Meta-analysis of the association of the SLC6A3 3′-UTR VNTR with cognition

The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3′ untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k = 10 samples, N = 1193 subjects), inhibition (k = 8 samples, N = 829 subjects), executive functions including inhibition (k = 10 samples, N = 984 subjects), attention (k = 6 samples, N = 742 subjects) and declarative long-term memory (k = 5 samples, N = 251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p > 0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults.     

Depression and the role of genes involved in dopamine metabolism and signalling

Major depressive disorder (MDD) is a common psychiatric disorder and leading cause of disability worldwide. It is associated with increased mortality, especially from suicide. Heritability of MDD is estimated around 40%, suggesting that genotyping is a promising field for research into the development of MDD. According to the dopamine theory of affective disorders, a deficiency in dopaminergic neurotransmission may play a role in the major symptoms of MDD. Specific polymorphisms in genes that affect dopamine transmission could increase susceptibility to MDD. To determine the extent to which these genes influence vulnerability to MDD, we discuss genes for crucial steps in dopamine neurotransmission: synthesis, signalling and inactivation. The val158met polymorphism of the COMT gene exemplifies the lack of consensus in the literature: although it is one of the most reported polymorphisms that relates to MDD vulnerability, its role is not corroborated by meta-analysis. Gene–gene interactions and gene–environment interactions provide more explanatory potential than single gene associations. Two notable exceptions are the DRD4 and DAT gene: both have variable tandem repeat polymorphisms which may have a “single gene” influence on susceptibility to MDD.     

Primer-independent initiation of RNA synthesis by SeMV recombinant RNA-dependent RNA polymerase

Sesbania mosaic virus (SeMV), a single-strand positive-sense RNA plant virus, belongs to the genus Sobemoviruses. Mechanism of replication in Sobemoviruses is poorly understood. In the present study, SeMV RNA-dependent RNA polymerase (RdRp) was overexpressed and purified as a thioredoxin-tagged protein. The recombinant SeMV RdRp could synthesize RNA from genomic or subgenomic RNA templates, even in the absence of the protein primer, VPg. Analysis of the product indicated that it was double-stranded and that the mode of initiation was de novo. Mutational analysis of the 3′ UTR of subgenomic RNA revealed that a stem-loop structure at the 3′ end was important. Further, analysis of this stem-loop showed that the SeMV RdRp was capable of recognizing stem-loop structures of various lengths and forms. These results demonstrate that the SeMV RdRp is capable of primer-independent RNA synthesis in vitro.     

Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement— A systematic review and meta analysis

Introduction

Warfarin is the most widely used oral anticoagulant. It has been suggested that anticoagulation effect of warfarin is significantly associated with the polymorphism of certain genes, including Cytochrome P450 complex subunit 2C9 (CYP2C9), Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1), Gamma-Glutamyl Carboxylase (GGCX) and Apolipoprotein E (APOE) etc. The purpose of the present study was to conduct a systemic review and meta-analysis to investigate the relationship between mean daily warfarin dose (MDWD) and VKORC1 single nucleotide polymorphisms (SNPs).

Materials and Methods

Inclusion and exclusion criteria were made, and the studies between 2004 and present were searched. References were examined, and experts were consulted for additional information. Data were extracted. Revman 4.2.10 software was applied to analyze the relationship between MDWD and VKORC1 SNPs.

Results

Total 19 studies were included in the meta-analysis. The frequencies of 1173TT and − 1639 AA in Asian patients were higher than those in Caucasian and African populations. Patients with VKORC1 1173 CT and 1173 CC required 44% [95% Confidence Interval (CI); 32%, 56%] and 97% [73%, 122%] higher MDWD than 1173 TT carriers, − 1639GA and − 1639GG carriers required 52% [41%, 64%] and 102% [85%, 118%] higher MDWD than − 1639AA carriers, 3730GA and 3730AA carriers required 27% [3%, 58%] and 52% [3%, 109%] higher MDWD than 3730GG carriers. In addition, 1173C, − 1639 G and 3730 A carriers required 63% [44%, 82%], 61% [49%, 73%] and 32% [4%, 59%] higher MDWD than 1173TT, − 1639 AA and 3730GG, respectively. Sensitive analyses demonstrated that the impacts of gene polymorphism on warfarin dosage requirement were significantly different between Caucasian and Asian population, and the results of meta-analyses were stable and reliable.

Conclusion

This is the first meta-analysis about the impact of VKORC1 gene polymorphism on warfarin dose requirement. Our studies showed that gene polymorphisms of VKORC1 significantly associated with the variation of interindividual warfarin dose requirement variation, and the effects are different in ethnicities.     

Construction and efficacy of a new live chimeric C-strain vaccine with DIVA characteristics against classical swine fever

To develop the new classical swine fever (CSF) vaccine candidate with differentiating infected vaccinated animals (DIVA) characteristics, a chimeric CSF virus (CSFV) was constructed based on an infectious cDNA clone of the CSF vaccine C-strain. The 5’- and 3’-untranslated regions (UTRs) and partial E2 region (residues 690-860) of the C-strain were substituted with the corresponding regions of bovine viral diarrhoea virus (BVDV) to construct the chimeric cDNA clone pC/bUTRs-tE2. The chimeric virus rC/bUTRs-tE2 was generated by several passages of pC/bUTRs-tE2-transfected PK15 cells. Stable growth and genetic properties of rC/bUTRs-tE2 were obtained after 30 serial passages. Compared to parental rC/bUTRs-tE2 (1^st passage), two residue mutations (M834K and M979K) located in E2 in rC/bUTRs-tE2 P30 were observed. Compared to the C-strain, rC/bUTRs-tE2 exhibited unchanged cell tropism and decreased plaque-forming ability. Substituting the C-strain UTRs with the BVDV UTRs resulted in significantly increased viral replication in PK15 cells. Compared to CSFV E^rns-positive and BVDV tE2-negative antibody responses induced by the CSF vaccine C-strain, immunization of rabbits and piglets with rC/bUTRs-tE2 resulted in serological profiles of CSFV E^rns- and BVDV tE2-positive antibodies, which are used to serologically discriminate pigs that are clinically infected and vaccinated. Vaccination of piglets with rC/bUTRs-tE2 conferred complete protection against lethal CSFV challenge. Our results suggest that rC/bUTRs-tE2 is a promising new CSF marker vaccine candidate.