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    • The frequency of GSTM and GSTT null genotypes vary

    2022-03-11

    The frequency of GSTM1 and GSTT1 null genotypes vary in different populations. For example, Hiragi et al. (2007) reported a frequency of 17–35% for the GSTM1 null genotype and 22–44% for the GSTT1 null genotype in Brazilians of African descent (Hiragi et al., 2007). Chen, Liu, and Relling (1996) reported that the frequency of the GSTT1 null genotype was significantly higher in African-Americans compared with whites (24.1% vs. 15.0%, P=0.019), and the frequency of the GSTM1 null genotype was significantly higher in whites compared with African-Americans in the US (53.5% vs. 27.6%, P<0.001) (Chen et al., 1996). A multi-institutional case–control study that included African-Caribbean men investigated the role of GSTM1 and GSTT1 deletions in prostate cancer and reported that the frequencies of the GSTM1 and GSTT1 null genotypes assessed at a study site in Jamaica were 26.2% and 35.2%, respectively, (Taioli et al., 2011). Recently, Rahbar et al. reported that the frequencies of the null genotypes of GSTM1 and GSTT1 in Jamaican children were 26.0% and 22.0%, respectively (Rahbar, Samms-Vaughan, Ma, et al., 2014). For the GSTP1Ile105Val polymorphism, there are three common genotypes (Ile/Val, Ile/Ile, Val/Val), and the replacement of adenine by guanine at nucleotide 562 results in the change of amino hedgehog inhibitor from isoleucine to valine at codon 105 of the GSTP1 protein. Researchers have used different classifications (e.g., co-dominant, recessive, dominant, and additive models) for a variety of disease association studies (Ramprasath et al., 2011, Safarinejad et al., 2011, Sreeja et al., 2008, Tamer et al., 2004, Wei et al., 2013). The frequency of the GSTP1 polymorphism varies across different populations, as shown in the International Haplotype Map (HapMap) project (The International HapMap Consortium, 2003). Specifically, it has been reported that the allele frequency of Ile varies from 50% to 63% for the four African populations: African ancestry in the Southwest United States, Luhya in Webuye, Kenya, Maasai in Kinyawa, Kenya, and Yoruba in Ibadan, Nigeria (Lakkakula et al., 2013). We recently reported that the hedgehog inhibitor allele frequency of Ile is 51% for the Jamaican population (Rahbar, Samms-Vaughan, Ma, et al., 2014). A study using a family-based association design (mother of ASD case and her parents) found that a haplotype consisting of two polymorphisms in the GSTP1 gene (Ile105Val and Ala114Val) was significantly over-transmitted to the mothers [odds ratio (OR)=2.67; 95% CI, 1.39–5.13] compared to two other haplotypes (Williams et al., 2007). A subsequent genotype analysis identified the GSTP1 Ile105Val allele as responsible for this effect. A case–control study reported an increased odds of ASD (OR=2.02; 95% CI, 1.03–4.04) for individuals with the null polymorphism of GSTM1 compared with unrelated unaffected controls (Buyske et al., 2006). Additionally, a marginally increased ASD risk was observed for individuals with the GSTM1 null polymorphism alone (OR=1.37; 95% CI, 0.98–1.96), although in combination with a polymorphism in the reduced folate carrier gene, the OR was 3.78 (95% CI, 1.80–7.95) (James et al., 2006). A limited number of studies have investigated the interactive effects of genetic factors in relation to ASD (Anderson et al., 2008, Anderson et al., 2009, Ashley-Koch et al., 2007, Bill and Geschwind, 2009, Bowers et al., 2011, Campbell et al., 2008, Kim et al., 2008, Kumar and Christian, 2009, Ma et al., 2005). Bowers et al. (2011) highlighted that investigators usually do not examine interactions between genes because of the complexities involved to obtain measures of the effects (Bowers et al., 2011). It is possible that individual effects of genes are not statistically significant, but when these effects are investigated in an interactive model, the findings become statistically significant (Cordell, 2009). Although limited information is available regarding the relationship between oxidative stress and ASD, some studies have reported on potential associations. For example, a study by Adams et al. (2011) reported that compared to TD children, children with ASD had significantly higher levels of oxidative stress markers (P<0.001), including oxidized glutathione, the ratio of oxidized to reduced glutathione, and plasma nitrotyrosine (Adams et al., 2011). Additionally, a more recent study from Saudi Arabia reported that children with ASD had lower mean levels of GST compared to TD controls (0.30 vs. 0.61μmol/min/ml plasma; P<0.001) (Alabdali, Al-Ayadhi, & El-Ansary, 2014). The long term goal of our Jamaican Autism Project is to investigate the roles of exposures to environmental toxins (e.g., mercury, lead, arsenic, cadmium, and manganese) and GST genes (GSTT1, GSTM1, GSTP1), potential gene–gene interactions, and gene–environment interactions in relation to ASD. In this paper, we describe the genotype frequencies of the three aforementioned GST genes in Jamaican children with and without ASD. In addition, we investigate the role of these GST genes and their pair-wise gene–gene interactions in relation to ASD.