Search

Introduction: The 15q25 region has been associated with lung-cancer risk and might also be associated with the prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 in the survival of patients with early-stage non–small-cell lung cancer (NSCLC). Methods: Five hundred and eighty-three consecutive patients with surgically resected NSCLC were enrolled. The rs6495309C > T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival (OS) and disease-free survival (DFS) was analyzed. Results: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for OS=0.56, 95% confidence interval=0.41–0.75, p = 0.0001; and adjusted hazard ratio for DFS=0.61, 95% confidence interval=0.48–0.79, p = 0.0001). An association between the rs6495309C > T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous-cell carcinomas and adenocarcinomas. Conclusion: The CHRNA3 rs6495309C > T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C > T polymorphism can help identify patients at high risk of a poor disease outcome.

The functional polymorphism Ser326Cys (rs1052133) in the human 8-oxoguanine DNA glycosylase (hOGG1) gene has been implicated in bladder cancer risk. However, reports of this association between the Ser326Cys polymorphism and bladder cancer risk are conflicting. In order to help clarify this relationship, we made a meta-analysis of seven case-control studies, summing 2521 cases and 2408 controls. We used odds ratios (ORs) with 95% confidence intervals (95%CIs) to assess the strength of the association. Overall, no significant association between the hOGG1 Ser326Cys polymorphism and bladder cancer risk was found for Cys/Cys vs Ser/Ser (OR = 1.10, 95%CI = 0.74-1.65), Ser/Cys vs Ser/Ser (OR = 1.07, 95%CI = 0.81-1.42), Cys/Cys + Ser/Cys vs Ser/Ser (OR = 1.08, 95%CI = 0.87-1.33), and Cys/Cys vs Ser/Cys + Ser/Ser (OR = 1.04, 95%CI = 0.65-1.69). Even when stratified by ethnicity, no significant association was observed. We concluded that the hOGG1 Ser326Cys polymorphism does not contribute to susceptibility to bladder cancer.

Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT. Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS. Methods: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra-or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures. Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P = 0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P = 0.02) and MMP-2 CT genotype (hazard ratio 3.5, P = 0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs. Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT.

INTRODUÇÃO: Muitos estudos têm investigado a associação do polimorfismo VNTR (número variável de repetições em série) localizado na região promotora do gene da enzima monoamina oxidase A (MAOA) com alterações no comportamento humano e em diversos transtornos psiquiátricos. OBJETIVO: O objetivo do presente trabalho foi revisar a literatura sobre a participação desse polimorfismo funcional na modulação do comportamento humano para o desenvolvimento dos transtornos psiquiátricos. MÉTODO: A pesquisa foi realizada na literatura em inglês, de janeiro de 1998 a junho de 2009, disponível no Medline, Embase, Web of Science e na base de dados PsycInfo, utilizando os seguintes termos: "MAOA e comportamento humano" e "MAOA e psiquiatria". RESULTADOS: Foram encontrados 3.873 estudos. Desses, 109 foram selecionados e incluídos na revisão. Encontrou-se associação de alelos de baixa atividade do VNTR com transtorno de personalidade antissocial, transtorno de conduta, transtorno de déficit de atenção e hiperatividade, jogo patológico e dependência de substâncias. Alelos da alta atividade da MAOA foram associados a depressão, ansiedade, neuroticismo e anorexia nervosa. Não se encontrou associação entre polimorfismos da MAOA e esquizofrenia e transtorno bipolar. CONCLUSÃO: Os principais achados dão suporte ao papel do polimorfismo VNTR da região promotora do gene da MAOA em alguns transtornos psiquiátricos, apesar das divergências encontradas devidas às dificuldades metodológicas de estudos em genética. De modo geral, os estudos associam os alelos de baixa atividade da MAOA com comportamentos impulsivos e agressivos ("comportamentos hiperativos"), enquanto os alelos de alta atividade do gene são mais associados a "comportamentos hipoativos". INTRODUCTION: A functional variable number of tandem repeats (VNTR) polymorphism of the promoter region of the monoamine oxidase A (MAOA) gene has been described and many studies have investigated the association of this polymorphism with human behaviors, as well as with several psychiatric disorders. OBJECTIVE: This study aimed to review the literature on the role of the VNTR functional polymorphism of the promoter region of the MAOA gene on the modulation of human behavior for the development of psychiatric disorders. METHOD: Searches on the Medline, Embase, Web of Science and PsycInfo databases were performed including works from January 1998 to June 2009. The words used were: "MAOA and human behavior" and "MAOA and psychiatry". RESULTS: Several studies were found (N = 3,873). After the selection process, 109 papers were included in the review. There was found an association of MAOA low activity alleles with antisocial personality disorder, conduct disorder, ADHD, pathological gambling, and substance abuse. High activity alleles were associated with neuroticism, anorexia nervosa and depression and anxiety disorders. There was no association between the MAOA polymorphisms and bipolar disorder and schizophrenia. DISCUSSION: The main findings, summarized in this paper, support a role of MAOA VNTR polymorphism in some psychiatric disorders although some divergences were found due to methodological difficulties in genetic studies. In general, the studies associated the low activity alleles with impulsivity and aggressive behavior ("hyperactive behaviors"), and the high activity alleles of the gene with "hypoactive behaviors", such as depression and anxiety, which demonstrates a modulation of the MAOA enzyme in "hyperactive" and "hypoactive" disorders.

Background/Aims: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We therefore studied common genetic variation in candidate genes for height in extremely tall Dutch. Methods: We included 116 constitutionally tall cases with height >2 SD and 103 controls with normally distributed height Results: The HMGA2 gene SNP was significantly associated with tall stature. Using a logistic regression model, we calculated that carrying the HMGA2 (rs1042725) C allele significantly increased the odds of being tall (OR = 1.53, 95% CI 1.02–2.28; p = 0.03). In addition, controls with one or two copies of the C allele were significantly taller than controls carrying the TT genotype [TC: mean (SD) +0.61 (0.21) SDS; p = 0.004, and CC: +0.77 (0.25) SDS; p = 0.003]. Conclusion: Our study shows that a common polymorphism in the HMGA2 gene is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution.

Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction.Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed.We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum.We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

Numerous genes modulate dopamine and consequently prefrontal cortical function. Some of these genes – notably catechol-O-methyltransferase – have been shown to impact a variety of core cognitive processes that are dependent upon the prefrontal cortex. This demonstration that a single functional polymorphism can contribute so dramatically to individual differences heralds a new era for neuropsychiatry. Although enormous detail remains to be discovered about these various genes that regulate neurotransmitters, how they interact and how they affect brain systems, there is much excitement and promise regarding new neuropsychopharmacological possibilities. However, this new research program is magnitudes more complex than any enterprise embarked on hitherto and requires the development, validation and deployment of novel behavioural and neurophysiological phenotypes in order to unravel the pathologies within neural functional systems. This research foundation is essential if these genetic breakthroughs are to ...

There is increasing evidence that people with autism spectrum disorders (ASDs) have abnormalities in the serotonergic system. For example, a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR long/short polymorphism) has been reported to confer risk for ASDs, and to affect cortical grey matter volume in young children. However, the persistence of this association later in development is unknown. Hence, we investigated whether variation in the 5HTTLPR long/short polymorphism modulates brain anatomy in older people with ASD. We related 5HTTLPR long/short polymorphism in 43 adolescents and adults with ASD to brain anatomy using structural magnetic resonance imaging and voxel-based morphometry. There were no significant associations between brain anatomy and genotype. When considered alongside evidence of a relationship between 5HTTLPR genotype and brain volume amongst children with autism, our findings raise the possibility that the relationship between 5HTTLPR polymorphism and brain anatomy in ASDs anatomy may differ as a function of age and/or ASD subdiagnosis.

Objectives The stress response is related to both physiological and psychological factors and is strongly marked by a neuroendocrine component. Genetic factors are believed to underlie individual differences in the degree of stress resilience and thereby contribute in determining susceptibility to stress-related pathologies like major depressive disorder (MDD). Little, however, is known about the genetic influence on the endocrine and behavioural stress response in relation to MDD.Methods Here, we sought to examine the effects of the catechol-o-methyltransferase polymorphism on psychological stress in three groups of individuals with different degrees of susceptibility to MDD (i.e. healthy controls, healthy high risk probands to MDD and those suffering from MDD). This genotype is involved in the metabolism of catecholamines (dopamine, norepinephrine and epinephrine).Results Allelic variations of this polymorphism were found to influence the degree of subjective stress experience and plasma epinephrine stress response. Interactions between catechol-o-methyltransferase polymorphism and diagnostic group in measures of plasma epinephrine, cortisol and subjective responses to psychological stress were also found, with the influence of the different alleles on these measures differing between healthy controls relative to MDD patients and high risk probands. Conclusion These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.

Summary We sequenced the lymphotoxin alpha (LTA) promoter and identified LTA10G>A in strong linkage with LTA252G>A and LTA723C>A. Stimulated cells from LTA723AA: LTA252GG:LTA10AA individuals had significantly higher LTA mRNA levels than LTA723CC:LTA252AA:LTA10GG and LTA723AA:LTA252AG:LTA10GA individuals, suggesting that this diplotype may contain a functional polymorphism explaining the observed disease associations with LTA252G>A.

Five new species of stenolaematous bryozoans are described from the Middle Callovian of Moscow City (Krasnopresnenskii Region) and the Moscow Region (Gzhel’ Railroad Station and the quarry between the small towns of Rechitsy and Troshkovo): Entalophora alexeevi sp. nov., Cellulipora retshitsiensis sp. nov., Diplosolen pravus sp. nov., Siphodictyum primarium sp. nov., and Ceata kamushkiensis sp. nov. The last four species belong to the genera that have never been recorded from deposits older than the Lower Cretaceous. The presence of different types of heterozooecia in these bryozoans shows that the functional polymorphism of zooids developed considerably in the class Stenolaemata as early as the Middle Jurassic.

(a) Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Narino. Bogota, Colombia. (b) Faculty of Science, Universidad Antonio Narino. Bogota, Colombia. (c) INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015, Paris, France. (d) Corresponding Author: Prof. Dr. Diego A. Forero, MD, PhD. Laboratory of NeuroPsychiatric Genetics, School of Medicine, Universidad Antonio Narino. Bogota, Colombia. Email: diego.forero@uan.edu.co.

The aim of this study was to investigate the association between a potentially functional polymorphism (rs153109, -964A G) in the promoter region of interleukin-27 (IL-27) gene and the risk of papillary thyroid cancer (PTC) in a Chinese population. Genotype of IL-27 -964A G polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Serum IL-27p28 levels were determined using enzyme-linked immunosorbent assay (ELISA). No significant difference was noticed in IL-27 -964A G polymorphism between PTC patients and healthy controls in the overall analysis. However, analysis of clinical features showed that PTC patients carrying the GG genotype or G allele had significantly decreased risks for developing lymph node metastasis compared with those carrying the AA genotype or A allele (GG vs. AA: OR = 0.38, 95 % CI, 0.20-0.72; G vs. A: OR = 0.63, 95 % CI, 0.44-0.86). Furthermore, ELISA results demonstrated that serum IL-27p28 levels were significantly decreased in PTC patients compared with those in controls (P 0.05). Serum IL-27p28 levels in healthy controls with the GG genotype were significantly high compared with those carrying AA genotype or the AG genotype (P 0.05). In conclusion, our results suggest that IL-27 -964A G polymorphism may be associated with the decreased risk for lymph node metastasis of PTC.

Raising intact male pigs would have a significant economic impact on the pork industry. However, the presence of skatole (a major cause of boar taint) in meat from intact male pigs could be highly objectionable to consumer. The excessive accumulation of skatole in fat is a major cause of boar taint, and is associated with defective expression of cytochrome P4502E1 (CYP2E1). In pigs, it has been found that CYP2E1 is negatively correlated with accumulation of skatole. The searching for polymorphism of CYP2E1 and the relevant functional analysis would help develop a genetic marker for the selection of pigs with low skatole levels in fat. The aim of this study was to measure the expression pattern of CYP2E1 mRNA in various tissues of the pig, to identify genetic polymorphisms, and to evaluate the functional relevance of polymorphic sites with respect to the skatole level in fat. We show herein that a substitution of G --A at base 1423 of the CYP2E1 gene in the liver causes a significant decrease in the expressed CYP2E1 level. Our data suggest that the G --A substitute might be at least partially responsible for a high level of skatole in pigs. We believe that this is an important step toward the selection of genetic markers for boar taint by lowering fat levels of skatole in fat.

Objectives Initial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery. We investigated whether functional polymorphisms in the apolipoprotein E ( APOE), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-A (TNF-A), interleukin-1A (IL-1A), interleukin-1B (IL-1B), and interleukin-6 (IL-6) genes are related with outcome after aneurysmal SAH. Methods Genotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference. Results Patients carrying any IGF-1 non-wild type allele had a lower risk of a poor outcome ( OR 0.4, 95% CI 0.2 - 1.0), while carriers of the TNF-A non-wild type allele had a higher risk ( OR 2.3, 95% CI 1.0 - 5.4). We could not demonstrate an association with outcome for APOE ( APOE epsilon 4 OR 0.4, 95% CI 0.1 - 1.2; APOE epsilon 2 OR 0.7, 95% CI 0.2 - 2.4), IL-1A ( OR 1.8, 95% CI 0.8 - 4.0), IL-1B ( OR 0.7, 95% CI 0.3 - 1.5) and IL-6 ( OR 0.7, 95% CI 0.3 - 1.8) polymorphisms. Conclusions Variation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF-1 wild type allele or carriers of the TNF-A non-wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.

the cell surface. Mhc-I polymorphism is considered critical for eliciting immune responses to a diversity of antigens, and thus, for the health and conservation of a species. Based on restriction fragment length polymorphism it was concluded that whales generally have low Mhc-I polymorphism. This was attributed to the weak pathogenic pressure in aquatic habitats. Since gray whales’ habits might favor their encounter with diverse pathogens, resulting in selection pressures for Mhc variability, we searched for functional polymorphism of gray whale’s

The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus.A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes.These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Transporter-assisted uptake of serotonin (5-HT) and dopamine (DA) has been accounted for activities in human behavior or mental status, because they are the sites of action of widely used antidepressant and psychoactive drugs. Both the human serotonin transporter (5-HTT) and human dopamine transporter (DAT1) genes are good candidates for etiological involvement in various psychiatric conditions. The serotonin transporter gene has two types of functional polymorphisms. One is serotonin transporter linked polymorphic region (5-HTTLPR) consisting of length variation of the repetitive sequence containing 20～23-bp-long repeat elements in the 5’-upstream region of the gene. Another polymorphism is that serotonin transporter variable number of tandem repeats(5-HTTVNTR) in its second intron. Both polymorphisms affect the transcription ratio of5-HTT gene and may modify neuronal transmission by changing its protein expression. On the other hand, DAT1 gene has a variable number of tandem repeats type polymorphism(DAT1VNTR) in the 3’-untranslated region of the mRNA, which was also reported to change its gene expression. So polymorphic variations of transporters would change the behavioral and neuropathological tendency. Here, the feature of those two transporters and their relations to psychiatric disorders are described.

Notch signaling pathway has been implicated in the prognosis of non-small cell lung cancer (NSCLC). This study was conducted to determine the association between single nucleotide polymorphisms (SNPs) in the Notch pathway genes and survival outcomes of surgically resected NSCLC. Among the 64 SNPs analyzed in the discovery set, 8 SNPs were significantly associated with overall survival (OS) or disease-free survival (DFS). Among the 8 SNPs, the association was consistently observed only for DTX1 rs1732786A>G in the validation sets. In combined analysis, the rs1732786A>G was significantly associated with better OS and DFS (adjusted HR aHR for OS, 0.81; 95% CI, 0.68-0.95; P = 0.01; aHR for DFS, 0.82; 95% CI, 0.72-0.94; P = 0.003; under codominant model). To verify the functional relevance of the rs1732786A>G in DTX1 promoter region, we conducted dual-luciferase reporter assays. The G allele showed significantly higher luciferase activity than the A allele (P < 0.005) in lung cancer cell lines. The relative expression level of DTX1 mRNA was significantly lower in tumor tissues than in nonmalignant lung tissue (P = 0.003). Moreover, the level of DTX1 mRNA expression in tumor tissue increased as the number of G allele increased (P trend = 0.02). Higher levels of DTX1 mRNA expression were significantly correlated with a better OS and DFS (P = 0.03 and P = 0.002). Our results suggest that the DTX1 rs1732786 A>G polymorphism may affect DTX1 expression and may be a useful marker for predicting the prognosis of patients with early stage NSCLC. Citation Format: Shin Yup Lee, Janghyuck Lee, Kyung Min Shin, Ji Woong Son, Jae Yong Park. A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5727. doi:10.1158/1538-7445.AM2017-5727

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158)Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158)Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158)Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) has been associated with a large number of human diseases and endophenotypes. The aim of this study was to develop a novel cost-effective assay to genotype this polymorphism. The novel assay was based on the combination of allele-specific PCR and high-resolution melting in a qPCR platform. Melt-curve analysis allowed a clear differentiation of the three genotypes. This novel assay could be implemented in the study of a large number of diseases and endophenotypes related to COMT dysfunction and could be extended for the analysis of other functional polymorphisms.

Catalase (CAT) activity is likely to be affected by functional polymorphism of C-262 T (rs1001179) in the CAT gene (OMIM: 115500). It is hypothesized that individuals with the lower expressing forms of the CAT polymorphism may be more susceptible to breast cancer. Therefore, the present case-control study and meta-analysis were carried out. The present case-control study consisted of 407 females with breast cancer and a total of 395 healthy female from population matched with patients according to age. Genotypic analysis for the CAT C-262 T polymorphism was determined by PCR. We identified 7 eligible studies, including 10,471 subjects (4,959 patients, and 5,512 healthy controls) in relation to the CAT C-262 T polymorphism and breast cancer risk. Based on the present case-control study, the CT (OR = 0.90, 95% CI: 0.66-1.22, P = 0.484) and TT (OR = 0.68, 95% CI: 0.35-1.30, P = 0.245) genotypes were not associated with breast cancer risk compared to the CC genotype. For meta-analysis including all studies, there was significant heterogeneity between studies. The overall ORs of the breast cancer risk were not associated with the CT (Q-statistic = 14.90, df = 6, P0.05; OR = 1.01, 95% CI: 0.92-1.09, P = 0.862) and TT (Q-statistic = 2.57, df = 6, P0.05; OR = 1.03, 95% CI: 0.85-1.24, P = 0.770) genotypes. There was no association between C-262 T polymorphism of the CAT and risk of breast cancer.

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling.AimTo evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT.MethodsMatrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up.ResultsTwenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P=0.030) and reached 100% at 11.3years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3years for TT genotype. Patients without IBD showed a similar trend in 20years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC.ConclusionMatrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Although the monoamine oxidase-A (MAOA) gene has been linked to spatial learning and memory in animal models, convincing evidence in humans is lacking. Performance on an ecologically-valid, virtual computer-based equivalent of the Morris Water Maze task was compared between 28 healthy males with the low MAOA transcriptional activity and 41 healthy age- and IQ-matched males with the high MAOA transcriptional activity. The results revealed consistently better performance (reduced heading error, shorter path length, and reduced failed trials) for the high MAOA activity individuals relative to the low activity individuals. By comparison, groups did not differ on pre-task variables or strategic measures such as first-move latency. The results provide novel evidence of MAOA gene involvement in human spatial navigation using a virtual analogue of the Morris Water Maze task.

Transforming growth factor-β1 (TGF-β1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). But the involved genetic mechanism is unknown. Herein, the TGF-β1 C-509T polymorphism (rs1800469) was genotyped in a case-control study of 840 patients and 845 controls in Chinese population to explore the association between the polymorphism and susceptibility and prognosis of lone AF. As a result, the CT and/or TT genotypes had an increased lone AF risk [adjusted odds ratio (OR) = 1.50 for CT, OR = 3.72 for TT, and OR = 2.15 for CT/TT], compared with the TGF-β1CC genotype. Moreover, patients carrying CT/TT genotypes showed a higher possibility of AF recurrence after catheter ablation, compared with patients carrying CC genotype. In a genotype-phenotype correlation analysis using 24 normal left atrial appendage samples, increasing gradients of atrial TGF-β1 expression levels positively correlated with atrial collagen volume fraction were identified in samples with CC, CT and TT genotypes. The in vitro luciferase assays also showed a higher luciferase activity of the -509T allele than that of the -509C allele. In conclusion, the TGF-β1 C-509T polymorphism is involved in the etiology of lone AF and thus may be a marker for genetic susceptibility to lone AF and predicting prognosis after catheter ablation in Chinese populations. Therefore, we provide new information about treatment strategies and our understanding of TGF-β1 in AF. © 2014 Cao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8–12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene–Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

SummaryMolecular genetics and biochemical studies were performed in homozygotes for the R2 allele (4070G) in the factor V gene, most of them affected by coronary artery disease. Novel polymorphisms (G642T, 156Ser; T1328C, 385Met/Thr), among which a functional candidate (A6755G, 2194Asp/Gly) located in the C2 domain of FV, were identified in the R2 gene. In chromatographic studies R2 FV appeared qualitatively identical to normal FV. However, a relative increase of the more thrombogenic and more glycosylated FV isoform (FV1) was observed in plasma of 2194Gly homozygotes (mean FV1/FV2 ratio 0.71, 95% CI 0.66-0.77) as compared to R2-free controls (0.37, 95% CI 0.34-0.40). We conclude that carriership of the R2 FV gene is associated with an imbalance between the two functionally different FV isoforms, and propose that genetically determined differential glycosylation of FV could represent a novel mechanism of thrombotic disease.

Catechol-O-methyltransferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. There is a functional polymorphism of the COMT gene, Val108Met in the soluble form of the enzyme (Vall58Met in the membrane-bound form). Involvement of the dopaminergic systems in alcoholism has been suggested in mice and humans. We examined associations between this polymorphism and alcoholism in 175 Japanese alcoholics and 354 age- and gender-matched Japanese controls. No significant difference in the allelic distributions in alcoholics and controls and no significant associations between antisocial behaviors in alcoholics and this polymorphism were observed. Therefore, the COMT gene is not likely to play a significant role in alcoholism. © 1999 Lippincott Williams & Wilkins.

A functional polymorphism in the NQO1 gene, featuring a 609C>T substitution,leading to proline to serine amino-acid and enzyme activity changes, has been implicated in cancer risk. However, individually published investigations showed inconclusive results, especially for leukemia. In this study, we therefore performed a meta- analysis of 21 publications with a total of 3,634 cases and 4,827controls, mainly for leukemia. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of leukemia and performed subgroup analyses by ethnicity and leukemia type. We found that the variant TT homozygous genotype o was associated with a modestly increased risk of leukemia (TT versus CT/CC: OR = 1.23, 95%CI = 1.00 - 1.51, heterogeneity = 0.76; I 2 = 0%). Following further stratified analyses, increased risk was only observed in subgroups of Caucasians. This meta-analysis suggests that the NQO1 609T allele is a high-penetrance risk factor for leukemia in Caucasians. The effect on leukemia may be modified by ethnicity and leukemia type, and the small sample sizes of the subgroup analyses suggest that further larger studies are needed.

The potentially functional polymorphism Arg72Pro in p53 gene has been implicated in glioma risk, but published studies have mixed findings. The aim of current investigation was to identify whether p53 Arg72Pro polymorphism was significantly associated with the risk of glioma. By searching the databases of PubMed, EMBASE, and Web of Science, our meta-analysis included ten eligible studies consisting of 2,645 glioma cases and 3,920 control subjects. The association between p53 Arg72Pro polymorphism and glioma risk was assessed by summarizing the odds ratios (ORs) with the corresponding 95 % confidence intervals (CIs). We found that there was no overall risk of glioma in relation to any genetic model of p53 Arg72Pro polymorphism. Similar results were implicated in the analyses which are subgrouped by ethnicity and source of controls. This nonsignificant association remained stable when analyses were restrained to the studies consistent with HWE. In conclusion, our meta-analysis, based on the combined data from published papers before May 2013, reveals no evidence for significant association between p53 Arg72Pro polymorphism and glioma risk.

Accumulating evidence has identified that polymorphism residing in the microRNA (miRNA) binding site of target genes can affect the strength of miRNA binding and influence individual susceptibility to cancer. Recently, an insertion/deletion polymorphism (rs3783553 ttca/-) at miRNA-122 binding site in the interleukin-1A 3′ untranslated region has been demonstrated to be functional. We aimed to investigate the association between the rs3783553 polymorphism and the risk of gastric cancer (GC). We genotyped the rs3783553 polymorphism in 207 GC patients and 381 healthy controls by using a polymerase chain reaction method. We found that the ins/ins (ttca/ttca) genotype of the rs3783553 polymorphism was associated with a significantly decreased risk of GC (P = 0.02, odds ratio = 0.48, 95 % confidence interval 0.26–0.90). This finding suggests that the rs3783553 polymorphism may be a protective factor for the development of GC.

Factors that influence the variation in occurrence of antipsychotic-related parkinsonism in elderly have not been well elucidated. The aim of this study was to investigate whether previous identified and studied genetic polymorphisms at DRD2, ANKK1, DRD3, HTR2A, HTR2C, RGS2, COMT, and BDNF genes are associated with antipsychotic-related parkinsonism in elderly patients.This cross-sectional study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. The investigated predictors were polymorphisms in DRD2 (141CIns/Del and C957T), ANNK1 (TaqIA), DRD3 (Ser9Gly), HTR2A (-1438G>A and His452Tyr), HTR2C (Cys23Ser and -759C/T), RGS2 (+2971C>G), COMT (G158A), and BDNF (Val66Met). Frequencies of the -759 T allele of the HTR2C gene and the 158A allele of the COMT gene were significantly higher in patients without antipsychotic-induced parkinsonism (AIP) (nominal P = 0.03 and P = 0.02, respectively). -759 T allele carriership in females was associated with a lower risk of AIP (adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.85). The decrease in risk of AIP in carriers of the COMT 158A allele did not reach statistical significance. No significant associations were found between AIP and the remaining selected polymorphisms.Although validation is needed, this study suggests that carriership of the -759 T allele of the HTR2C gene in females may be protective against development of parkinsonism in elderly patients during treatment with haloperidol.

NAD(P)H:quinone oxidoreductase 1 (NQO1) rs1800566 (Pro187Ser) is a functional polymorphism which leads to a proline-to-serine amino acid substitution at codon 187 in the NQO1 protein and enzyme activity changes. NQO1 rs1800566 polymorphism was implicated to be associated with a risk of bladder cancer, but published studies showed inconclusive results. We performed a meta-analysis of nine publications with a total of 2,661 cases and 2,738 controls on the association between NQO1 rs1800566 polymorphism and risk of bladder cancer. Data were extracted from those included studies, and the pooled odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI) was calculated to assess the association. We found that there was no association between NQO1 rs1800566 polymorphism and risk of bladder cancer under all four genetic models (Ser vs. Pro, OR = 1.06, 95 % CI = 0.97–1.16, P = 0.21, I2 = 31 %; SerSer vs. ProPro, OR = 1.12, 95 % CI = 0.89–1.42, P = 0.33, I2 = 44 %; SerSer/ProSer vs. ProPro, OR = 1.08, 95 % CI = 0.96–1.21, P = 0.20, I2 = 27 %; SerSer vs. ProPro/ProSer, OR = 1.06, 95 % CI = 0.85–1.32, P = 0.59, I2 = 36 %). Meta-analysis of those eight studies from Europeans also showed that there was no association between NQO1 rs1800566 polymorphism and risk of bladder cancer under all four genetic models (Ser vs. Pro, OR = 1.02, 95 % CI = 0.93–1.13, P = 0.66, I2 = 20 %; SerSer vs. ProPro, OR = 0.99, 95 % CI = 0.75–1.30, P = 0.93, I2 = 38 %; SerSer/ProSer vs. ProPro, OR = 1.04, 95 % CI = 0.92–1.17, P = 0.55, I2 = 6 %; SerSer vs. ProPro/ProSer, OR = 0.98, 95 % CI = 0.75–1.28, P = 0.87, I2 = 39 %). This meta-analysis suggests that the NQO1 rs1800566 polymorphism is not associated with a risk of bladder cancer. Further studies with larger samples are needed, especially for studies in Asians and Africans.

Objective: The amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. Methods: The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the -1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. Results: There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. Conclusions: COMT Val108/158Met and DBH -1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. Significance: We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date. (C) 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland All rights reserved.