Association of glutathione-S-transferase M1,P1, and T1 gene polymorphisms with treatment response in childhood acute lymphocytic leukemia

@#<p style="text-align: justify;">There is still a strong need for new treatment strategies that will maintain remission and prolong survival in patients with acute lymphoblastic leukemia (ALL). The glutathione-S-transferase (GST) enzymes, which are coded by highly polymorphic genes, have been associated with the risk of developing cancer and were found to regulate effect of cancer treatment drugs.<br /><strong>OBJECTIVES:</strong> The present study determines the association of GSTM1, GSTP1 and GSTT1 polymorphisms and treatment response in terms of occurrence of adverse events and relapse in ALL in Filipino children.<br /><strong>METHODS:</strong> This is a follow up study on the 2007 investigation done by Alcausin et al. which determined the association of the GST P1, M1, and T1 polymorphisms and occurrence of ALL. Four-year follow-up data were available for 46 out of the 50 patients from January 2007 to May 2011. Odds ratios (OR) as measures of association of GST M1, P1 and T1 gene polymorphisms with treatment outcomes were estimated at 95% confidence interval.<br /><strong>RESULTS:</strong> Results show a trend towards predisposition to elevation of liver enzymes in patients with GSTT1 and GSTP1 mutant genotypes showing an OR (95% Cl) of 2.0 (0.62-6.49). The presence of GSTM1 null genotype showed a trend towards protection from occurrence of relapse basing on both crude and adjusted ORs, 0.58 (0.16-2.07) and 0.23 (0.05-1.20), respectively. However, these results are not statistically significant.<br /><strong>CONCLUSION: </strong>The GSTP1 heterozygous genotype conferred increased predisposition to elevation of liver enzymes while the GSTT1 null genotype was shown to be a possible risk factor towards the occurrence of both infection and elevation of liver enzymes during chemotherapy. Furthermore, the GSTM1 null genotype appears to be protective from occurrence of relapse. It is recommended to do similar large-scale studies in the future to obtain more conclusive results.</p>

Genetic polymorphisms in CYP1A1, GSTM1, GSTP1, GSTT1, NAT1 and NAT2 and oral cavity cancer risk among Filipinos

Polymorphisms in metabolic genes have been shown to modulate susceptibility to oral cavity cancer. Cases (n=176) and controls (n=317) from the Filipino population were genotyped for selected polymorphisms in CYP1A1, GSTM1, GSTP1, GSTT1, NAT1 and NAT2. Medical and diet histories, occupational exposure and demographic data were also collected for all subjects. The CYP1A1m1/m1 genotype is protective against oral cancer, while being homozygous for the GSTP1 c.313G genotype and heterozygous for the NAT1*10 homozygotes and non-homozygotes for the CYP1A1 m1 allele. The risk from heterozygosity for the NAT1*10 allele was limited to subjects who were not homozygous for the GSTP1 c.313G genotype remained a significant oral cancer risk modifier, together with environmental variables, the homozygous GSTP1 c.313G genotype remained a significant oral cancer risk modifier, together with environmental risk factors, such as smoking, passive smoking, inverted smoking and tobacco chewing, and environmental protective factors, i.e. moderate consumption of fish sauce (patis) and shrimp paste (bagoong). The GSTP1 c.313G polymorphism increases susceptibility for oral cavity cancer in the Filipino population.

Characterization of mutations and polymorphisms in the G6PD among Filipino newborns with glucose-6-phosphate dehydrogenase deficiency

Background. Glucose-6-phosphate (G6PD) deficiency is the most prevalent enzyme deficiency to date. The global prevalence of G6PD deficiency is estimated at around 330 million people affected with the disease worldwide. This 4.9 percent prevalence, correlates highly with geographic areas endemic to malaria. It is the most common among the disorders in the Newborn Screening (NBS) panel in the Philippines, with one confirmed case for every 52 newborns (1:52). This paper determines the molecular background of G6PD deficiency among Filipino newborns detected by newborn screening. Methods. A total of 200 cases confirmed to have G6PD deficiency, 180 males and 20 females, were identified through the Philippine Newborn Screening Program from 2001-2003. Genomic DNA was extracted from dried blood spots followed by multiplex polymerase chain reaction using multiple tandem forward primers and a common reverse primer (MPTP) to detect previously reported common mutations and polymorphisms in exons 5, 6, 9, 11 and 12 of the G6PD gene. Results. Of the 200 samples analyzed, mutations and polymorphisms in the G6PD gene were identified in 148 cases (74%). The most common mutation was a G to A transition on nucleotide 871 (Viangchan) of exon 9 in combination with a silent mutation on exon 11, accounting for 32.9% of the cases. This was followed by a C to T transition on nucleotide 1360 (Union) in 21.1 % of the cases. Other mutations were Vanua Lava in 10%, Chatham in 9.4% and Canton in 3.5% of the newborns. The silent polymorphism on nucleotide 1311 was present in 12.9% of cases. There were combinations of these mutations and polymorphisms present in a minority of cases. Conclusion. Results of this study showed the molecular heterogeneity underlying G6PD deficiency among Filipino newborns.

Genotype-phenotype correlations in Filipino patients with type 3 gaucher disease

Gaucher disease is an inherited glycolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, skeletal abnormalities, anemia and thrombocytopenia. We present here the corresponding genotypes and the genotype-phenotype correlations of 3 Filipino patients. Clinical phenotypes and genotypes were documented by reviewing the charts of 3 Filipino patients with Gaucher disease. Clinical parameters such as liver and spleen sizes, hematologic variables, disease types and response to enzyme replacement therapy were compared. Likewise, quantitative enzyme assays and mutation analysis were reviewed. All have the type III neuronopathic Gaucher disease. Patients 1 and 2 are twin sisters who both have mild mental retardation with Patient 1 having a concomitant seizure disorder. They have the corresponding genotype of p.L444/p.P319A. Patient 3 has global developmental delay, oculomotor apraxia, pyramidal tract signs and carries the p.L444P/p.G202R/p.G202R genotype. Genotype-phenotype correlations for the 3 patients showed that their genotypes are compatible with the severe neuronopathic type of disease.

A master of science in genetic counseling program in the Philippines

In the Philippines, there is an urgent need to expand the clinical services for diagnosis, management and emotional support for patients with genetic conditions and their family members. Despite the lack of trained providers with specialization in genetics, public health related geneticsprograms are continuously being implemented. These address these current demands,strategic planning began in 2009 between local medical geneticists and international genetic professionals to develop the curriculum for an advanced degree in genetic counseling program. The board of regents at the University of the Philippines approved the proposed curriculum in January 2011, and training of the Philippines first cohort of genetic counseling students commenced in June 2011. The successful implementation of the MS of Genetic Counseling program will provide the opportunity to incorporate the match needed genetic counseling services in the country.

Mutations of the phenylalanine hydroxylase (PAH) gene in Filipino patients with phenylketonuria

INTRODUCTION: Phenylketonuria (PKU), an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency, leads to hyperphenylalaninemia and neurological damage if untreated. This is the first study in the Philippines to identify the disease-causing mutations in the PAH gene of clinically diagnosed Filipino PKU patients. METHODS: The study included four unrelated PKU patients detected by the Philippine Newborn Screening Program from 1996 to 2008. Plasma amino acid analyses for all patients showed increased phenylalanine and low to normal tyrosine levels consistent with the diagnosis of PKU. Mutations in the PAH gene were identified by genomic DNA extraction from dried blood spots of the patients, PAH exon amplification by polymerase chain reaction and subsequent bi-directional DNA sequence analysis. RESULTS: All patients presented with significantly elevated phenylalanine levels on bacterial inhibition assay and thin layer chromatography. Urinary pterins confirmed the diagnosis of Tetrahydrobiopterin deficiency in two patients while the other 2 patients had the Classical PKU phenotype. Four previously identified mutations in the PAH gene (p.I65T, p.R413P, p.EX6-96A>G, p.R243Q) were identified in those with Classical PKU. CONCLUSION: The present results confirm the heterogeneity of mutations at the PAH locus in Filipinos. Neonatal screening and the use of molecular diagnosis significantly aid in the medical management and genetic counseling of patients and their families.

Mutations of the steroid 21-hydroxylase gene among Filipino patients with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH), an autosomal recessive disorder, is due to deficiency of the enzymes involved in adrenal steroidogenesis. Phenotypic manifestations vary as a result of the degree of glucocorticoid or mineralocorticoid deficiency and androgen excess present. Among Filipinos, the estimated crude incidence of CAH is approximately 1 in 7,000, which is higher than what is reported in most populations. More than 90% of all cases result from a 21-hydroxylase (21-OH) (cytochrome P450c21) enzyme deficiency involving two 21-OH genes, the active gene (CYP21) and a pseudogene (CYP21P). Studies have shown that mutations result from unequal crossover during meiosis which leads to complete deletion of the gene, gene conversion events or to point mutations. To date, there are no published data on the types of mutations present among Filipinos diagnosed with congenital adrenal hyperplasia. The objective of this study is to describe the profile of Filipino patients diagnosed with CAH and to determine the disease-causing alleles in the 21-OH gene of these patients. Using a method of combined differential polymerase chain reaction and amplification created restriction site approach, direct probing for the presence of known mutations in exons 1,3,4,6,7,8 and intron 2 of the CYP21 and CYP21P genes among Filipino patients with CAH was performed. A total of 12 unrelated CAH patients were examined. A majority of these cases had a premature splicing error mutation at nucleotide 656 of intron 2. The determination of the most frequent alleles in our population can facilitate rapid screening for mutations in the 21-OH gene and lead to a definitive diagnosis of CAH.

Glucose-6-phosphate dehydrogenase deficiency in Filipino neonates with jaundice

OBJECTIVES: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common of all clinically significant enzyme defects of red blood cells. It has a high rate of prevalence in the Philippines. Concern about hemolytic anemia and jaundice due to unrecognized G6PD deficiency led us to determine the prevalence of G6PD deficiency among jaundiced neonates in the Philippine General Hospital, a tertiary referral hospital in the Philippines. It was hypothesized that G6PD deficiency was more prevalent in neonates with jaundice than in the normal population. We also compared the clinical presentation and course (hospital stay and days of phototherapy requirement) for G6PD deficient and G6PD normal neonates. MATERIALS AND METHODS: We studied 102 clinically jaundiced neonates admitted to the nursery of the Philippine General Hospital. Blood samples in individual microtainers were quantitatively tested for G6PD activity using a commercial G6PD assay kit. The clinical presentation and hospital courses of patients were statistically compared using the t-test for single proportions. RESULTS: G6PD deficiency was diagnosed in 17 of 102 cases[16.7% (95% CI: 10.0 to 25.3)], which is significantly higher than the normal population (p CONCLUSION: The prevalence of G6PD deficiency among jaundiced neonates was found to be higher than the normal population thus, early detection of this enzymopathy, regardless of sex, and close surveillance of the affected newborns is important in reducing the risk of severe hyperbilirubinemia.