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JAMA Network Open Nov 2019The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2.
OBJECTIVE
To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region.
DATA SOURCES
PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD.
STUDY SELECTION
Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies.
DATA EXTRACTION AND SYNTHESIS
After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.
MAIN OUTCOMES AND MEASURES
The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data.
RESULTS
A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples.
CONCLUSIONS AND RELEVANCE
In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.
Topics: Alcoholism; Case-Control Studies; Female; Gene Frequency; Genome-Wide Association Study; Humans; Male; Middle Aged; Receptors, Dopamine D2
PubMed: 31702801
DOI: 10.1001/jamanetworkopen.2019.14940 -
BMC Infectious Diseases Jun 2016The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in... (Review)
Review
BACKGROUND
The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in phenotype, ethnicity and parasite species. Leishmaniasis is caused exclusively by L. donovani in Sri Lanka with localized cutaneous leishmaniasis (LCL) being the predominant form. We report here an association study of human leucocyte antigen (HLA) class I and II genes with LCL in Sri Lanka, the first on HLA associations in cutaneous leishmaniasis in a South Asian population.
METHODS
An existing DNA repository of 200 each of patients and controls was typed for HLA-DQ by PCR-SSP. Next generation sequencing-based typing for HLA-A, HLA-B and HLA-DRB1 alleles was done in a subset of 280 samples. Association tests were performed on 28,489 genotyped and imputed SNPs spanning a region of 1.4 Mb across the HLA genes. To compare our results with similar studies, we carried out a systematic review to document all HLA associations reported to-date for cutaneous and muco-cutaneous leishmaniasis.
RESULTS
DRB1*04 DQB1*02 (P = 0.03; Pc = 0.09), DRB1*07 DQB1*02 (P = 0.03; Pc = 0.09) haplotypes were absent in patients. B*07 (P = 0.007; Pc = 0.13; OR = 0.36; 95 % CI = 0.17-0.77) allele and DRB1*15 DQB1*06 (P = 0.00; Pc < 0.01; OR = 0.3; 95 % CI = 0.2-.0.6) haplotype were over represented in controls and DRB1*15 (P = 0.002; Pc = 0.01) allele was over represented in patients. Two SNPs (rs281864595/rs1050517) in the antigen recognition region of HLA-B, comprised a haplotype more frequent in controls (P = 0.04). The alleles identified by the systematic review to predispose or to protect from cutaneous/mucocutaneous leishmaniasis remained highly heterogeneous in different populations studied.
CONCLUSIONS
Our preliminary findings suggest a role for some class I and class II HLA genes in determining predisposition to LCL in this population which should be corroborated with further studies. The systematic review reiterates this need, as the purported susceptibility or protection gained by certain HLA alleles or haplotypes has rarely been independently verified.
Topics: Adolescent; Adult; Alleles; Asian People; Case-Control Studies; Child; Child, Preschool; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; HLA-A Antigens; HLA-B Antigens; HLA-DQ beta-Chains; HLA-DRB1 Chains; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Leishmaniasis, Cutaneous; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sri Lanka; Young Adult
PubMed: 27301744
DOI: 10.1186/s12879-016-1626-8 -
Journal of Neurology Jun 2022Adult polyglucosan body disease (APBD) is a rare but probably underdiagnosed autosomal recessive neurodegenerative disorder due to pathogenic variants in GBE1. The... (Review)
Review
Adult polyglucosan body disease (APBD) is a rare but probably underdiagnosed autosomal recessive neurodegenerative disorder due to pathogenic variants in GBE1. The phenotype is characterized by neurogenic bladder dysfunction, spastic paraplegia, and axonal neuropathy. Additionally, cognitive symptoms and dementia have been reported in APBD but have not been studied systematically. Using exome sequencing, we identified two previously unreported bi-allelic missense GBE1 variants in a patient with severe memory impairment along with the typical non-cognitive symptoms. We were able to confirm a reduction of GBE1 activity in blood lymphocytes. To characterize the neuropsychological profile of patients suffering from APBD, we conducted a systematic review of cognitive impairment in this rare disease. Analysis of 24 cases and case series (in total 58 patients) showed that executive deficits and memory impairment are the most common cognitive symptoms in APBD.
Topics: Cognitive Dysfunction; Glycogen Storage Disease; Humans; Mutation, Missense; Nervous System Diseases
PubMed: 34999962
DOI: 10.1007/s00415-022-10960-z -
BMC Medical Genetics May 2012Genetic variations in TGFB1 gene have been studied in relation to coronary heart disease (CHD) risk, but the results were inconsistent. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Genetic variations in TGFB1 gene have been studied in relation to coronary heart disease (CHD) risk, but the results were inconsistent.
METHODS
We performed a systematic review of published studies on the potential role of TGFB1 genetic variation in CHD risk. Articles that reported the association of TGFB1 genetic variants with CHD as primary outcome were searched via Medline and HuGE Navigator through July 2011. The reference lists from included articles were also reviewed.
RESULTS
Data were available from 4 studies involving 1777 cases and 7172 controls for rs1800468, 7 studies involving 5935 cases and 10677 controls for rs1800469, 7 studies involving 6634 cases and 9620 controls for rs1982073, 5 studies involving 5452 cases and 9999 controls for rs1800471, and 4 studies involving 5143 cases and 4229 controls for rs1800472. The pooled odds ratios (ORs) for CHD among minor T allele carriers of rs1800469, minor C allele carriers of rs1982073, and minor C allele carriers of rs1800471 versus homozygous major allele carriers was 1.14 (95% confidence interval [CI]: 1.05-1.24), 1.18 (95% CI: 1.04-1.35), and 1.16 (95% CI: 1.02-1.32), respectively. No substantial heterogeneity for ORs was detected among the included Caucasian populations for all SNPs. However, for rs1800471, the statistical significance disappeared after adjusting for potential publication bias. No significant association was found between rs1800468 and rs1800472 variants and CHD risk.
CONCLUSION
Minor allele carriers of two genetic variants (rs1800469 and rs1982073) in TGFB1 have a 15% increased risk of CHD.
Topics: Coronary Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Polymorphism, Single Nucleotide; Risk; Transforming Growth Factor beta1; White People
PubMed: 22607024
DOI: 10.1186/1471-2350-13-39 -
PloS One 2014A consensus has not been reached regarding the association of several different gene polymorphisms and susceptibility to obstructive sleep apnea syndrome (OSAS). We... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
A consensus has not been reached regarding the association of several different gene polymorphisms and susceptibility to obstructive sleep apnea syndrome (OSAS). We performed a meta-analysis to better evaluate the associations between 5-HT2A, 5-HTT, and LEPR polymorphisms, and OSAS.
METHOD
5-HT2A, 5-HTT, and LEPR polymorphisms and OSAS were identified in PubMed and EMBASE. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect models. The associations between these polymorphisms and OSAS risk were assessed using dominant, recessive and additive models.
RESULTS
Twelve publications were included in this study. The -1438 "A" allele of 5-HT2A was identified as a candidate genetic risk factor for OSAS (OR: 2.33, 95%CI 1.49-3.66). Individuals carrying the -1438 "G" allele had a nearly 70% reduced risk of OSAS when compared with AA homozygotes (OR: 0.30, 95%CI 0.23-0.40). There was no significant association between 5-HT2A 102C/T and OSAS risk, using any model. The "S" allele of 5-HTTLPR conferred protection against OSAS (OR: 0.80, 95%CI 0.67-0.95), while the "10" allele of 5-HTTVNTR contributed to the risk of OSAS (OR: 2.08, 95%CI: 1.58-2.73). The "GG" genotype of LEPR was associated with a reduced risk of OSAS (OR: 0.39, 95%CI 0.17-0.88).
CONCLUSION
The meta-analysis demonstrated that 5-HTR-1438 "A" and 5-HTTVNTR "10" alleles were significantly associated with OSAS. The "S" allele of 5-HTTLPR and the "GG" genotype of LEPR conferred protection against OSAS. Further studies, such as Genome-Wide Association study (GWAS), should be conducted in a large cohort of OSAS patients to confirm our findings.
Topics: Case-Control Studies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2A; Receptors, Leptin; Risk; Serotonin Plasma Membrane Transport Proteins; Sleep Apnea, Obstructive
PubMed: 24755731
DOI: 10.1371/journal.pone.0095856 -
Acta Diabetologica Oct 2014Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in... (Meta-Analysis)
Meta-Analysis Review
Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29-1.79) and 1.39 (95 % CI 1.11-1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.
Topics: CTLA-4 Antigen; Diabetes Mellitus, Type 1; Genetic Predisposition to Disease; Humans; Male; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22; Risk Factors; Young Adult
PubMed: 25005490
DOI: 10.1007/s00592-014-0613-z -
Medicine Oct 2022To explore the association between Angiotensin Converting Enzyme (ACE) insert(I)/defect(D) gene polymorphism and the susceptibility to idiopathic pulmonary fibrosis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To explore the association between Angiotensin Converting Enzyme (ACE) insert(I)/defect(D) gene polymorphism and the susceptibility to idiopathic pulmonary fibrosis (IPF).
METHODS
Searching PubMed, EMbase, CENTRAL, MEDLINE, CBM, China National Knowledge Infrastructure, WanFang Database and VIP Chinese Science database through a computer and collect the literature from China and foreign countries published before January 22, 2022. Screen the literatures and extract data such as first author, year of publication, diagnostic criteria and gene frequency, and draw a funnel chart and perform Begg's Test and Egger's test to evaluate publication bias. The influence analysis was performed for heterogeneous results and at the same time, the trial sequential analysis (TSA) was also conducted to confirm the robustness of the meta-analysis results. Registration number: CRD42021259341.
RESULTS
There were a total of 4 literatures (4 studies conducted in the Chinese Han population), and a total of 292 IPF patients and 351 healthy controls were included in this study. The results showed that in the Chinese Han population, the ACE I/D gene polymorphism was associated with the susceptibility of IPF (D vs I: [odds ratio, OR] = 0.53, 95% confidence interval [95%CI] [0.42, 0.67], P < .00001; DD vs II: [OR] = 0.37, 95%CI [0.24, 0.57], P < .00001; DD vs II + ID:[OR] = 0.30, 95%CI [0.21, 0.43], P < .00001), and the angiotensin II (Ang Ⅱ) level of IPF patients was higher than that of the control group (mean difference [MD] = 14.29, 95%CI [11.20,17.37], P < .00001).The TSA also confirmed that D allele was closely related to the susceptibility of IPF.
CONCLUSION
In the Chinese Han population, the D allele of the ACE I/D gene polymorphism is associated with the susceptibility of IPF.
Topics: Humans; Alleles; Angiotensin II; Genetic Predisposition to Disease; Idiopathic Pulmonary Fibrosis; INDEL Mutation; Peptidyl-Dipeptidase A
PubMed: 36221416
DOI: 10.1097/MD.0000000000030942 -
EBioMedicine Nov 2016Increasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Increasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease of various tumors. However, the associations between DNMTs variations and gastric cancer (GC) risk were still conflicting. We aimed to assess the effect of DNMTs polymorphisms on the susceptibility to GC.
METHODS
Firstly, we did a meta-analysis for 7 SNPs (rs16999593, rs2228611, rs8101866 in DNMT1, rs1550117, rs13420827 in DNMT3A, rs1569686, rs2424913 in DNMT3B). Four genetic models (homozygote, heterozygote, dominant and recessive model) were used. Moreover, a meta-sensitivity and subgroup analysis was performed to clarify heterogeneity source. Lastly, 17 SNPs that couldn't be meta-analyzed were presented in a systematic review.
FINDINGS
20 studies were included, 13 studies could be meta-analyzed and 7 ones could not. Firstly, a meta-analysis on 13 studies (3959 GC cases and 5992 controls) for 7 SNPs showed that GC risk increased in rs16999593 (heterozygote model: OR 1.36, 95%CI 1.14-1.61; dominant model: OR 1.36, 95%CI 1.15-1.60) and rs1550117 (homozygote model: OR 2.03, 95%CI 1.38-3.00; dominant model: OR 1.20, 95%CI 1.01-1.42; recessive model: OR 1.96, 95%CI 1.33-2.89) but decreased in rs1569686 (dominant model: OR 0.74, 95%CI 0.61-0.90). The remaining SNPs were not found associated with GC risk. Furthermore, the subgroup analysis indicated that for rs1550117 and rs1569686, the significant associations were particularly found in people from Chinese Jiangsu province (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.48, 95%CI 0.36-0.64) and that PCR-RFLP was a sensitive method to discover significant associations (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.49, 95%CI 0.37-0.65). Lastly, a systematic review on 7 studies for 17 SNPs suggested that rs36012910, rs7560488 and rs6087990 might have a potential effect on GC initiation.
CONCLUSION
This meta-analysis demonstrated that rs16999593 and rs1550117 could contribute to GC risk and that rs1569686 might be a protective factor against gastric carcinogenesis. By using these SNPs as biomarkers, it is feasible to estimate the risk of acquiring GC and thus formulate timely preventive strategy.
Topics: Alleles; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Odds Ratio; Polymorphism, Single Nucleotide; Risk; Stomach Neoplasms; DNA Methyltransferase 3B
PubMed: 27789275
DOI: 10.1016/j.ebiom.2016.10.028 -
Frontiers in Oncology 2023Single nucleotide polymorphisms (SNPs) interfere with the function of certain genes and thus may influence the probability of skin cancer. The correlation between SNPs...
BACKGROUND
Single nucleotide polymorphisms (SNPs) interfere with the function of certain genes and thus may influence the probability of skin cancer. The correlation between SNPs and skin cancer (SC) lacks statistical power, however. Therefore, the purpose of this study was to identify the gene polymorphisms involved in skin cancer susceptibility using network meta-analysis and to determine the relationship between SNPs and SC risk.
METHODS
PubMed, Embase, and Web of Science were searched for articles including "SNP" and different types of SC as keywords between January 2005 and May 2022. The Newcastle-Ottawa Scale was used to assess bias judgments. The odds ratio (ORs) and their 95% confidence intervals () were determined to estimate heterogeneity within and between studies. Meta-analysis and network meta-analysis were carried out to identify the SNPs associated with SC. The -score of each SNP was compared to obtain the rank of probability. Subgroup analyses were performed by cancer type.
RESULTS
A total of 275 SNPs from 59 studies were included in the study. Two subgroup SNP networks using the allele model and dominant model were analyzed. The alternative alleles of rs2228570 (FokI) and rs13181 (ERCC2) were the first-ranking SNPs in both subgroups one and two of the allele model, respectively. The homozygous dominant genotype and heterozygous genotype of rs475007 in subgroup one and the homozygous recessive genotype of rs238406 in subgroup two were most likely to be associated with skin cancer based on the dominant model.
CONCLUSIONS
According to the allele model, SNPs FokI rs2228570 and ERCC2 rs13181 and, according to the dominant model, SNPs MMP1 rs475007 and ERCC2 rs238406 are closely linked to SC risk.
PubMed: 36874118
DOI: 10.3389/fonc.2023.1094309 -
Frontiers in Genetics 2020A compound heterozygous () variant is a type of germline variant that occurs when each parent donates one alternate allele and these alleles are located at different... (Review)
Review
A compound heterozygous () variant is a type of germline variant that occurs when each parent donates one alternate allele and these alleles are located at different loci within the same gene. Pathogenic germline variants have been identified for some pediatric cancer types but in most studies, variants are overlooked. Thus, the prevalence of pathogenic variants in most pediatric cancer types is unknown. We identified 26 studies (published between 1999 and 2019) that identified a variant in at least one pediatric cancer patient. These studies encompass 21 cancer types and have collectively identified 25 different genes in which a variant occurred. However, the sequencing methods used and the number of patients and genes evaluated in each study were highly variable across the studies. In addition, methods for assessing pathogenicity of variants varied widely and were often not reported. In this review, we discuss technologies and methods for identifying variants, provide an overview of studies that have identified variants in pediatric cancer patients, provide insights into future directions in the field, and give a summary of publicly available pediatric cancer sequencing data. Although considerable insights have been gained over the last 20 years, much has yet to be learned about the involvement of variants in pediatric cancers. In future studies, larger sample sizes, more pediatric cancer types, and better pathogenicity assessment and filtering methods will be needed to move this field forward.
PubMed: 32508881
DOI: 10.3389/fgene.2020.00493