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PubMed2004

GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population.

Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione S-transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N-acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N-acetylation and O-acetylation of aromatic amines. Cytochrome p450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital-based case-control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997-2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR-RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11-2.56) and 1.74 (95% CI = 1.02-2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08-7.10). We observed a trend (p-value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16-2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27-5.23). NAT2 slow acetylator was associated with marginally increased risk of bladder cancer (OR = 1.50, 95% CI = 0.99-2.27), and the OR for the joint effect with occupational exposure of aromatic amines was 3.26 (95% CI = 1.06-9.95). SULT1A1 Arg213His polymorphism showed a marginal protective effect. These findings suggest that individual susceptibility to bladder cancer may be modulated by GSTM1, GSTT1 and NAT2 polymorphisms.

Adult↗
PubMed2005

[Genetic polymorphism of tumor necrosis factor-alpha in patients with chronic benzene poisoning].

OBJECTIVE: To study the relationship between genetic polymorphism of tumor necrosis factor-alpha (TNF-alpha, sites at -238 nt and -308 nt) and susceptibility to chronic benzene poisoning. METHOD: The polymorphism of TNF-alpha gene were detected by nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique from 50 benzene poisoning patients and 60 control individuals exposed to benzene. RESULTS: The frequency of the TNF-alpha-238G/G, A/G and A/A in controls (95%, 5% and 0%, respectively), were not significantly different from those in patients (92%, 6% and 2%, respectively, P > 0.05). The frequency of the TNF-alpha-308G/G, A/G and A/A in patients were 76%, 24% and 0% respectively, and that in control individuals were 93%, 7% and 0% respectively. Chi(2) test showed that frequency of TNF-alpha-308A/G in patients was significantly higher than that in controls (chi(2) = 6.22, P = 0.013). Logistic analysis showed that TNF-alpha-308A/G was the independent risk factor of benzene poisoning (OR = 5.3, P < 0.05). CONCLUSION: Individuals with TNF-alpha-308A/G gene polymorphism are susceptible to benzene poisoning.

Adult↗
PubMed2004

Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children.

BACKGROUND: Biotransformation plays a crucial role in carcinogen activity and many genetic polymorphisms in xenobiotic metabolising enzymes have been associated with an increased risk of cancer. Such polymorphisms can lead to considerable variation in the activities of these enzymes, which are crucial in carcinogen and drug metabolism. These variations could play a role in the risk of developing paediatric acute lymphoblastic leukaemia (ALL) by their varying action on environmental carcinogens. PROCEDURE: The present study looked for two polymorphisms (m1 and m2) in the CYP1A1, CYP2D6*4 genes and deletions of the glutathione S-transferases (GSTM1 and GSTT1) in 118 paediatric ALL patients and 118 age matched control children. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study gene polymorphisms. RESULTS: In children with ALL, CYP1A1 m1 polymorphism was evident in 42.4% of subjects and CYP1A1 m2 in 37.3%. These were significantly different from the results obtained for control children (20.3% for CYP1A1 m1 and 19.5% for m2). Subjects with CYP1A1 m1 homozygous variant had a sixfold risk and CYP1A1 m2 a fourfold risk. In contrast, CYP2D6*4 was more prevalent in the controls than in the cases. Subjects with GSTM1 deletions had increased risk of ALL (OR = 2.1, P = 0.009). The odds ratios for both CYP1A1 m1 and m2 homozygous polymorphisms being associated with childhood ALL was 5.67 (95% CI = 2.11-15.27). The odds ratios for both GSTM1 and GSTT1 deletions being associated with ALL was 2.78 (95% CI = 0.67-11.56). CONCLUSIONS: These results suggest that genetic polymorphisms of xenobiotic metabolising enzymes appear to influence susceptibility to childhood ALL.

Adolescent↗
PubMed1994

Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism.

In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.

Amino Acid Sequence↗
PubMed2001

The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.

The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2 and CYP2C9*3, differing from the wild-type CYP2C9*1 by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect of CYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9 genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutant CYP2C9 allele (n = 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day; P < 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9 allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.

Adolescent↗
PubMed1989

Genetic polymorphism of horse serum protein 3 (SP3).

Two-dimensional agarose gel (pH 8.6)-horizontal polyacrylamide gel (pH 9.0) electrophoresis of horse serum samples, followed by general protein staining, revealed genetic polymorphism of an unidentified protein tentatively designated serum protein 3 (SP3). The SP3 fractions appeared distinctly when a 14% concentration of acrylamide was used in the separation gels. The 2-D mobilities of SP3 fractions were quite similar to that of albumin. Family data were consistent with the hypothesis that the observed SP3 phenotypes were controlled by four co-dominant, autosomal alleles (D, F, I, S). Evidence was provided that the F allele can be further divided into two alleles (F1 and F2); the mobilities of F1 and F2 variants were very similar. Each of the SP3 alleles gave rise to one fraction and each of the heterozygous types showed two fractions. More than 600 horses representing five different breeds (Swedish Trotter, North-Swedish Trotter, Thoroughbred, Arab and Polish Tarpan) were typed for SP3, and allele frequency estimates were calculated. SP3 was highly polymorphic in all breeds studied.

Animals↗
PubMed2006

Peroxisome proliferator-activated receptor (PPAR) delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects.

AIMS: Previous studies have shown that the peroxisome proliferator-activated receptor delta (PPARD) genetic polymorphism affects cholesterol metabolism in Whites. This association was not observed in a Korean population in a separate study, but this study showed a link between the PPARD polymorphism and body weight and fasting plasma glucose. The purpose of this study was to determine whether polymorphisms of PPARD influence glucose and cholesterol metabolism in Chinese subjects. We investigated the association between the polymorphism (-87T/C) of the human PPARD gene and phenotypes related to body weight, insulin sensitivity, glucose and lipid metabolism in Chinese subjects. METHODS: Unrelated Chinese subjects (n = 663) in Shanghai were studied; 287 had newly diagnosed Type 2 diabetes mellitus and 376 were non-diabetic control subjects over 40 years old. Clinical parameters were collected and genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In normal glucose tolerant (NGT) subjects, the C allele carriers had higher fasting plasma glucose concentrations (P = 0.0078) and a lower insulin sensitivity index (ISI) (P = 0.0365). The C allele carriers also showed higher concentrations of low-density lipoprotein cholesterol (P = 0.0261) and percentage of body fat (P = 0.0357). There was a trend towards higher visceral adiposity in C allele carriers, but the difference was not significant (P = 0.0830). In diabetes patients, similar results were detected for plasma glucose concentrations (fasting plasma glucose P < 0.0001, 2-h plasma glucose P = 0.0052) and insulin sensitivity (homeostasis model assessment of insulin resistance P = 0.0094; ISI P = 0.0058). CONCLUSION: The PPARD-87T/C polymorphism is associated with higher fasting plasma glucose concentrations in both NGT and diabetic subjects, largely due to impaired insulin sensitivity.

Blood Glucose↗
PubMedDate not supplied

[Genetic polymorphism of biotransforming enzymes and genotoxic effects of styrenes].

A cross-sectional study was carried out on laminators producing glass-fibre reinforced plastics, to evaluate the role of genetic polymorphism of xenobiotic metabolising enzymes on the genotoxicity of styrene. Clastogenic effects, evaluated by the micronucleus test, are related with end-of-shift urinary concentration of 4-vinylphenol and seem to be modulated by NQO1 polymorphism; aneuploidogenic effects, evaluated by the identification of centromers in micronuclei using the fluorescence in situ hybridisation technique with a pancentromeric probe, are related with before-shift urinary levels of mandelic and phenylglyoxylic acids and seem to be modulated by the GSTM1 polymorphism.

Adult↗
PubMedDate not supplied

Genetic polymorphism of cytochrome P-450-dependent phencyclidine hydroxylation in mice. Comparison of phencyclidine hydroxylation in humans.

A mouse model of P-450 phencyclidine 3-cyclohydroxylase (P-450 PCP 3-cyclohydroxylase) genetic polymorphism is described. Up to a 3-fold difference was observed in the constitutive liver microsomal activity of P-450 PCP 3-cyclohydroxylase between "slow" (A/J and DBA/2J) and "rapid" (C57BL/6J and BALB/CJ) phencyclidine (PCP) metabolizers. The segregation of slow and rapid hydroxylator phenotypes between 17 recombinant inbred mouse strains derived from A/J and C57BL/2J mice suggests control of the activity by a single gene located on the X-chromosome or, less likely, on chromosome 17. A liver deficiency of P-450 PCP 3-cyclohydroxylase was observed in the New Zealand rabbit and Wistar rat, as well as in some human subjects. Any relationship of P-450 PCP 3-cyclohydroxylase polymorphism to other well characterized P-450 polymorphisms in mice (aryl hydrocarbon hydroxylase and coumarin hydroxylase) was excluded on the basis of differences in inducibility and activity distribution among the inbred mouse strains. Lack of relationship to the P-450 debrisoquine hydroxylase was confirmed by direct comparison of both activities in the same mouse and human liver microsomes. The pharmacological consequence of the observed polymorphism in mice appears to be that the rapid PCP metabolizers are more resistant to the effects of PCP compared to the slow metabolizers as based upon its ED50 and duration of action in A/J and C57BL/6J mice. The relevance of this data to humans remains to be determined, but clearly the latter show marked differences in PCP 3-cyclohydroxylase activity, which separate into low, intermediate, and high groups.

Animals↗
PubMed2006

Exposure assessment of benzene in Thai workers, DNA-repair capacity and influence of genetic polymorphisms.

Exposure to benzene can cause DNA damage and the subsequent development of cancer. In this study, study subjects were 31 laboratory workers at a petrochemical factory and 31 gasoline service attendants. Control subjects were 34 workers from a mail sorting service center. Occupational exposures to benzene were assessed using biomarkers of exposure in blood and urine. Induction of DNA-repair capacity was assessed as a biomarker of early effect. The effects of polymorphisms in a metabolizing gene (CYP2E1), in detoxification genes (NQO1 and GSTT1), and in a DNA-repair gene (XRCC1, codon 399) on biomarker levels were evaluated. The mean individual benzene exposure of laboratory workers (24.40+/-5.82 ppb) and that of gasoline service attendants (112.41+/-13.92 ppb) were significantly higher than in controls (1.39+/-0.17 ppb, p<0.001). Blood benzene levels of laboratory workers (169.12+/-30.60 ppt) and gasoline service attendants (483.46+/-59.62 ppt) were significantly higher than those of the controls (43.30+/-4.89 ppt, p<0.001). Trans,trans-muconic acid levels in post-shift urine samples collected from laboratory workers (0.14+/-0.02 mg/g creatinine) and gasoline service attendants (0.20+/-0.02 mg/g creatinine) were significantly higher than in urine samples of controls (0.04+/-0.01 mg/g creatinine, p<0.001). The level of benzene exposure was correlated with blood benzene levels (R2=0.65, p<0.01) and post-shift urinary trans,trans-muconic acid concentrations (R2=0.49, p<0.01). As a biomarker of early effect, DNA-repair capacity was assessed by use of the cytogenetic challenge assay, i.e., chromosomal aberrations in peripheral lymphocytes were assessed after challenging blood cultures with 1 Gy gamma radiation. A significantly lower DNA-repair capacity--determined as dicentrics in laboratory workers (0.17 per metaphase cell) and in gasoline service attendants (0.19 per metaphase cell) compared with controls (0.12 per metaphase cell, p<0.001)--was observed. The frequency of deletions in laboratory workers (0.22 per metaphase cell) and gasoline service attendants (0.39 per metaphase cell) were significantly higher than in control workers (0.16 per metaphase cell, p<0.01 and p<0.001, respectively). An increase in radiation-induced dicentrics and deletions indicate a lower DNA-repair capacity in benzene-exposed workers. The influence of genetic polymorphisms on the biomarkers was assessed. Benzene-exposed workers who carried CYP2E1*1/*5 or *5/*5 genotypes excreted slightly higher levels of trans,trans-muconic acid than workers who carried the CYP2E1*1/*1 genotype. In this study, NQO1 and GSTT1 genotypes did not have any effect on the levels of trans,trans-muconic acid. In the case of XRCC1, laboratory workers with 399Arg/Gln or Gln/Gln had a lower DNA-repair capacity--measured as radiation-induced frequency of dicentrics and deletions--than those with the 399Arg/Arg genotype (p<0.01). Our results show that biomarkers of internal dose and early biological effect in people occupationally exposed to benzene are influenced by genetic polymorphisms in susceptibility genes.

Benzene↗
PubMed2001

[Clinical significance and strategies to analyze genetic polymorphisms].

A DNA polymorphism can be defined as a difference in the primary sequence of DNA, and the frequency of the rarer allele among the general population exceeds 1%. Several types of polymorphisms, including minisatellite and microsatellite markers, deletion or insertion of short nucleotide sequences, and single nucleotide polymorphisms(SNPs), are present in human genome, with different frequencies and different distribution patterns. SNPs are very common and clinically important, because they often appear within genes, particularly within coding sequences. The biological significance of a polymorphism differs significantly depending upon its location within the genome. For example, polymorphisms located outside genes usually do not have biological consequences, and will be used merely as markers for genetic linkage. On the other hand, those located within a gene may cause subtle changes in transcription, mRNA stability, or protein conformation if amino acid substitution occurs. These subtle changes in biologically important factors then alter susceptibility to certain disorders. Environmental factors often interact with genes. Relationships between genetic polymorphisms and disease susceptibility have been reported on many kinds of human diseases, including neurological and psychiatric disorders, infectious diseases, endocrine and metabolic disorders, malignancy, as well as cardiovascular diseases. Recent years have seen the progress in novel strategies for rapid genotyping of a large numbers of polymorphisms, and also, for searching unknown SNPs.

Genetic Predisposition to Disease↗
PubMed2004

High throughput screening of genetic polymorphisms by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

In the post genomic era, the screening of many different genetic polymorphisms in large populations represents a major goal that will facilitate the understanding of individual genetic variability in the development of multi factor diseases and in drug response and toxicities. The increasing interest in these pathogenetic and pharmacogenomic studies by both academic and pharmaceutical industry researchers has increased the demand for broad genome association studies. This demand has produced a boom in the development of new and robust high throughput screening methods for genotype analysis. Matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) represents an emerging and powerful technique for DNA analysis because of its high speed, accuracy, no label requirement, and cost-effectiveness. So far, many MALDI-TOF MS approaches have been developed for rapid screening of single nucleotide polymorphisms (SNPs), variable sequences repeat, epigenotype analysis, quantitative allele studies, and for the discovery of new genetic polymorphisms. The more established methods are based on single base primer extension and minisequencing implemented with new chemical features to overcome the limitations associated with DNA analysis using MALDI-TOF MS. These new promising methods of genotyping include both photochemical and other different chemical and enzyme cleavage strategies that facilitate sample automation and MS analysis for both real-time genotyping and resequencing screening. In this review, we analyze and discuss in depth the advantages and the limitations of the more recent developments in MALDI-TOF MS analysis for large-scale genomic studies applications.

Automation↗
PubMed2000

Genetic polymorphism of 4 STR loci on chromosome 17 in Chinese Han.

OBJECTIVE: To analyze genetic polymorphism of D17S1290, D17S1293, D17S1303 and D17S1308 in Chinese Hans. METHODS: Fifty unrelated individuals were analyzed by PCR amplification fragment length polymorphism analysis method. RESULTS: 9, 7, 5, 5 alleles were observed at these 4 STR loci respectively, the genotypes distributions in Chinese Hans were in accordance with Hardy-Weinberg equilibrium, the expected heterozygosities for these loci were 0.770, 0.828, 0.608, 0.669 respectively, the polymorphism information contents(PIC) were 0.763, 0.820, 0.602, 0.662 respectively. CONCLUSION: The results demonstrate these 4 STR loci can be used for genetic analysis.

China↗
PubMed2000

Somatic mutations and genetic polymorphisms of the PPP1R3 gene in patients with several types of cancers.

Recently, we found nonsense and missense mutations of the PPP1R3 (protein phosphatase 1, regulatory subunit 3) gene in diverse human cancer cell lines and primary lung carcinomas, indicating that PPP1R3 functions as a tumor suppressor in human carcinogenesis. In this study, to assess the prevalence of PPP1R3 mutations in human primary cancers and the genetic diversity of the PPP1R3 gene in the human population, somatic mutations and genetic polymorphisms in the PPP1R3 gene were examined in 137 pairs of cancerous and non-cancerous tissues of patients with cancers of colon, ovary, and liver. Five somatic mutations including two missense mutations were detected in three cancerous tissues consisting of two colorectal carcinomas and one ovarian carcinoma. Five novel single nucleotide polymorphisms (SNPs) associated with the substitution of amino acids were also identified in cancer patients, in addition to five known nonsynonymous SNPs, including three previously reported ones as having an impact on the susceptibility to insulin resistant disorders. Differences in the activities and properties of multiple PPP1R3 proteins, which are produced in human cells due to variable somatic mutations and genetic polymorphisms in the PPP1R3 gene, can be involved in human carcinogenesis and susceptibility to diseases.

Amino Acid Substitution↗
PubMed2025

The role of candidate genetic polymorphisms in covid-19 susceptibility and outcomes.

BACKGROUND: This study aims to investigate the association between candidate host genetic polymorphisms and COVID-19 susceptibility, severity, hospitalization, hypoxia, and their combined effect, measured by the polygenic risk score (PRS). METHODS: Three hundred and seventy-six Lebanese participants, comprising 151 controls and 225 cases, were included. Clinical data were obtained from questionnaires and medical records. DNA isolated from peripheral blood was genotyped for ACE1 rs1799752, ACE2 rs2074192, TMPRSS2 rs75603675 and OAS1 rs107746771 using TaqMan assays, and for TMPRSS2 rs35074065 using Sanger Sequencing. Candidate genetic variants were analyzed in association with COVID-19 susceptibility, severity, hospitalization and hypoxia, using univariate and multivariate models. PRS constructed from the weighted sum of variants was evaluated in association with COVID-19 outcomes. RESULTS: In this study, there were no statistically significant differences in the frequencies of candidate variant alleles between cases, controls and within disease outcomes subgroups, after adjustment for confounders. PRS was not associated with COVID-19 susceptibility and hospitalization, it however significantly predicted COVID-19 severity (P&#x2009;=&#x2009;0.01). CONCLUSION: This study highlights the importance of genetic testing for key host genes involved in COVID-19 life cycle and eventually measuring the PRS which proves to be an important tool for prognosis assessment in vulnerable individuals, potentially enhancing patient care.

Polymorphism, Genetic↗
PubMed1999

[Genetic polymorphisms of serum orosomucoid in Han population in Nanjing of China].

OBJECTIVE: To determine the genetic polymorphisms of serum orosomucoid (ORM) in Han population in Nanjing of China and provide genetic data for studying the individual variance in the plasma protein binding of weak alkaline drugs. METHODS: The desialylated sera from 220 unrelated subjects were analyzed by isoelectric focusing on polyacrylamide gels followed by immunoblotting. RESULTS: The band patterns of ORM showed that the polymorphism of the structural locus ORM1 was controlled by three codominant autosomal alleles, ORM1*F1, ORM1*F2 and ORM1*S, which presented five phenotypes, ORM1 F1(47.27%), ORM1 S(5.46%), ORM1 F1F2 (3.18%), ORM1 F1S(43.64%), and ORM1 F2S(0.45%). The allele frequencies were: ORM1*F1=0.7068, ORM1*F2=0.0182, ORM1*S=0.2750. CONCLUSION: The ORM1 locus is polymorphic and the ORM2 locus is monomorphic in sera from the Han people in Nanjing of China.

Alleles↗
PubMed2005

Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene.

Magnetic resonance imaging (MRI) studies have shown some morphological and volumetric peculiarities in brains of schizophrenic patients. The authors explored the influence of genetic polymorphisms at interleukin-1beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes on these abnormalities. Hippocampus, lateral ventricles, and dorsolateral prefrontal cortex gray matter volumes were measured in a sample of 23 DSM-IV diagnosed schizophrenic patients of Spanish origin using MRI scans; MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n = 45). IL-1B and IL-1RN genes, involved in neurodevelopment and neurodegenerative processes, were analyzed in the patient sample. Patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left (P = 0.002) and right (P = 0.01) ventricles. Sex and illness duration were controlled for in the analyses. Our results, though preliminary, suggest that IL-1RN gene might contribute to the ventricular volumetric changes observed in schizophrenic patients.

Adult↗
PubMed1996

Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurines such as mercaptopurine and thioguanine. TPMT activity exhibits genetic polymorphism, with about 1 in 300 inheriting TPMT-deficiency as an autosomal recessive trait. If treated with standard dosages of thiopurines. TPMT-deficient patients accumulate excessive thioguanine nucleotides (TGN) in hematopoietic tissues, leading to severe hematopoietic toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10-15-fold lower dosage of these medications. The human gene encoding polymorphic TPMT has been cloned and characterized, and two mutant alleles have recently been isolated from TPMT-deficient and heterozygous patients (TPMT*2, TPMT*3), permitting development of PCR-based methods to identify TPMT-deficient and heterozygous patients prior to therapy. TPMT*3 is the predominant mutant allele in American whites, accounting for about 75% of mutations in this population. Ongoing studies aim to better define the influence of TPMT activity on thiopurine efficacy, to identify additional mutant alleles and determine their frequency in different ethnic groups, to elucidate the mechanism(s) for loss of function of mutant proteins, to identify potential endogenous substrates and to define the molecular mechanisms of TPMT regulation. Together, these advances bold the promise of improving the safety and efficacy of thiopurine therapy.

Alleles↗