al 2007;Ag undez and Ladero 2008;Piacentini et al 2013). The hGSTM1/hGSTT1 double-null genotype is associated with poor treatment outcome in acute myeloid leukemia and with increased risk of drug-induced liver injury (Lucena et al 2008;Xiao et al 2014).…”

GSTM1andGSTM5Genetic Polymorphisms and Expression in Age-Related Macular Degeneration

“…GSTM1 and GSTM5 have been localized within the NSR and RPE/choroid of the human eye, and both genes had reduced mRNA and protein in AMD eyes (without null genotype 0/0) in the same pan-retinal studies (15). Piacentini et al analysis of GSTM1 polymorphisms have recently emphasized the importance of using genotype association (+/+, +/0, 0/0) over phenotype (present, null) when looking at GSTM1 protein function (32). Oz et al performed phenotype analysis with PCR of peripheral blood leukocytes for GSTM1 , GSTT1 and GSTP1 in exudative AMD vs. controls and found that paired homozygous deletions for GSTM1 / GSTT1 or GSTM1 / GSTP1 increase AMD risk (33).…”