-
Journal of the... 2020The previous studies on angiotensin converting enzyme (ACE) insertion/deletion (I/D) genetic polymorphism and glioma risk were inconsistent. Therefore, we performed a... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The previous studies on angiotensin converting enzyme (ACE) insertion/deletion (I/D) genetic polymorphism and glioma risk were inconsistent. Therefore, we performed a meta-analysis to assess the association between ACE I/D polymorphisms and glioma risk.
METHODS AND RESULTS
In total, four populations (1110 cases and 1335 controls) on ACE I/D polymorphism were included. Overall, the meta-analysis demonstrated no significant association between ACE I/D polymorphism and glioma risk. In addition, the analysis of the association of ACE I/D polymorphism and clinical grade also showed no significant association.
CONCLUSION
Our meta-analysis didn't find a significant association between ACE I/D polymorphism glioma risk. However, further studies with larger sample size and more ethnic groups are required to confirm the results.
Topics: Brain Neoplasms; Gene Deletion; Genetic Predisposition to Disease; Glioma; Humans; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Assessment
PubMed: 33045911
DOI: 10.1177/1470320320963939 -
Journal of the... 2020The correlation of the angiotensin-converting enzyme () insertion/deletion (I/D) polymorphism with pediatric asthma risk was assessed in this meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The correlation of the angiotensin-converting enzyme () insertion/deletion (I/D) polymorphism with pediatric asthma risk was assessed in this meta-analysis.
METHODS
PubMed, Web of Science, Embase and CNKI databases were systematically searched for relevant literature, followed by application of odds ratios (OR) along with 95% confidence interval (CI) for determining the strength of relationship.
RESULTS
Seven articles with 802 cases and 632 controls fulfilled the inclusion criteria. As a result, the I/D polymorphism was related to elevated pediatric asthma risk (D vs I: OR = 1.87, 95% CI = 1.59-2.20; dominant model: OR =1.53, 95% CI = 1.28-1.81; recessive model: OR =1.54, 95% CI = 1.28-1.85; DD vs II: OR =2.95, 95% CI = 2.19-3.98; DI vs II: OR = 0.96, 95% CI = 0.78-1.19). Subgroup analysis stratified by race revealed significant interrelation in Asians.
CONCLUSION
This meta-analysis demonstrated that the I/D polymorphism might be related to the risk of pediatric asthma.
Topics: Asthma; Child; Gene Deletion; Genetic Predisposition to Disease; Humans; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Assessment
PubMed: 32475208
DOI: 10.1177/1470320320923475 -
Child's Nervous System : ChNS :... Jul 2020The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal... (Review)
Review
INTRODUCTION
The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS.
METHODS
We explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion.
RESULTS
Our systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS.
CONCLUSION
Spinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.
Topics: Adolescent; Airway Obstruction; Chromosome Deletion; Chromosomes, Human, Pair 10; Female; Humans; Infant; Infant, Newborn; Pierre Robin Syndrome; Spinal Diseases
PubMed: 32399800
DOI: 10.1007/s00381-020-04642-2 -
Translational Cancer Research May 2020Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) exhibit a beneficial therapeutic effect on non-small cell lung cancer (NSCLC). However, almost...
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) exhibit a beneficial therapeutic effect on non-small cell lung cancer (NSCLC). However, almost all patients with EGFR-mutant lung cancer develop drug resistance to these agents. Common drug resistance mechanisms include the mutation, amplification, mutation, polymorphism deletion and gene mutations. Some NSCLC exhibit transformation into small cell lung cancer (SCLC). A patient case of a 56-year-old man with lung adenocarcinoma (with symptoms of a cough and expectoration that had lasted 1 month) who exhibited an mutation (19-Del) and was treated with EGFR-TKIs is reported, which transformed into SCLC after failed to targeted therapy. Pathological examination and genome sequencing were carried out when every time the disease progressed, we obtained more comprehensive information and could keep track of the patient's progress. So, we could adjust the treatment plan at any time according to the results of pathological examination and gene detection. We can get some implications: (I) patients with mutant lung adenocarcinoma with the double inactivation of RB1 and TP53 genes exhibit an increased risk of SCLC transformation; (II) after SCLC transformation, therapeutic strategies should be adequately adjusted, when SCLC was controlled by chemotherapy the targeted therapy should be considered for the treatment of adenocarcinoma; (III) evidence of the benefits of immunotherapy in patients with SCLC transformation is insufficient; (IV) the achievement of the SCLC phenotype is a late phenomenon during TKI therapy and the prognosis of patients after SCLC diagnosis is poor.
PubMed: 35117735
DOI: 10.21037/tcr-19-2291 -
American Journal of Medical Genetics.... Jun 2020Variations in MYT1L, a gene encoding a transcription factor expressed in the brain, have been associated with autism, intellectual disability, and schizophrenia. Here we... (Meta-Analysis)
Meta-Analysis
Variations in MYT1L, a gene encoding a transcription factor expressed in the brain, have been associated with autism, intellectual disability, and schizophrenia. Here we provide an updated review of published reports of neuropsychiatric correlates of loss of function and duplication of MYT1L. Of 27 duplications all were partial; 33% were associated exclusively with schizophrenia, and the chromosomal locations of schizophrenia-associated duplications exhibited a distinct difference in pattern-of-location from those associated with autism and/or intellectual disability. Of 51 published heterozygous loss of function variants, all but one were associated with intellectual disability, autism, or both, and one resulted in no neuropsychiatric diagnosis. There were no reports of schizophrenia associated with loss of function variants of MYT1L (Fisher's exact p < .00001, for contrast with all reported duplications). Although the precise function of the various mutations remains unspecified, these data collectively establish the candidacy of MYT1L as a reciprocal mutation, in which schizophrenia may be engendered by partial duplications, typically involving the 3' end of the gene, while developmental disability-notably autism-is associated with both loss of function and partial duplication. Future research on the specific effects of contrasting mutations in MYT1L may provide insight into the causal origins of autism and schizophrenia.
Topics: Autistic Disorder; Gene Deletion; Gene Duplication; Gene Expression Regulation; Genetic Association Studies; Genetic Variation; Humans; Intellectual Disability; Mutation; Nerve Tissue Proteins; Phenotype; Schizophrenia; Transcription Factors
PubMed: 32267091
DOI: 10.1002/ajmg.b.32781 -
Clinical Gastroenterology and... Aug 2020Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer... (Review)
Review
BACKGROUND & AIMS
Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer (CRC) and polyposis syndromes. We performed a systematic review to provide a comprehensive overview of somatic mosaicism in patients with CRC and polyposis syndromes.
METHODS
We searched PubMed through March 2018 to identify reports of mosaicism in patients with CRC or polyposis syndromes. We divided the final set of studies into 3 subgroups describing APC mosaicism, mosaicism in other CRC susceptibility genes, and epigenetic mosaicism.
RESULTS
Of the 232 articles identified in our systematic search, 46 met the criteria for further analysis. Of these, 35 studies described mosaic variants or epimutations in patients with CRC or polyposis syndromes. Nineteen studies described APC mosaicism, comprising a total of 57 patients. Six described mosaicism in genes associated with familial CRC syndromes, such as Lynch and Cowden syndromes. Ten studies described epigenetic mosaicism, sometimes resulting from a germline variant (such as deletion of EPCAM).
CONCLUSIONS
We found that somatic mosaicism is underdiagnosed but critical for determining the clinical management of patients with de novo polyposis who possibly carry mosaic APC variants, and present a decision tree for the clinical management of these patients. Mosaicism in genes associated with susceptibility to CRC contributes to development of other familial CRC syndromes. Heritable epigenetic mosaicism is likely underestimated and could have a dominant pattern of inheritance. However, the inheritance of primary mosaic epimutations, without an underlying genetic cause, is complex and not fully understood.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Genetic Predisposition to Disease; Humans; Mosaicism; Neoplastic Syndromes, Hereditary
PubMed: 32147591
DOI: 10.1016/j.cgh.2020.02.049 -
Medicine Jan 2020Non-small cell lung cancer (NSCLC) has a poor prognosis despite conventional treatments of surgery, radiotherapy, and chemotherapy. Small-molecule tyrosine kinase... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Non-small cell lung cancer (NSCLC) has a poor prognosis despite conventional treatments of surgery, radiotherapy, and chemotherapy. Small-molecule tyrosine kinase inhibitors acting on epidermal growth factor receptor (EGFR) have shown high efficacy and low toxicity for NSCLC. In particular, combining erlotinib with the VEGF antibody bevacizumab has therapeutic value in NSCLC, but the drugs' separate effects as monotherapy and any adverse outcomes of combination therapy remain unclear.
OBJECTIVES
To determine the efficacy and safety of erlotinib and bevacizumab for NSCLC, we conducted a meta-analysis and systematic review of randomized controlled trials.
DATA SOURCES
PubMed, Embase, Web of Science, and Cochrane databases were searched using keywords and manual review.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
We reviewed randomized controlled trials on the use of erlotinib combined with bevacizumab in adult patients with NSCLC, including data on outcome measures of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events.
STUDY APPRAISAL AND SYNTHESIS METHODS
After quality assessment, datasets were evaluated for heterogeneity. In the event of significant heterogeneity, a random-effects model was used to assess the overall outcome measures as a result of treatments. Subgroup analysis was conducted to evaluate the source of heterogeneity on PFS.
RESULTS
Compared with erlotinib or bevacizumab alone, the combined treatment did not significantly prolong OS (95% confidence interval [CI] = 0.84-1.11; P = .62) or increase the ORR (95% CI = 0.91-1.20; P = .52), but significantly improved PFS (95% CI = 0.58-0.73; P < .001). This improvement was especially notable in patients with the following characteristics: Eastern Cooperative Oncology Group Performance Status score of 0 or 1, female, no smoking history, adenocarcinoma, and EGFR Exon19 deletion or Exon21 Leu858Arg mutation. Combination therapy significantly increased incidence of grade 1-2 hypertension (20.3% vs 6.3%, 95% CI 1.73-5.88; P < .01) and severe diarrhea (10% vs 3.2%, 95% CI 1.36-6.60; P = .01).
LIMITATIONS
The low number of available randomized controlled trials could influence interpretation.
CONCLUSIONS
Compared with erlotinib or bevacizumab monotherapy, their combination effectively prolongs PFS but increases incidence of adverse events in NSCLC patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic
PubMed: 32011468
DOI: 10.1097/MD.0000000000018771 -
The Cochrane Database of Systematic... Jan 2020Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011.
OBJECTIVES
To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely.
SEARCH METHODS
We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials.
SELECTION CRITERIA
We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology.
MAIN RESULTS
The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing.
AUTHORS' CONCLUSIONS
Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
Topics: Adolescent; Amines; Child; Child, Preschool; Creatine; Cyclohexanecarboxylic Acids; Humans; Hydroxyurea; Neuroprotective Agents; Randomized Controlled Trials as Topic; Spinal Muscular Atrophies of Childhood; Thyrotropin-Releasing Hormone; gamma-Aminobutyric Acid
PubMed: 32006461
DOI: 10.1002/14651858.CD006282.pub5 -
Malaria Journal Jan 2020In 2017, nearly 80% of malaria morbidity and mortality occurred in sub-Saharan African (SSA) countries and India. Rapid diagnostic tests (RDTs), especially those... (Meta-Analysis)
Meta-Analysis
Prevalence of Plasmodium falciparum field isolates with deletions in histidine-rich protein 2 and 3 genes in context with sub-Saharan Africa and India: a systematic review and meta-analysis.
BACKGROUND
In 2017, nearly 80% of malaria morbidity and mortality occurred in sub-Saharan African (SSA) countries and India. Rapid diagnostic tests (RDTs), especially those targeting histidine-rich protein 2 (PfHRP2) of Plasmodium falciparum, have become an important diagnostic tool in these malaria-endemic areas. However, the chances of RDT-oriented successful treatment are increasingly jeopardized by the appearance of mutants with deletions in pfhrp2 and pfhrp3 genes. This systematic review and meta-analysis determines the prevalence of field P. falciparum isolates with deletion in pfhrp2 and/or pfhrp3 genes and their proportion among false-negative results in the PfHRP2-based RDTs in SSA and India.
METHODS
Eight electronic databases were used for searching potentially relevant publications for the systematic review analysis, wherein the main methodological aspects of included studies were analysed and some missing links in the included studies were identified.
RESULTS
A total of 19 studies were included, 16 from SSA and 3 from India. The pooled prevalence of pfhrp2 deletions was 8 and 5% while 16 and 4% for pfhrp3 gene deletions in Africa and India, respectively. The pooled proportion of pfhrp2 gene deletions found among false negative PfHRP2-based RDTs results was about 27.0 and 69.0% in Africa and India, respectively.
CONCLUSIONS
This review study indicates a relatively high proportion of both pfhrp2/3 genes deletions in P. falciparum isolates and among false-negative malaria cases using PfHRP2-based RDT results in SSA and India. Recently the deletions in pfhrp2/3 genes have also been reported from two African countries (Nigeria and Sudan). This review emphasizes the importance of more extensive studies and standardization of studies addressing the pfhrp2/3 gene deletions in malarious areas.
Topics: Africa South of the Sahara; Antigens, Protozoan; False Negative Reactions; Gene Deletion; Genome, Protozoan; India; Malaria, Falciparum; Plasmodium falciparum; Prevalence; Protozoan Proteins
PubMed: 31992330
DOI: 10.1186/s12936-019-3090-6 -
BMC Medical Genetics Jan 2020Psoriasis is a multifactorial disorder, impacted by both genetic and environmental factors. Herein, a meta-analysis assessed the association of angiotensin-converting... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Psoriasis is a multifactorial disorder, impacted by both genetic and environmental factors. Herein, a meta-analysis assessed the association of angiotensin-converting enzyme gene insertion/deletion (ACE I/D) polymorphism and psoriasis susceptibility.
METHODS
A systematic search was used in databases of PubMed/Medline, Scopus, Web of Science, and Cochrane Library up to January 2019 without language restriction. A dichotomous analysis was carried out by RevMan 5.3 using crude odds ratio (OR) and 95% confidence interval (CI) to investigate the association between ACE I/D polymorphisms and the risk of psoriasis. A funnel plot analysis was used by CMA 2.0 to estimate a significant existence of publication bias.
RESULTS
Out of 61 studies retrieved from the databases, 16 studies were included in the meta-analysis. The pooled ORs for models of D vs. I, DD vs. II, ID vs. II, ID + DD vs. II, and DD vs. II + ID genotypes were 0.96 [95%CI: 0.82, 1.12; P = 0.58], 0.99 [95%CI, 0.73, 1.36; P = 0.96], 0.81 [95%CI, 0.72, 0.91; p: 0.0003], 0.91 [95%CI, 0.73, 1.13; P = 0.40], and 1.05 [95%CI, 0.85, 1.30; P = 0.68], respectively. A significant difference between ACE polymorphisms in patients with/without family history for the disease [OR = 1.44; 95%CI: 1.24, 1.67; P < 0.001] and also in patients mild/severe psoriasis [OR = 0.70; 95%CI: 0.55, 0.88; P = 0.002] was identified.
CONCLUSION
The results of the meta-analysis showed that ACE I/D polymorphism may be associated with psoriasis susceptibility, while ID genotype seemed to have a protective role in Caucasian patients affected by psoriatic arthritis and in studies with hospital-based controls.
Topics: Angiotensins; Genetic Predisposition to Disease; Genotype; Humans; INDEL Mutation; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Psoriasis; White People
PubMed: 31914957
DOI: 10.1186/s12881-019-0943-3