Valine Allele Research Articles

Glutathione S-transferase M1, T1, and P1 genotypes and breast cancer risk: a study in a Portuguese population

Glutathione S-transferases are a superfamily of multifunctional enzymes that play a key role in Phase II metabolism, detoxifying therapeutic drugs, and various carcinogens by conjugation with glutathione. We undertook a case-control study in Central-Eastern Portuguese population to evaluate the association of null genotype in GSTM1 and GSTT1 along with the polymorphism in GSTP1 (A/G) and susceptibility to breast cancer. The population sample consisted of 85 patients with histological diagnosis of breast cancer and 102 healthy women. Genomic DNA was extracted from blood samples, and genotyping analyses were performed by PCR-based methods. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression. We found a increased breast cancer risk associated with GSTM1 null genotype (OR = 3.597; 95% CI = 1.849-6.999; P = 0.0001) and GSTT1 (OR = 2.592; 95% CI = 1.432-4.690; P = 0.002), but the presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The two-way combination of GSTM1 and GTTT1 null genotypes resulted in 8-fold increase for breast cancer risk (OR = 8.287; 95% CI = 3.124-21.980; P = 0.0001) and the three-way combination of GSTP1 105AA/AG and null genotypes for both GSTM1 and GSTT1 resulted in 5-fold increase for breast cancer risk (OR = 5.040; 95% CI = 1.392-18.248; P = 0.016). Our results suggest that GSTM1 and GSTT1 null genotype alone, both combined or combined with GSTP1 valine alleles, are associated with higher susceptibility to breast cancer development.

Association of cathechol O-methyltransferaser (COMT) polymorphism and executive function in adolescents

Event Abstract Back to Event Association of cathechol O-methyltransferaser (COMT) polymorphism and executive function in adolescents Sabine Kubesch1*, Laura Walk1 and Katrin Hille1 1 University of Ulm, Transfer Centre for Neuroscience and Learning, Germany The catechol O-methyltransferase (COMT) gene affects how long dopamine acts in the prefrontal cortex (PFC). The methionine (Met) allele results in COMT activity that is up to four times less pronounced than that conferred by the valine (Val) allele, resulting in greater PFC dopamine concentrations. Therefore, generally, the Met polymorphism is associated with better executive functions. Although having more dopamine in the PFC is beneficial for executive function, it also makes one more sensitive to stress. 53 healthy right-handed German students (24 girls) of grade 7 (13-14 years) participated in this study. Students were tested in their classrooms on the Dots task. The Dots task depends on the dorsolateral prefrontal cortex (DLPFC), which seems to be sensitive on the level of dopamine there. In the congruent condition of the Dots task, students must remember one higher-order rule. The incongruent condition requires holding one rule in mind plus steady state inhibition. In the mixed condition (incongruent and congruent trials were randomly intermixed) two rules must be remembered. Furthermore, cognitive flexibility is needed to switch between the rules as well as inhibition on the incongruent and switch trial. After data collection, cheek swabs were obtained from all students. DNA was extracted and genotyped for the COMT gene. Adolescents who were homozygous for the Met polymorphism (N=15) performed significantly worse on the dots incongruent condition and the dots mixed condition than students who were homozygous for Val (N=14) or heterozygous Met/Val (N=24). No differences were found in the congruent condition of the Dots task that places no demand on behavioral inhibition. Since we tested in a competitive situation in the classroom it seems that students homozygous for the valine version of the COMT gene or heterozygous showed better behavioral inhibition under this condition of mild stress than do students homozygous for the methionine version. Study results will be discussed within the context of stress and developmental changes in the dopaminergic system during childhood and adolescence. Conference: EARLI SIG22 - Neuroscience and Education, Zurich, Switzerland, 3 Jun - 5 Jun, 2010. Presentation Type: Poster Presentation Topic: General cognitive abilities Citation: Kubesch S, Walk L and Hille K (2010). Association of cathechol O-methyltransferaser (COMT) polymorphism and executive function in adolescents. Front. Neurosci. Conference Abstract: EARLI SIG22 - Neuroscience and Education. doi: 10.3389/conf.fnins.2010.11.00044 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 May 2010; Published Online: 31 May 2010. * Correspondence: Sabine Kubesch, University of Ulm, Transfer Centre for Neuroscience and Learning, Ulm, Germany, sabine.kubesch@znl-ulm.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sabine Kubesch Laura Walk Katrin Hille Google Sabine Kubesch Laura Walk Katrin Hille Google Scholar Sabine Kubesch Laura Walk Katrin Hille PubMed Sabine Kubesch Laura Walk Katrin Hille Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Association of the manganese superoxide dismutase polymorphism with vasospastic angina pectoris

Vasospastic angina (VSA) is closely related to endothelial dysfunction caused by oxidative damage. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that functions in mitochondria. There are two genetic variants of MnSOD arising from a substitution of an alanine for a valine in the signal peptide. We previously reported that the valine allele of MnSOD decreases the mitochondrial MnSOD (mtMnSOD) activity. Here, we investigated the association of the MnSOD polymorphism (Ala16Val) with VSA. Blood samples were collected from 618 healthy subjects who did not have any symptoms or other evidence suggesting angina pectoris, and 228 patients who underwent coronary angiography on suspicion of angina, and were diagnosed to have VSA by acetylcholine test. MnSOD genotype of each subject was determined by real-time polymerase chain reaction. The valine allele frequency was higher in the VSA patients (0.890) than in the healthy subjects (0.839) [odds ratio (OR)=1.55, p=0.0085]. In healthy subjects the MnSOD genotype distribution was as follows: alanine/alanine 1.9%, alanine/valine 28.3%, and valine/valine 69.8%, and in VSA patients the prevalence was: alanine/alanine 1.3%, alanine/valine 19.3%, and valine/valine 79.4%. Thus, the valine allele was closely associated with VSA (p=0.019). Multivariate logistic regression analysis showed valine/valine homozygosity to be an independent risk factor for VSA (OR=2.02, 95% CI 1.43, 2.85; p=0.0012). The valine variant of MnSOD signal peptide increases the risk of VSA.

Effect of Puberty Onset on Spontaneous Hepatitis B Virus e Antigen Seroconversion in Men

Male predominance is a remarkable phenomenon in hepatitis B virus (HBV)-related liver disease. This study elucidated the effects of puberty on spontaneous hepatitis B virus e antigen (HBeAg) seroconversion in boys. One-hundred HBeAg-positive chronic HBV-infected males recruited at younger than 10 years of age who had been followed for >10 years were selected randomly from our long-term followed cohort into this study. Serum testosterone levels, androgen receptor exon-1 CAG repeat number and steroid 5alpha reductase type II (SRD5A2, valine vs leucine alleles) polymorphism were determined. Serial clinical data, HBV genotype, and spontaneous HBeAg seroconversion age were also analyzed. Seventy-two subjects had spontaneous HBeAg seroconversion during the follow-up period. Subjects with serum testosterone levels > or =2.5 ng/mL at 15 years old (earlier-onset puberty, n = 87) had earlier HBeAg seroconversion (median age, 13.2 vs 22.5 years; hazard ratio = 2.95; P = .005), higher peak alanine aminotransferase levels when HBeAg positive (305.7 +/- 372.7 vs 154.8 +/- 126.0 IU/L; P = .006), and a greater HBV viral load reduction from 10 to 20 years of age (1.6 +/- 2.4 vs 0.2 +/- 1.4 log10 copies/mL; P = .009) than those with serum testosterone levels <2.5 ng/mL (later-onset puberty, n = 13). Valine allele carrier at the SRD5A2 V89L polymorphism was also associated with earlier spontaneous HBeAg seroconversion (median age, 11.7 vs 18.7 years; hazard ratio = 1.88; P = .028). Earlier-onset puberty and increased SRD5A2 enzyme activity are associated with earlier HBeAg seroconversion, higher serum alanine aminotransferase levels, and a greater HBV viral load decrement in chronic HBV infected males.

Polymorphisms of CYP1A1 I462V and GSTM1 genotypes and lung cancer susceptibility in Mongolian

AbstractAim: To study the genotype of cytochrome P450 1A1(CYP1A1) I462V and glutathions S-transferase M1( GSTM1) and the relationship of the genetic polymorphism of them with the susceptibility of lung cancer in Mongolia of China. Methods: Allele-specific PCR and a multiplex PCR were employed to identify the genotypes of I462V of CYP1A1 and GSTM1 in a case-control study of 210 lung cancer patients with bronchoscopy diagnosis and 210 matched controls free of malignancy. Results: The frequencies of the variant CYP1A1(Val/Val) genotypes and GSTM1(-) in lung cancer groups were higher than that in control groups (15.24% vs 7.4% and 56.67% vs 40.95% ). The individuals who carried with CYP1A1(Val/Val) or GSTM1(-) genotype had a significantly higher risk of lung cancer, the OR is 2.56 and 1.89 respectively. Stratified histologically the relative risk increased to 2.6 - fold when the patients carried with two valine alleles than the ones carried one valine allele in cases of SCC. GSTM1(-) genotype is the risk factor of SCC (OR=2.39) and AC(OR=2.16). The presence of at least one Val allele of CYP1A1 and GSTM1(-), the risk of lung cancer was increased, the OR was 4.15 for one Val allele and GSTM1(-) and 2.67 for two Val alleles and GSTM1 Considering ages and smoking status, the risk of lung cancer increased when the age less than 50 who carried with CYP1A1 valine (one or two) alleles or the age during the 51 to 65 who carried with GSTM1(-) genotype. The light smokers with CYP1A1 valine alleles and GSTM1(-) have a high risk for lung cancer. No association was found between the light and heavy drinkers with the susceptibility of lung cancer and the genetic polymorphisms of CYP1A1 I462V and GSTM1(-). Conclusion: The valine allele of CYP1A1 was the risk factors of lung cancer especially for SCC and GSTM1(-) also was the risk factor of lung cancer and especially for SCC and AC of Mongolian, China. Light smoking has a influence each other with genotype of CYP1A1 I462V and GSTM1(-) and susceptibility of lung cancer. No relationship was found between the susceptibility of lung cancer and drinkers with genetic polymorphisms of CYP1A1 I462V and GSTM1(-). The influence of genotypes on the susceptibility of lung cancer may depend on the ages. There may be a synergetic interaction between CYP1A1 valine allele and GSTM1(-) genotypes on the elevated susceptibility of lung cancer. So do those genotypes with light smokers. Key words polymorphism; genotype; lung cancer; cytochrome P450&amp;xFF1B;glutathione S-transferase Abbreviations: SCC, squamous cell carcinoma; AC, adenocarcinoma; SCLC, small cell lung cancer; LCLC, large cell lung cancer

Eating disorders and obesity: two sides of the same coin?

The eating disorders anorexia and bulimia nervosa have traditionally been regarded as entirely separate from obesity. Eating disorders have been regarded as Western culture-bound syndromes, arising in societies with excessive emphasis on weight, shape and appearance, and best treated by psychological therapies, in particular cognitive behavioural therapy or family-based interventions. In contrast, obesity has been considered a medical illness with metabolic and genetic origins, and thought to be best treated by mainstream medicine, involving dietary, drug or surgical treatment. We believe that this polarisation is fundamentally flawed, and research and treatment of both types of disorder would be better served by greater appreciation of the psychosocial components of obesity and the biological and genetic components of eating disorders. There are similarities in phenotype (such as excessive attempts at weight control, binge eating behaviours) and in risk factors (such as low self-esteem, external locus of control, childhood abuse and neglect, dieting, media exposure, body image dissatisfaction, weight-related teasing and shared susceptibility genes). One example of shared genetic risk is the brain-derived neurotrophic factor (BNDF) gene, in which the valine allele of the Val66Met amino acid polymorphism predisposes to obesity, whereas the methionine allele predisposes to eating disorders. Thus the evidence suggests that these disorders will have both shared and distinct susceptibility factors; some will predispose to both types of disorder, some will push in opposite directions, and some will separate them.

Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes.

Allelic variation in the gene encoding brain-derived neurotrophic factor (BDNF) has been associated with affective disorders, but generally not schizophrenia. Brain-derived neurotrophic factor variants may help clarify the status of schizoaffective disorder. To test the hypothesis that BDNF haplotypes are associated with psychiatric illness marked by a prominent affective component. Frequencies of a 5-marker BDNF haplotype were examined in 600 White participants across four diagnostic categories and healthy controls. Individuals with schizoaffective disorder and other affective disorders were significantly more likely to carry two copies of the most common BDNF haplotype (containing the valine allele of the Val66Met polymorphism) compared with healthy volunteers. Moreover, when compared with people with schizophrenia, individuals with schizoaffective disorder were significantly more likely to carry two copies of the common haplotype. To our knowledge, this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia. Variation in the BDNF gene may be associated with the clinical phenotype of affective dysregulation across several DSM-IV diagnostic categories.

Psychosis: A Category or a Dimension?

Can J Psychiatry. 2009;54(3): 137-139. The diagnostic entity of schizophrenia creates a loose boundary around a heterogeneous collection of interrelated and relatively distinct phenotypes. The Diagnostic and Statistical Manual of Mental Disorders (DSM)-V planning process is currently under way and it has once again ignited the debate about the boundaries of this diagnosis. One question concerns whether psychotic symptoms can occur in healthy people. A recent quantitative review of all reported incidence and prevalence studies of population rates of subclinical psychotic experiences revealed a median prevalence rate of around 5% and a median incidence rate of around 3%.1 Many people who hear voices can cope with them and even view them as a positive part of their lives. I remember one of my own patients who had been hallucinating for 25 years. The month after I prescribed clozapine, he began to complain about the absence of auditory hallucinations. He was feeling lonely, bored, and sad. I decided to decrease the dosage of clozapine so he could hear his voices momentarily during the day. This clinical situation was new to me because it encouraged me, for the first time, to let the voices resurface gradually to increase my patient's quality of life, instead of trying to eradicate them. This prompted me to review literature and make connections with groups of people who consider that hearing voices is not automatically something negative but may actually be positive. In a more personal and provocative book entitled Is It Normal to be Psychotic?,2 I described subjective experiences and discussions with colleagues concerning these dimensional aspects of psychosis. For instance, in the case of psychoticlike symptoms during an exposure to cannabis in a nonpatient, what makes a person experience psychotic symptoms? One hypothesis is that individual differences may reflect a genetic psychotic vulnerability (for example, for carriers of the valine allele of the COMT Val 158Met polymorphism i3,4) so that cannabis use may have no adverse influence on people with 2 copies of the methionine allele. Given that psychosis results from the interaction of many genes, it could be a continuous phenotype with mild forms present in the general population. Currently, 114 combinations of symptoms can lead to establishing the DSM-PV definition of schizophrenia, and different populations of patients are defined by different diagnostic systems (that is, DSM-III-R, DSM-IV, International Classification of Diseases, 10th edition, and Research Diagnostic Criteria). This raises questions about the validity of the current definition. Some clinicians lean toward a categorical approach, whereas others consider psychosis a dimensional phenomenon. In the 2 following In Review articles,5,6 the authors illustrate the debate between the dimensional and categorical approaches. In the first article,5 Dr Genevieve Letourneau and I review the literature about what could be considered as psychotic phenomena in the healthy or nonclinical population. Having attended some European meetings and symposia organized by the International Network for Training, Education and Research into Hearing Voices, I observed that this phenomenon can be considered either as a purely pathological or as a completely normal phenomenon. On another occasion, during a meeting with several members of our team (nurses and doctors), I mentioned that I was writing an article on auditory hallucinations in healthy people. Surprisingly, 8 out of 10 members of the team admitted (in certain cases, with details) that they had heard voices at some point during their life. It did not prevent them from being health professionals, working in psychiatry, and, for the majority, taking charge of psychotic people suffering from auditory hallucinations. This discussion reflected epidemiologic findings showing that nonclinical subjects can experience temporary or durable psychotic phenomena. …

Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome

Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them toward the lower end of dopamine turnover on the nonlinear function. A common polymorphism with valine to methionine substitution alters COMT activity that results in higher enzyme activity in the valine variant. Twenty-seven children with 22q11.2DS between 7 and 14 years old, and 21 age-matched typically developing children, performed a modified version of the Attention Network Test. Children with a single valine allele showed a reduction in response times when trials with incongruent flankers were repeated, whereas those who were hemizygous for the methionine allele did not show the same context-based response facilitation. Our results support that a single gene, COMT, could modulate PFC-dependent cognition.

Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

A Variation in the Cerebroside Sulfotransferase Gene Is Linked to Exercise-Modified Insulin Resistance and to Type 2 Diabetes

Aims. The glycosphingolipid β-galactosylceramide-3-O-sulfate (sulfatide) is present in the secretory granules of the insulin producing β-cells and may act as a molecular chaperone of insulin. The final step in sulfatide synthesis is performed by cerebroside sulfotransferase (CST) (EC 2.8.2.11). The aim of this study was to investigate whether two single nucleotide polymorphisms (SNP), rs2267161 located in an exon or rs42929 located in an intron, in the gene encoding CST are linked to type 2 diabetes (T2D). Methods. As a population survey, 265 male and female patients suffering from T2D and 291 gender matched controls were examined. Results. A higher proportion of T2D patients were heterozygous at SNP rs2267161 with both T (methionine) and C (valine) alleles present (49.8% versus 41.3%, P = .04). The calculated odd risk for T2D was 1.47 (1.01–2.15, P = .047). Among female controls, the homozygous CC individuals displayed lower insulin resistance measured by HOMA-IR (P = .05) than the C/T or TT persons; this was particularly prevalent in individuals who exercise (P = .03). Conclusion. Heterozygosity at SNP rs2267161 in the gene encoding the CST enzyme confers increased risk of T2D. Females with the CC allele showed lower insulin resistance.

AluI polymorphism of the bovine growth hormone (GH) gene, resumption of ovarian cyclicity, milk production and loss of body condition at the onset of lactation in dairy cows

Relationships among GH genotype ( AluI polymorphism), parity, metritis and interval from calving to first ovulation, milk production and body condition score (BCS) loss were determined in dairy cows ( n = 307) on four large-scale farms in Hungary. Cows with systemic signs of puerperal metritis or mastitis were excluded. Time of the first postpartum (PP) ovulation was obtained from milk progesterone profiles. Based on GH genotype determination, groups of leucine homozygous cows ( n = 246) and valine allele carriers ( n = 61) were formed. All animals became cyclic during the study period. The average interval to first ovulation was 27.6 ± 0.69-d PP (mean ± S.D.). Genotype had no effect on the commencement of ovarian cyclicity. First ovulation occurred sooner after calving in pluriparous than in primiparous cows. The greater BCS loss cows had during the first 30-d PP, the longer they took to resume cyclic ovarian function. The interval from calving to first ovulation was substantially affected by farm, but not by mild cases of puerperal metritis. Genotype was not related to cumulative 30-d milk yield or BCS loss after calving. Primiparous cows had lower milk yield than pluriparous ones. Cows with metritis lost more body condition than healthy individuals in the first month postpartum. We concluded that, under field conditions, AluI polymorphism of the bovine GH gene had no effect on the interval from calving to first ovulation and could not be directly related to differences in milk yield and to the extent of BCS loss during the first month after calving in Holstein–Friesian cows.

Interrelationship of growth hormone AluI polymorphism and hyperketonemia with plasma hormones and metabolites in the beginning of lactation in dairy cows

A polymorphic site of the growth hormone gene ( AluI polymorphism) that results in an amino acid change at position 127 of the protein chain (leucine, L to valine, V) has been linked to differences in circulating metabolites and metabolic hormones of calves and bulls and to milk yield traits of lactating cows. Our objective was to investigate the interrelationship of this polymorphism with plasma concentrations of β-hydroxybutyrate, insulin, IGF-I and leptin in postpartum dairy cows. Blood samples were taken from clinically healthy, spring-calving, group-fed Holstein-Friesian cows ( n = 257; 7 large-scale farms) 4–13 days after calving. Of all herds, 100 cows had plasma β-hydroxybutyrate levels above 1.2 mmol/l and 157 cows were normoketonemic. The proportion of valine carriers and LL cows was not different within groups of normo- and hyperketonemic animals. Genotype was not associated with plasma β-hydroxybutyrate, insulin, IGF-I and leptin levels either in all of the herds or in the two with the highest proportion of the valine allele carriers ( n = 28, 72%). We found significantly lower insulin, IGF-I and leptin concentrations in the presence of hyperketonemia compared to normoketonemic cows. There were strong negative correlations between BHB and the other blood parameters, while insulin, IGF-I and leptin were positively related to each other. In conclusion, in the first two weeks after calving we could not demonstrate any effect of AluI polymorphism on plasma concentrations of β-hydroxybutyrate and metabolic hormones studied. Hyperketonemia was associated with a significant decrease in insulin, IGF-I and leptin blood levels. We infer that cows homozygous for the leucine allele or carrying the valine allele may have a similar endocrine and metabolic response to the challenge of increased nutrient demand early postpartum and that the presence of hyperketonemia is mainly linked to the hormonal and metabolic changes occurring at the onset of lactation.

FCGR3A-158V/F Polymorphism May Correlate with the Levels of Immunoglobulin in Patients with Non-Hodgkin's Lymphoma after Rituximab Treatment as An Adjuvant to Autologous Stem Cell Transplantation.

Recent studies have indicated that patients who receive stem cell transplantation (SCT) and an adjuvant rituximab demonstrate an increased risk of developing hypogammaglobulinemia. We have found that such hypogammaglobulinemia were due to the delayed recovery of memory B cells with an abnormal cell marker expression and impaired immunoglobulin production in vitro. (Nishio et al. Eur J Haemtol, 2006, Nishio et al. Br J Haematol, 2007) However, no speculation has been made regarding what factor(s) determined the risk of developing hypogammaglobulinemia after autologous SCT with the identical conditioning regimen and rituximab. Accumulated evidences have shown that FCGR3A of valine (V) allele has a higher affinity to human IgG than the phenylalanine (F) allele, and that cells bearing the FCGR3A V allele mediate antibody dependent cellular cytotoxicity more effectively. Compatibly, previous clinical studies that have examined single nucleotide polymorphisms (SNPs) of Fc receptor genes demonstrated that FCGR3A gene SNPs are associated with the response to rituximab, as a single agent, in patients with follicular lymphoma or Waldenstrom's macroglobulinemia. These findings suggest that FCGR3A SNPs may be related to the levels of immunoglobulin after SCT and an adjuvant rituximab. To clarify this hypothesis, the FCGR3A-158V/F genotype and the levels of serum immunoglobulin six months after SCT were tested in twenty non- Hodgkin's lymphoma (NHL) patients having received autlogous peripheral blood stem cell transplantation (APBSCT) with an adjuvant rituximab. We also compared the levels of immunoglobulin in ten NHL patients who received an identical conditioning regimen and APBSCT, but no rituximab (control group). Of the twenty patients tested for the FCGR3A-158V/F polymorphism, seven patients (35%) had homozygous F/F (158 F/F), 12 (60%) had heterozygous V/F (158 V/F), and one (5%) had homozygous V/V (158 V/V). Since only one patient was found to have 158 V/V polymorphism in this study, we defined those patients who had 158 F/F as the low affinity group, while those who had at least one 158 V allele were defined as the high affinity group following the previous definition by Anolik et al (Arthritis Rheum 2003). The three groups were not different in terms of gender, age, the disease stage, bone marrow involvement or number of extranodal sites involved at diagnosis. Before starting induction therapy, there was no significant difference in the levels of immunoglobulin among three groups. However, after APBSCT, the levels of IgG were significantly lower in the low affinity group (6.87 ± 2.38 g/l) than those in the high affinity group (10.20 ± 2.43 g/l) and control group (10.64 ± 3.04 g/l; both P<0.05). In addition, a significant difference was seen in the levels of IgA between the low affinity group (0.95 ± 0.64 g/l) and control group (1.63 ± 0.51 g/l) (P<0.05). The levels of IgA in the high affinity group (1.19 ± 0.55 g/l) were not significantly different from either those of control group or the low affinity group. In contrast to the levels of IgG or IgA, no significant differences were observed in the levels of IgM among three groups. These data suggest that the FCGR3A genotype may influence not only the outcome of rituximab therapy, but also the levels of IgG and IgA after APBSCT and rituximab.

Relation of glutathione S‐transferase T1, M1 and P1 genotypes and breast cancer risk

The aim of this study was to investigate associations between genetic variability in specific Glutathione S-transferases (GST) genes (GSTM1, GSTT1 and GSTP1) and susceptibility to breast cancer. Genotypes of blood specimen DNA were determined for 65 women with incident cases of breast cancer and 108 control subjects. Associations between specific genotypes and the development of breast cancer were examined by the use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Neither GSTT1 nor GSTM1 homozygous null genotype was associated with a significant increased risk of developing breast cancer. The presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The risk of breast cancer associated with a combined GSTT1 and GSTM1 null genotype was 3.37 (95% CI = 0.76-2.95, p = 0.115). The only significant association between increased risk of breast cancer development and GSTs polymorphisms was found when GSTT1 null, GSTM1 null and the presence of valine in GSTP1 in codon 105 were combined (p < 0.048, OR = 3.75, 95% CI = 1.01-13.90). Our findings suggest that combined genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.

CYP1A1 gene polymorphism and polycystic ovary syndrome

The aim of this study was to assess the rates of variant alleles of cytochrome P4501A1 ( CYP1A1) in patients with polycystic ovary syndrome (PCOS). It was designed as a case–control study in Hacettepe University, Faculty of Medicine, Department of Obstetrics and Gynecology and Genetics. Forty-eight patients with PCOS served as the study group. Ninety-six regularly cycling women with no clinical and biochemical evidence of hyperandrogenism and polycystic ovary appearance served as the controls. The CYP1A1 variant alleles of all patients were determined via polymerase chain reaction. The rate of the CYP1A1 isoleucine (Ile)/valine (Val) allele was significantly higher in patients with PCOS than in the controls (OR: 7.8, 95% CI: 3.45–17.52, P < 0.001). However, there was no statistically significant difference in the distribution of Val/Val genotype (OR: 4.0, 95% CI: 0.60–26.73). The rate of any Val genotype (Ile/Val or Val/Val) was significantly higher in patients with PCOS compared with the control group (OR: 7.4, 95% CI: 3.33–16.46, P < 0.001). In conclusion, the patients with PCOS had a 7.8-fold higher frequency of CYP1A1 Ile/Val genotype and a 7.4-fold higher frequency of CYP1A1 of any Val genotype (Ile/Val or Val/Val).

Polymorphisms in the MGMT Gene as Predictors of Leukemia Risk and Response to Therapy in Children with AML.

Approximately 40% of patients treated with chemotherapy for pediatric AML will relapse after initial treatment and 8–10% will die of toxic side effects of chemotherapy. This highly variable response to standardized treatment protocols is due in part to genetic variation among patients in the metabolism of chemotherapeutic agents and in the response to the DNA damage they induce. We have analyzed polymorphisms in the coding region of the DNA alkylation repair gene O6-Methylguanine-DNA Methyltransferase (MGMT) in 356 patients with de novo pediatric AML to determine whether naturally occurring MGMT variant alleles correlate with leukemia susceptibility, treatment efficacy, and the incidence of adverse effects of chemotherapy. The polymorphism rs2308321 (Ile143Val) has been shown to modify biochemical properties of the MGMT protein, with altered substrate specificity of the rare valine allele (G genotype) compared with the isoleucine allele (A genotype) (Margison et al, Carcinogenesis , 26;1473, 2005). All patients were treated on Children's Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C, thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C and G-CSF). Patients received intensification with a single course of high dose Ara-C and L-asparaginase unless a family donor was available when allogeneic transplant was performed after busulfan and cyclophosphamide. Black children were significantly more likely to have a homozygous wild-type AA genotype than white children (p=0.002). When compared to a healthy control population, there was no correlation between MGMT polymorphisms and the risk of AML overall. However, in a case-case comparison of genetic sub-types of AML, children with a variant allele (AG or G/G genotype) were significantly more likely to have monosomy 7 than AA cases (9% vs 1%; p=0.01); in contrast, children with trisomy 8 were significantly more likely to have an AA genotype (8% vs 0%; p=0.028). The presence of at least one G allele was associated with a significant reduction in the incidence of relapse. There was no effect on treatment-related mortality (TRM). In a multivariate Cox model adjusted for race, the increased risk of relapse (RR) associated with the variant G allele remained significant (hazard ratio 1.72 95% CI 1.03–2.86; p=0.037). These results suggest that genotyping at the rs2308321 polymorphism in the MGMT gene could be useful in the risk stratification of patients with AML prior to therapy.A/AA/G+G/GN% ± 2 SEN% ± 2 SEp-value5yr OS from end of course 128054 ± 67671 ± 110.0315yr RR from end of course 128043 ± 67627 ± 110.0145yr TRM from end of course 128014 ± 47614 ± 80.11

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P=0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.