ValVal Genotype Research Articles

GSTM1 and GSTP1 Polymorphisms Affect Outcome in Colorectal Adenocarcinoma.

Background and Objectives: Despite improvements in screening programs, a large number of patients with colorectal cancer (CRC) are diagnosed in an advanced disease stage. Previous investigations imply that glutathione transferases (GSTs) might be associated with the development and progression of CRC. Moreover, the detoxification mechanism of oxaliplatin, which represents the first line of treatment for advanced CRC, is mediated via certain GSTs. The aim of this study was to evaluate the significance of certain GST genetic variants on CRC prognosis and the efficacy of oxaliplatin-based treatment. Materials and Methods: This prospective study included 523 patients diagnosed with CRC in the period between 2014 and 2016, at the Digestive Surgery Clinic, University Clinical Center of Serbia, Belgrade. Patients were followed for a median of 43.47 ± 17.01 months (minimum 1-63 months). Additionally, 109 patients with advanced disease, after surgical treatment, received FOLFOX6 treatment as a first-line therapy between 2014 and 2020. The Kaplan-Meier method was used to analyze cumulative survival, and the Cox proportional hazard regression model was used to study the effects of different GST genotypes on overall survival. Results: Individuals with the GSTM1-null genotype and the GSTP1 IleVal+ValVal (variant) genotype had significantly shorter survival when compared to referent genotypes (GSTM1-active and GSTP1 IleIle) (log-rank: p = 0.001). Moreover, individuals with the GSTM1-null genotype who received 5-FU-based treatment had statistically significantly shorter survival when compared to individuals with the GSTM1-active genotype (log-rank: p = 0.05). Conclusions: Both GSTM1-null and GSTP1 IleVal+ValVal (variant) genotypes are associated with significantly shorter survival in CRC patients. What is more, the GSTM1-null genotype is associated with shorter survival in patients receiving FOLOFOX6 treatment.

Combinations of fibrinolytic gene polymorphisms (plasminogen activator inhibitor type 1 4G/5G, factor XIII Val34Leu and angiotensin-converting enzyme I/D) in women with idiopathic infertility.

During normal pregnancy depressed fibrinolytic system is caused by changes in many factors, which could be influenced by different gene polymorphisms. The aim of this study was to investigate the combination of fibrinolysis-related gene polymorphisms in women with idiopathic infertility. We genotype polymorphisms 4G/5G in plasminogen activator inhibitor type 1 (PAI-1), Val34Leu in factor XIII (FXIII) and I/D in angiotensin-converting enzyme (ACE) gene. The patients group consisted of 83 females with idiopathic infertility, while the control group included 121 females with at least one born child. The alleles and genotypes distributions showed no significant differences between analyzed groups. Although higher frequency of PAI-1 5G5G genotype in patients did not reach statistical significance, 5G5G genotype of PAI-1 in combination with ValVal genotype of FXIII leads to higher risk for infertility (P < 0.05). In addition, when we added ACE I/D polymorphism in analysis, the 4G in PAI-1 and D allele in ACE, showed protective effect in combination with FXIII polymorphism (P < 0.05). The finding that combined homozygosity of 5G of PAI-1, commonly associated with greater fibrinolytic activity and bleeding tendency, in combination with Val genotype of FXIII impose a risk for female idiopathic infertility. The protective effect of alleles 4G (PAI-1) and D (ACE) suggest that different combinations of polymorphisms influencing fibrinolysis could lead to better established hemostatic balance and reproductive success. Further analyses, with larger number of samples, as well as assessment of additional biochemical parameters of fibrinolysis, should be performed to clarify the role of gene polymorphisms on fibrinolysis and consequently their influence on reproductive success.

Abstract 13770: Experiences of Ethnic Discrimination and COMT Val158Met Polymorphism Are Associated With Depressive Symptoms in Hispanic Adults at Risk for Cardiovascular Disease

Introduction: There is emerging evidence that ethnic discrimination, commonly experienced among U.S. Hispanics, is associated with depressive symptoms, increasing cardiovascular disease (CVD) risk. Genetic variants in dopaminergic pathways may moderate this association. The catechol-O-methyltransferase Val158Met polymorphism is a potential candidate because the Met allele is associated with increased risk for depressive symptoms. The purposes of this study were to examine associations among ethnic discrimination, Val158Met polymorphism, and depressive symptoms, and to explore if Val158Met moderates the association between discrimination and depressive symptoms in Hispanic adults. Methods: Participants were 124 Hispanic adults with 2+ CVD risk factors. Ethnic discrimination was measured with the Experiences of Discrimination instrument, which measures discrimination experiences across 9 settings (e.g. at work). Scores range from 0 to 45; higher scores indicate more experiences of discrimination. Depressive symptoms were measured using the Patient Health Questionnaire-8. Scores range from 0 to 21; higher scores indicate more depressive symptoms. DNA was isolated from saliva and analyzed for Val158Met genotype. A hierarchical linear regression was conducted adjusting for sex, age, income, education, acculturation, and years in the U.S. Discrimination was entered in Step 1 and Val158Met in Step 2 to examine the association with depressive symptoms. To assess moderation, a discrimination*Val158Met interaction term was entered in Step 3. Results: Participants were aged 40.2 ± 9.3 years and mostly female (74.2%). Discrimination was positively associated with depressive symptoms (p = 0.041). Participants with at least one Met allele at the Val158Met polymorphism had more depressive symptoms than those with a Val-Val genotype (p = 0.049). No moderation effect was found. Conclusion: Findings suggest that discrimination and Val158Met genotype independently influence depression in Hispanic adults, which may increase risk for depression and CVD in certain individuals. This highlights the need to explore mechanisms underpinning these associations, and to address the impact of discrimination on depression and CVD disparities.

GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1, GSTT1and GSTP1, are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype (p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.

Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure.

Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1∗B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 “risk-associated” genotype (OR = 2.8, p = 0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p = 0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.

The Catechol-O-Methyltransferase and Dopamine Transporter Genes Moderated the Impact of Peer Relationships on Adolescent Depressive Symptoms: A Gene-Gene-Environment Study.

Behavioral genetics studies and new empirical evidence suggest that depression cannot simply be explained by the influence of single genes but that gene-gene-environment interactions are important to better understanding the etiology of depression. The present study investigated the main and interactive effects of COMT gene Val158Met polymorphism, DAT1 gene rs27072 polymorphism, and peer relationships (i.e., peer acceptance and rejection) on adolescent depressive symptoms. In a sample of 1045 Chinese Han adolescents (Mage = 12.34 ± 0.47 years, 50.1% girls), saliva samples, self-reported depressive symptoms and within-classroom peer nominations were collected. After controlling for gender, age, and SES, the three-way interaction of COMT, DAT1, and peer acceptance significantly concurrently predicted adolescent depressive symptoms. Adolescents with ValVal genotype of COMT and CC genotype of DAT1 were more sensitive to acceptance, compared to their counterparts carrying other combined genotypes. However, a similar three-way interaction was not significant in the case of peer rejection. Additionally, the split-half validation generally replicated these findings. More importantly, this study underscores complex polygenic underpinnings of depression and lends support for the gene-gene-environment interactions implicated in the etiology of depressive symptoms.

Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer.

Introduction: Additional or better markers are needed to guide the clinical monitoring of patients with non-muscle-invasive bladder cancer (NMIBC). Aim: To investigate the influence of occupational exposures and genetic polymorphisms on recurrence and progression of NMIBC. Methods: The study includes 160 NMIBC patients. We collected on questionnaire information on demographic variables, lifetime smoking history, lifetime history of occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons. Genetic polymorphism (glutathione S-transferase M1; T1; P1 (GSTM1; GSTT1; GSTP1); N-acetyltransferase 1; 2 (NAT1; NAT2); cytochrome P450 1B1 (CYP1B1); sulfotransferase 1A1 (SULT1A1); myeloperoxidase (MPO); catechol-O-methyltransferase (COMT); manganese superoxide dismutase (MnSOD); NAD(P)H:quinone oxidoreductase (NQO1); X-ray repair cross-complementing group 1; 3 (XRCC1; XRCC3) and xeroderma pigmentosum complementation group (XPD)) was assessed in peripheral blood lymphocytes. DNA adducts were evaluated by 32P-postlabeling. Predictors of recurrence (histological confirmation of a newly found bladder tumor) and progression (transition of tumor from low-grade to high-grade and/or increase in TNM stage) were identified by multivariate Cox proportional hazard regression with stepwise backward selection of independent variables. Hazard ratios (HR) with 95% confidence interval (95%CI) and two-tail probability of error (p-value) were estimated. Results: The risk of BC progression decreased with the homozygous genotype “ValVal” of both COMT and MnSOD (HR = 0.195; 95%CI = 0.060 to 0.623; p = 0.006). The results on BC recurrence were of borderline significance. No occupational exposure influenced recurrence or progression. Conclusion: Our results are supported by experimental evidence of a plausible mechanism between cause (ValVal genotype of both MnSOD and COMT) and effect (decreased progression of tumor in NMIBC patients). The genetic polymorphisms associated with better prognosis may be used in clinic to guide selection of treatment for patients initially diagnosed with NMIBC. However, external validation studies are required.

Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders

Background: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis.Methods: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored.Results: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype.Conclusions: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.

Effects of the Interaction Between the Level of Anxiety and the Val66Met Polymorphism of the Brain-Derived Neurotrophic Factor Gene on Attention in Patients with Schizophrenia Spectrum Disorders

The effects of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and levels of trait anxiety (negative emotionality) on attention were studied in 90 patients with schizophrenia and schizoaffective psychosis. Attention was evaluated using auditory event-related potentials (ERP) and neuropsychological testing. Genotype was found to have a significant effect (anxiety was not) on the efficiency of performing the neuropsychological test on attention and the amplitude of the ERP P300 wave in the frontal and temporal leads. Carriers of the Met allele has poorer performance of the attention task than subjects with the ValVal genotype, and also showed a lower P300 wave amplitude. Genotype combined with the level of anxiety was found to affect the N100 wave in response to the non-significant stimulus, significant differences being seen only in the group with a low level of anxiety: the Met allele was associated with lower N100 amplitudes. Among patients with high levels of anxiety, N100 wave amplitude was independent of the BDNF gene variant present. It is suggested that people with high levels of anxiety expend more effort to solve the task correctly at the early stages of signal recognition, the amplitudedecreasing effect of the “risk allele” being eliminated.

Тревожность и полиморфизм Val66Met гена BDNF — предикторы выраженности депрессии при ишемической болезни сердца

In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

Association of the COMT and DRD2 Genes with the Ability of Schizophrenia Patients to Understand the Mental State of Other People

With the aim of identifying the role of dopamine transmission in impairments to the ability of schizophrenia patients to understand the mental state of other people, we searched for associations between this component of social cognition and genes encoding the DRD2 receptor and the enzyme COMT in 209 schizophrenia patients and 172 healthy people. Neuropsychological assessment of subjects consisted of solving verbal tasks involving second-order false beliefs (FB2) and assessment of the ability to detect faux pas. An association was found between the Val158Met polymorphism of the COMT gene and success in solving FB2 tasks by schizophrenia patients. This association was linked with sexual dimorphism. Impairments were seen in female patients carrying the Met allele. In male patients, a tendency to more marked impairment was linked with the ValVal genotype. Analysis of correlations between the COMT Val158Met marker and the ability to solve FB2 tasks and neurocognitive and clinical symptoms suggested that the association detected in female patients was mediated, at least partly, by increased stress reactivity in carriers of the Met allele due to the acuteness of patients’ status and its consequences for cognitive functioning.

Involvement of the BDNF Gene in Loneliness in Adolescence: A Report of Opposite Gene Effects in Boys and Girls

Previous research has shown that loneliness has a heritable component and that genes within the serotonin-, dopamine-, and oxytocin systems are related to loneliness in adolescence. In the present study, the relation between the BDNF Val66Met polymorphism and loneliness in adolescent boys and girls was examined in a longitudinal study spanning five annual waves (N = 305). Latent growth curve modeling (LGCM) was used to examine the baseline level and the change in loneliness over time. The main finding was that the BDNF gene was not related to loneliness in the total sample. A BDNF by sex interaction was found, in that Met carrying girls had the highest levels of loneliness at baseline, whereas in boys the ValVal genotype was related to higher levels of loneliness. Our results underline the importance of sex-stratified analyses when examining effects of the BDNF genotype and the necessity of conducting gene studies to intermediate phenotypes of loneliness.

Relationship between the COMT-Val158Met and BDNF-Val66Met Polymorphisms, Childhood Trauma and Psychotic Experiences in an Adolescent General Population Sample

ObjectivePsychotic experiences occur at a much greater prevalence in the population than psychotic disorders. There has been little research to date, however, on genetic risk for this extended psychosis phenotype. We examined whether COMT or BDNF genotypes were associated with psychotic experiences or interacted with childhood trauma in predicting psychotic experiences.MethodPsychiatric interviews and genotyping for COMT-Val158Met and BDNF-Val66Met were carried out on two population-based samples of 237 individuals aged 11-15 years. Logistic regression was used to examine for main effects by genotype and childhood trauma, controlling for important covariates. This was then compared to a model with a term for interaction between genotype and childhood trauma. Where a possible interaction was detected, this was further explored in stratified analyses.ResultsWhile childhood trauma showed a borderline association with psychotic experiences, COMT-Val158Met and BDNF-Val66Met genotypes were not directly associated with psychotic experiences in the population. Testing for gene x environment interaction was borderline significant in the case of COMT-Val158Met with individuals with the COMT-Val158Met Val-Val genotype, who had been exposed to childhood trauma borderline significantly more likely to report psychotic experiences than those with Val-Met or Met-Met genotypes. There was no similar interaction by BDNF-Val66Met genotype.ConclusionThe COMT-Val158Met Val-Val genotype may be a genetic moderator of risk for psychotic experiences in individuals exposed to childhood traumatic experiences.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles

Elevated risk of hypertension induced by arsenic exposure in Taiwanese rural residents: possible effects of manganese superoxide dismutase (MnSOD) and 8-oxoguanine DNA glycosylase (OGG1) genes

Heavy metals, including arsenic and lead, may lead to cellular oxidative damage that is linked to hypertension. Manganese superoxide dismutase (MnSOD) is a scavenger of reactive oxygen species, and 8-oxoguanine DNA glycosylase (OGG1) is the major glycosylase that repairs DNA lesions. Interestingly, whether there is an elevated risk of hypertension with arsenic or lead exposure in individuals with genetic variations in MnSOD or OGG1 has not yet been investigated. Questionnaires were administered to 240 Taiwanese rural residents. Blood pressure and biochemical indicators were assessed in each subject. Urinary levels of arsenic and lead were measured with atomic absorption spectrometry; and MnSOD and OGG1 genotypes were identified via polymerase chain reaction. There was a dose-response relationship between urinary arsenic levels and risk of hypertension (P = 0.021, test for trend). However, there was no association between urinary lead levels and hypertension risk. Individuals with high urinary arsenic levels and the MnSOD Val-Ala/Ala-Ala genotypes had a greater risk of hypertension than those with low urinary arsenic levels and the MnSOD Val-Val genotype (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 1.7-10.3). Subjects with a high urinary arsenic level and the OGG1 Cys-Cys genotype also had a greater risk of hypertension than those with a low urinary arsenic level and the OGG1 Ser-Ser/Ser-Cys genotypes (OR = 3.4, 95% CI = 1.1-10.7). Thus, both MnSOD and OGG1 genotypes may be prone to an increased risk of hypertension associated with arsenic exposure.

Molecular Genetic Studies of Early-Onset Schizophrenia

Early-onset schizophrenia is characterized by a more severe course and unfavorable outcome. We report here our studies of a number of genes which may be involved in the pathogenesis of this type of schizophrenia: the genes for brain-derived neurotrophic factor (the Val66Met polymorphism), the serotonin transporter (5-HTTLPR), the type 2A serotonin receptor (T102C), and the D2 dopamine receptor (Taq1A). The study group consisted of 65 patients (age at onset was less than 15 years). The control group consisted of 111 healthy subjects aged 6–26 years (mean age 18.9 ± 6.7 years). Among the genes studied, the only one found to be associated with the disease was the Val66Met polymorphism. The frequency of the ValVal genotype was higher in the group of patients with schizophrenia (p = 0.03; odds ratio 2.1, confidence interval 1.1–4.0). These results support our previous observation of a relationship between this genotype and the continuous form of schizophrenia identified in studies of an independent group of patients without evaluation of age at onset, and lead to the conclusion that the ValVal genotype can be regarded as a marker for the more severe form of schizophrenia.

Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia

A single nucleotide polymorphism (val66met) in the brain derived neurotrophic factor (BDNF) gene has been shown to be a risk factor for a number of psychiatric disorders, including schizophrenia. This polymorphism has also been shown to have effects on prefrontal brain morphology and function. This study aims to clarify the effects of the val66met polymorphism on prefrontal brain function in a population at high genetic risk for schizophrenia. The Edinburgh High Risk Study has followed young individuals who had one first- or second-degree relative with schizophrenia and a minimum of one further genetic relative with the illness. A sample of 62 individuals provided both genetic and functional imaging data using the Hayling sentence completion task. Individuals with the BDNF ValVal (presumed risk) genotype (n = 41) showed relatively increased activation of the anterior cingulate cortex in relation to Met carrier individuals (n = 21) during sentence completion conditions versus baseline, against a background of similar levels of task performance. It appeared from further investigation that this relatively increased activation was attributable to a failure to disengage or suppress activation in the high risk ValVal group during the task condition, suggesting that BDNF may contribute to the abnormal default network reported in schizophrenia. These results suggest that this gene affects prefrontal brain function in those at high genetic risk for the disorder, unconfounded by medication effects. BDNF may therefore be one of the heritable factors involved in the development of abnormal prefrontal function in schizophrenia. © 2010 Wiley-Liss, Inc.

Significance of Serum Tumor Necrosis Factor-Alpha and its Combination with Her-2 Codon 655 Polymorphism in the Diagnosis and Prognosis of Breast Cancer

The present study was conducted to clarify the diagnostic and prognostic significance of TNF-alpha and its combination with HER-2 Ile655Val SNP in breast cancer. In this case-control study, 56 consecutive patients with primary breast cancer were prospectively evaluated. The control group consisted of 45 healthy women. Serum concentrations of TNF-alpha were measured by quantitative sandwich enzyme immunoassay (ELISA). HER-2 SNP was genotyped using the PCR-RFLP method. Serum TNF-alpha was significantly increased in patients compared to controls. ROC analysis indicated a cutoff point of 11.00 pg/mL to classify breast cancer patients (sensitivity, 86%; specificity, 71%). Elevated TNF-alpha levels were associated with larger, poorly differentiated, invasive and advanced-stage tumors, and >3 positive lymph nodes. Regarding HER-2 SNP, patients with Ile-Val and Val-Val genotypes had significant TNF-alpha elevation compared with homozygous Ile-Ile patients. In multivariate analysis, high serum TNF-alpha remained an independent prognostic factor of worse overall survival; its combination with Val-Val genotype predicted a worse prognosis than high TNF-alpha alone. Serum TNF-a could be used clinically as a useful tumor marker for diagnosis, disease extent and outcome of breast cancer. The negative impact on survival seems to be enhanced through the interaction with HER-2 Ile655Val SNP.

The catechol-O-methyl-transferase gene in tardive dyskinesia

Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: ORAA=2.22, 95% CI:1.23–4.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n=6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (ORValVal=1.63, 95% CI: 1.09–2.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.

Genetic Polymorphism of Manganese Superoxide Dismutase is Associated with Childhood Asthma

Objective. Cellular defenses against allergens and reactive oxygen species (ROS) exposure are critical in the pathogenesis of asthma. CD14 is a receptor for various bacterial products, such as lipopolysaccharides (LPS), and is also a mediator of inflammatory processes. Manganese superoxide dismutase (MnSOD) is an ROS scavenger, and myeloperoxidase (MPO) can convert hydrogen peroxide into hypochlorous acid; thus, they are considered to be involved in inflammatory defense. The authors conducted a case-control study to evaluate the susceptibility to childhood asthma based on CD14, MnSOD, and MPO genes. Methods. The CD14 −260, MnSOD −9, and MPO −463 genotypes were identified by polymerase chain reactions for 116 asthmatic children and 232 healthy controls. Questionnaires were administered to obtain demographic characteristics. Allergen testing used common Taiwanese aeroallergens. Results. A higher level of parental education, family history of asthma, incense burning at home, allergen-test positive, and the MnSOD Val-Ala/Ala-Ala genotypes (matched relative risk = 2.0; 95% confidence interval = 1.0–4.2) were significantly associated with childhood asthma. Interactions between CD14, MnSOD, MPO genotypes and allergy status were significantly associated with asthma risk in these children (all p <.001). Furthermore, atopic cases with MnSOD Val-Ala/Ala-Ala (log eosinophil 2.66/mm3, log total serum immunoglobulin E [IgE] 2.48 IU/ml) or Val-Val (log eosinophil 2.61/mm3, log total serum IgE 2.63 IU/ml) genotypes had elevated eosinophil counts and total serum IgE levels as compared to nonatopic cases with MnSOD Val-Val genotype (log eosinophil 2.27/mm3, log total serum IgE 1.83 IU/ml). Conclusions. Susceptible MnSOD genotypes might modulate the development of asthma in Taiwanese children.