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Moyer AM, Salavaggione OE, Hebbring SJ et al.: Glutathione S-transferase T1 and M1: gene sequence variation and functional genomics. Clin. Cancer Res. 13, 7207-7216 (2007). Genetic variations in the glutathione S-transferases GSTT1 and GSTM1 have been studied in many human populations, and association of these variations with environmentally-related cancers, drug-induced hepatotoxicity and even chronification of viral hepatitis has been shown. However, studies carried out to date have been limited to gene deletion, designated as null alleles, and no extensive studies on other types of genetic variations have been carried out. This study is of great importance, as it describes the occurrence and the allele frequencies for 18 SNPs in the GSTT1 gene, including four nonsynonymous SNPs, and 69 SNPs, two of which are nonsynonymous, in the GSTM1 gene. The GSTT1 SNPs leading to the amino acid substitutions Asp43Asn, Thr65Met, Thr104Pro and a single nucleotide deletion in exon 4 cause a decrease in immunoreactive protein. Interestingly, the previously described nonsynonymous GSTT1 SNPs rs2266635 (Ala21Thr), rs11550606 (Leu30Pro), rs17856199 (Phe45Cys), rs11550605 (Thr104Pro), rs2266633 (Asp141Asn) and rs2234953 (Glu173Lys) were not identified in 400 subjects, thus indicating that these variant alleles are expected to occur at extremely low frequencies. This study reinforces the need to combine SNP databases and resequencing. On combining the data reported in this study with SNP databases, the most promising target SNPs for GSTT1 association studies are those causing the amino acid changes Asp43Asn, Thr65Met, Thr104Pro and the single nucleotide deletion in exon 4. These gene variants should be analyzed in African-American and Hispanic subjects to increase the predictive capacity of genetic tests. For Caucasians and Oriental subjects, testing for null alleles seems to be sufficient.

Introduction: Glutathione S-transferases pi pi 1, alpha alpha 1 and mu mu 3 are members of an enzymatic superfamily involved in the conjugation and detoxification of carcinogens. Polymorphisms affecting the genes encoding these enzymes may modify their ability to neutralize carcinogens. Our aim was to investigate whether these polymorphisms affect the risk of developing hepatocellular carcinoma in humans. Methods: A total of 184 white Spanish patients diagnosed with hepatocellular carcinoma and 248 healthy control subjects from the same ethnic origin were included. GSTA1*B promoter allele, GSTM3*B 3-bp-deleted allele and GSTP1 Ile105Val SNP were identified. Results: No differences were found between the distribution of the studied polymorphisms, or in the allele frequencies for variant alleles in patients and controls: 0.411 and 0.371 for GSTA1, 0.116 and 0.131 for GSTM3, and 0.285 and 0.309 for GSTP1, respectively. Among patients the GSTP1 mutated allele was more frequent in those drinking more than 50g ethanol/day (odds ratio: 2.00; 95% confidence intervals: 1.06--3.78). Age at diagnosis, gender, tobacco use and hepatitis B and C viral status did not influence these results. Conclusion: We conclude that the studied polymorphisms affecting GSTP1, GSTA1 and GSTM3 genes are probably not related to the risk of developing hepatocellular carcinoma in the studied population.

Genetic variations in the glutathione -transferases and have been studied in many human populations, and association of these variations with environmentally-related cancers, drug-induced hepatotoxicity and even chronification of viral hepatitis has been shown. However, studies carried out to date have been limited to gene deletion, designated as null alleles, and no extensive studies on other types of genetic variations have been carried out. This study is of great importance, as it describes the occurrence and the allele frequencies for 18 SNPs in the gene, including four nonsynonymous SNPs, and 69 SNPs, two of which are nonsynonymous, in the gene. The SNPs leading to the amino acid substitutions Asp43Asn, Thr65Met, Thr104Pro and a single nucleotide deletion in exon  4 cause a decrease in immunoreactive protein. Interestingly, the previously described nonsynonymous SNPs rs2266635 (Ala21Thr), rs11550606 (Leu30Pro), rs17856199 (Phe45Cys), rs11550605 (Thr104Pro), rs2266633 (Asp141Asn) and rs2234953 (Glu173Lys) were not identified in 400 subjects, thus indicating that these variant alleles are expected to occur at extremely low frequencies. This study reinforces the need to combine SNP databases and resequencing. On combining the data reported in this study with SNP databases, the most promising target SNPs for association studies are those causing the amino acid changes Asp43Asn, Thr65Met, Thr104Pro and the single nucleotide deletion in exon  4. These gene variants should be analyzed in African-–American and Hispanic subjects to increase the predictive capacity of genetic tests. For Caucasians and Oriental subjects, testing for null alleles seems to be sufficient.

Introduction: Glutathione S-transferases ππ1, αα1 and µµ3 are members of an enzymatic superfamily involved in the conjugation and detoxification of carcinogens. Polymorphisms affecting the genes encoding these enzymes may modify their ability to neutralize carcinogens. Our aim was to investigate whether these polymorphisms affect the risk of developing hepatocellular carcinoma in humans. Methods: A total of 184 white Spanish patients diagnosed with hepatocellular carcinoma and 248 healthy control subjects from the same ethnic origin were included. GSTA1*B promoter allele, GSTM3*B 3-bp-deleted allele and GSTP1 Ile105Val SNP were identified. Results: No differences were found between the distribution of the studied polymorphisms, or in the allele frequencies for variant alleles in patients and controls: 0.411 and 0.371 for GSTA1, 0.116 and 0.131 for GSTM3, and 0.285 and 0.309 for GSTP1, respectively. Among patients the GSTP1 mutated allele was more frequent in those drinking more than 50 g ethanol/day (odds ratio: 2.00; 95% confidence intervals: 1.06--3.78). Age at diagnosis, gender, tobacco use and hepatitis B and C viral status did not influence these results. Conclusion: We conclude that the studied polymorphisms affecting GSTP1, GSTA1 and GSTM3 genes are probably not related to the risk of developing hepatocellular carcinoma in the studied population.

Glutathione -transferases π1, αα1 and µµ3 are members of an enzymatic superfamily involved in the conjugation and detoxification of carcinogens. Polymorphisms affecting the genes encoding these enzymes may modify their ability to neutralize carcinogens. Our aim was to investigate whether these polymorphisms affect the risk of developing hepatocellular carcinoma in humans. A total of 184 white Spanish patients diagnosed with hepatocellular carcinoma and 248 healthy control subjects from the same ethnic origin were included. promoter allele, 3-bp-deleted allele and Ile105Val SNP were identified. No differences were found between the distribution of the studied polymorphisms, or in the allele frequencies for variant alleles in patients and controls: 0.411 and 0.371 for , 0.116 and 0.131 for , and 0.285 and 0.309 for , respectively. Among patients the mutated allele was more frequent in those drinking more than 50  g ethanol/day (odds ratio: 2.00; 95% confidence intervals: 1.06-–3.78). Age at diagnosis, gender, tobacco use and hepatitis B and C viral status did not influence these results. We conclude that the studied polymorphisms affecting and genes are probably not related to the risk of developing hepatocellular carcinoma in the studied population.