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Pediatric Neurology Aug 2023Wilson disease (WD) is a hereditary disorder of copper metabolism, caused by mutations in the ATP7B gene. There are more than 1000 pathogenic variants identified in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Wilson disease (WD) is a hereditary disorder of copper metabolism, caused by mutations in the ATP7B gene. There are more than 1000 pathogenic variants identified in ATP7B. R778L is the most common ATP7B mutation in China.
METHODS
To estimate whether R778L is associated with the onset age of WD and other clinical variables. Genotyping results of ATP7B gene were collected in our 22 patients with WD. We then conducted a systematic review and meta-analysis in databases, using the keywords Wilson disease and R778L mutation.
RESULTS
After the screening, a total of 23 studies were included, including 3007 patients with WD. Patients with R778L mutation presented at an earlier age (standardized mean difference [SMD] = -0.18 [95% confidence interval, -0.28 to 0.08], P = 0.0004) and had lower ceruloplasmin concentration (SMD = -0.21 [95% confidence interval, -0.40 to -0.02], P = 0.03) than the patients without the R778L mutation. However, sex (odds ratio [OR] = 1.07 [95% confidence interval, 0.89 to 1.29], P = 0.32) and first presentation were not associated with R778L mutation in WD (hepatic: OR = 1.37 [95% confidence interval, 0.87 to 2.16, P = 0.17; neurological: OR = 0.79 [95% confidence interval, 0.48 to 1.30, P = 0.35; mix: OR = 1.04 [95% confidence interval, 0.42 to 2.53, P = 0.87; asymptomatic/others: OR = 1.98 [95% confidence interval, 0.49 to 7.96, P = 0.34).
CONCLUSIONS
Our results indicated that the R778L mutation is associated with an earlier presentation and lower ceruloplasmin concentration in China.
Topics: Humans; Ceruloplasmin; China; Copper-Transporting ATPases; Hepatolenticular Degeneration; Mutation
PubMed: 37354629
DOI: 10.1016/j.pediatrneurol.2023.04.026 -
European Archives of... Oct 2023Allergic and non-allergic rhinorrhea in the forms of acute or chronic rhinosinusitis can mean a watery nasal discharge that is disabling. Primary objective was to review... (Review)
Review
PURPOSE
Allergic and non-allergic rhinorrhea in the forms of acute or chronic rhinosinusitis can mean a watery nasal discharge that is disabling. Primary objective was to review the evidence supporting the hypothesis that rhinorrhea is due to increased chloride secretion through the CFTR chloride channel.
METHODS
The structure of the evidence review followed the EQUATOR Reporting Guidelines. Databases searched from inception to February 2022 included Pubmed, EMBASE and the Cochrane library using keywords "Rhinorrhea", "chloride", "chloride channel", "CFTR" and "randomized controlled trial". Quality assessment was according to the Oxford Centre for Evidence-based Medicine.
RESULTS
49 articles were included. They included randomized controlled trials out of which subsets of data with the outcome of rhinorrhea on 6038 participants were analysed and in vitro and animal studies. The review revealed that drugs, which activate CFTR are associated with rhinorrhea. Viruses, which cause rhinorrhea like rhinovirus were found to activate CFTR. The chloride concentration in nasal fluid showed an increase in patients with viral upper respiratory tract infection. Increased hydrostatic tissue pressure, which is an activator of CFTR was observed in allergic upper airway inflammation. In this condition exhaled breath condensate chlorine concentration was found to be significantly increased. Drugs, which can reduce CFTR function including steroids, anti-histamines, sympathomimetic and anticholinergic drugs reduced rhinorrhea in randomized controlled trials.
CONCLUSIONS
A model of CFTR activation-mediated rhinorrhea explains the effectiveness of anticholinergic, sympathomimetic, anti-histamine and steroid drugs in reducing rhinorrhea and opens up avenues for further improvement of treatment by already known specific CFTR inhibitors.
Topics: Animals; Chloride Channels; Cystic Fibrosis Transmembrane Conductance Regulator; Chlorides; Sympathomimetics; Nasal Mucosa; Randomized Controlled Trials as Topic
PubMed: 37338585
DOI: 10.1007/s00405-023-08067-w -
Reviews in Medical Virology Sep 2023Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019... (Meta-Analysis)
Meta-Analysis Review
Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019 (COVID-19). However, identified SNPs are inconsistent across studies, and there is no compelling consensus that COVID-19 status is determined by genetic factors. Here, we conducted a systematic review and meta-analysis to determine the effect of genetic factors on COVID-19. A random-effect meta-analysis was performed to estimate pooled odds ratios (ORs) of SNP effects, and SNP-based heritability (SNP-h ) of COVID-19. The analyses were performed using meta-R package, and Stata version 17. The meta-analysis included a total of 96,817 COVID-19 cases and 6,414,916 negative controls. The meta-analysis showed that a cluster of highly correlated 9 SNPs (R > 0.9) at 3p21.31 gene locus covering LZTFL1 and SLC6A20 genes was significantly associated with COVID-19 severity, with a pooled OR of 1.8 [1.5-2.0]. Meanwhile, another 3 SNPs (rs2531743-G, rs2271616-T, and rs73062389-A) within the locus was associated with COVID-19 susceptibility, with pooled estimates of 0.95 [0.93-0.96], 1.23 [1.19-1.27] and 1.15 [1.13-1.17], respectively. Interestingly, SNPs associated with susceptibility and SNPs associated with severity in this locus are in linkage equilibrium (R < 0.026). The SNP-h on the liability scale for severity and susceptibility was estimated at 7.6% (Se = 3.2%) and 4.6% (Se = 1.5%), respectively. Genetic factors contribute to COVID-19 susceptibility and severity. In the 3p21.31 locus, SNPs that are associated with susceptibility are not in linkage disequilibrium (LD) with SNPs that are associated with severity, indicating within-locus heterogeneity.
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; COVID-19; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Membrane Transport Proteins
PubMed: 37303119
DOI: 10.1002/rmv.2466 -
Neuroscience and Biobehavioral Reviews Sep 2023Recent lifestyle changes have resulted in tremendous peer pressure and mental stress, and increased the incidences of chronic psychological disorders; like addiction,... (Review)
Review
Recent lifestyle changes have resulted in tremendous peer pressure and mental stress, and increased the incidences of chronic psychological disorders; like addiction, depression and anxiety (ADA). In this context, the stress-tolerance levels vary amongst individuals and genetic factors play prominent roles. Vulnerable individuals may often be drawn towards drug-addiction to combat stress. This systematic review critically appraises the relationship of various genetic factors linked with the incidences of ADA development. For coherence, we focused solely on cocaine as a substance of abuse in this study. Online scholarly databases were used to screen pertinent literature using apt keywords; and the final retrieval included 42 primary-research articles. The major conclusion drawn from this systematic analysis states that there are 51 genes linked with the development of ADA; and 3 (BDNF, PERIOD2 and SLC6A4) of them are common to all the three aspects of ADA. Further, inter-connectivity analyses of the 51 genes further endorsed the central presence of BDNF and SLC6A4 genes in the development of ADA disorders. The conclusions derived from this systematic study pave the way for future studies for the identification of diagnostic biomarkers and drug targets; and for the development of novel and effective therapeutic regimens against ADA.
Topics: Humans; Cocaine-Related Disorders; Depression; Brain-Derived Neurotrophic Factor; Anxiety; Anxiety Disorders; Cocaine; Serotonin Plasma Membrane Transport Proteins
PubMed: 37271299
DOI: 10.1016/j.neubiorev.2023.105270 -
Renal Failure Dec 2023The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to... (Meta-Analysis)
Meta-Analysis Review
Comparative safety of sodium-glucose co-transporter 2 inhibitors in elderly patients with type 2 diabetes mellitus and diabetic kidney disease: a systematic review and meta-analysis.
The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to analyze the safety of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus (T2DM) and DKD. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to March 2023. Randomized controlled trials (RCTs) were included. Data including patient characteristics and interesting outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean difference (MD) with 95% CIs, respectively. A total of 14 RCTs with 59874 participants were finally included. There were 38,252 males (63.9%) and 21,622 females (36.1%). The patients' mean age was > 64.6 years. SGLT2 inhibitors could delay the further decline of estimated glomerular filtration rate (eGFR) when eGFR ≥ 60 ml/min/1.73m (MD: 2.36; 95%CI [1.15-3.57]). SGLT2 inhibitors in elderly patients with eGFR < 60 ml/min/1.73m (RR: 0.86; 95%CI [0.67-1.11]) may have a relatively increased risk of acute kidney injury compared to eGFR ≥ 60 ml/min/1.73m. SGLT2 inhibitors increased the incidence of genital mycotic infections (RR: 3.47; 95%CI [2.97-4.04]) and diabetic ketoacidosis (RR: 2.25; 95%CI [1.57-3.24]). Except for genital mycotic infections and diabetic ketoacidosis, other adverse reactions were few, indicating that SGLT2 inhibitors are relatively safe for elderly patients with T2DM and DKD. Safety and renoprotection may be diminished when SGLT2 inhibitors are used in elderly patients with eGFR < 60 ml/min/1.73m.
Topics: Male; Female; Humans; Aged; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Nephropathies; Diabetic Ketoacidosis; Diabetes Mellitus, Type 2; Symporters; Glucose; Sodium; Hypoglycemic Agents
PubMed: 37246403
DOI: 10.1080/0886022X.2023.2217287 -
Bipolar Disorders Dec 2023Glutamatergic transmission and N-methyl-D-aspartate receptors (NMDARs) have been implicated in the pathophysiology schizophrenic spectrum and major depressive disorders.... (Review)
Review
OBJECTIVES
Glutamatergic transmission and N-methyl-D-aspartate receptors (NMDARs) have been implicated in the pathophysiology schizophrenic spectrum and major depressive disorders. Less is known about the role of NMDARs in bipolar disorder (BD). The present systematic review aimed to investigate the role of NMDARs in BD, along with its possible neurobiological and clinical implications.
METHODS
We performed a computerized literature research on PubMed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, using the following string: (("Bipolar Disorder"[Mesh]) OR (manic-depressive disorder[Mesh]) OR ("BD") OR ("MDD")) AND ((NMDA [Mesh]) OR (N-methyl-D-aspartate) OR (NMDAR[Mesh]) OR (N-methyl-D-aspartate receptor)).
RESULTS
Genetic studies yield conflicting results, and the most studied candidate for an association with BD is the GRIN2B gene. Postmortem expression studies (in situ hybridization and autoradiographic and immunological studies) are also contradictory but suggest a reduced activity of NMDARs in the prefrontal, superior temporal cortex, anterior cingulate cortex, and hippocampus.
CONCLUSIONS
Glutamatergic transmission and NMDARs do not appear to be primarily involved in the pathophysiology of BD, but they might be linked to the severity and chronicity of the disorder. Disease progression could be associated with a long phase of enhanced glutamatergic transmission, with ensuing excitotoxicity and neuronal damage, resulting into a reduced density of functional NMDARs.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Bipolar Disorder; Depressive Disorder, Major; Neurons; Gyrus Cinguli
PubMed: 37208966
DOI: 10.1111/bdi.13335 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576 -
Archives of Suicide Research : Official... 2024Suicide is defined as the action of harming oneself with the intention of dying. It is estimated that worldwide, one person dies by suicide every 40 s, making it a...
Suicide is defined as the action of harming oneself with the intention of dying. It is estimated that worldwide, one person dies by suicide every 40 s, making it a major health problem. Studies in families have suggested that suicide has a genetic component, so the search for genetic variants associated with suicidal behavior could be useful as potential biomarkers to identify people at risk of suicide. In Mexico, some studies of gene variants related to neurotransmission and other important pathways have been carried out and potential association of variants located in the following genes has been suggested: , , , , , , , , , and This systematic review shows the genetic studies conducted on the Mexican population. This article contributes by compiling the existing information on genetic variants and genes associated with suicidal behavior, in the future could be used as potential biomarkers to identify people at risk of suicide.
Topics: Humans; Mexico; Suicide; Suicidal Ideation; Biomarkers; RGS Proteins; Serotonin Plasma Membrane Transport Proteins; Protein Serine-Threonine Kinases
PubMed: 36772904
DOI: 10.1080/13811118.2023.2176269 -
European Journal of Human Genetics :... Feb 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.
Topics: Humans; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Interactions; Folic Acid; Gout Suppressants; HLA-B Antigens; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neoplasm Proteins; Pharmacogenetics
PubMed: 36056234
DOI: 10.1038/s41431-022-01180-0 -
Molecular Psychiatry Aug 2023The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin... (Meta-Analysis)
Meta-Analysis
The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
Topics: Humans; Depression; Serotonin; Receptor, Serotonin, 5-HT1A; Tryptophan; Hydroxyindoleacetic Acid; Antidepressive Agents; Serotonin Plasma Membrane Transport Proteins
PubMed: 35854107
DOI: 10.1038/s41380-022-01661-0