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International Journal of Stroke :... Feb 2013Paraoxonase is known to play an important role in the pathophysiology of atherosclerosis. Genetic variants of the paraoxonase gene have been implicated as risk factors... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Paraoxonase is known to play an important role in the pathophysiology of atherosclerosis. Genetic variants of the paraoxonase gene have been implicated as risk factors for atherosclerotic diseases such as coronary artery disease, but individual genetic association studies examining the relationship between the paraoxonase gene polymorphisms and ischaemic stroke have yielded inconsistent results.
AIM
This study aimed to evaluate the association between the paraoxonase gene variants and ischaemic stroke using systematic review with meta-analysis.
METHODS
Relevant studies were identified by searching English and Chinese databases extensively. Allele and genotype frequencies for each included study were extracted. The odds ratio was calculated using a random-effects or fixed-effects model. A Q statistic was used to evaluate homogeneity, and Egger's test and funnel plot were used to assess publication bias.
RESULTS
A total of 28 studies were included and identified for the current meta-analysis. It was found that the R allele or RR genotype of paraoxonase 1 Q192R polymorphism had an increased risk for ischaemic stroke in the general population (192R allele: odds ratio: 1·21, 95% confidence interval: 1·08-1·35, P = 0·0009 and 192RR genotype: odds ratio: 1·25, 95% confidence interval: 1·06-1·49, P = 0·009 in general population, respectively), but there was no significant association between other genetic variants of paraoxonase gene and ischaemic stroke.
CONCLUSIONS
Existing evidence indicates that the Q192R polymorphism (the R allele and RR genotype) is associated with an increased risk of ischaemic stroke in the general population. Future studies with larger sample sizes will be necessary to confirm the present results.
Topics: Alleles; Aryldialkylphosphatase; Brain Ischemia; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Genetic; Stroke
PubMed: 22631428
DOI: 10.1111/j.1747-4949.2012.00813.x -
Human Reproduction Update Apr 2020Through carrier screening, prospective parents can acquire information about whether they have an increased risk of conceiving a child affected with an autosomal...
BACKGROUND
Through carrier screening, prospective parents can acquire information about whether they have an increased risk of conceiving a child affected with an autosomal recessive or X-linked condition. Within the last decade, advances in genomic technologies have facilitated a shift from condition-directed carrier screening to expanded carrier screening (ECS). Following the introduction of ECS, several studies have been performed to gauge the interest in this new technology among individuals and couples in the general population.
OBJECTIVE AND RATIONALE
The aim of this systematic review was to synthesize evidence from empirical studies that assess the interest in ECS among individuals and couples in the general population. As the availability and accessibility of ECS grow, more couples who are a priori not at risk based on their personal or family history will be presented with the choice to accept or decline such an offer. Their attitudes and beliefs, as well as the perceived usefulness of this screening modality, will likely determine whether ECS is to become a widespread reproductive genetic test.
SEARCH METHODS
Four databases (Pubmed, Web of Science, CINAHL, Cochrane Library) were systematically searched to identify English language studies performed between January 2009 and January 2019 using the following search terms: carrier screening, carrier testing, attitudes, intention, interest, views, opinions, perspectives and uptake. Studies were eligible for inclusion if they reported on intentions to undergo a (hypothetical) ECS test, uptake of an actual ECS offer or both. Two researchers performed a multistep selection process independently for validation purposes.
OUTCOMES
Twelve empirical studies performed between 2015 and 2019 were included for analysis. The studies originated from the USA (n = 6), the Netherlands (n = 3), Belgium (n = 1), Sweden (n = 1) and Australia (n = 1). The sample size of the studies varied from 80 to 1669. In the included studies, 32%-76% of respondents were interested in a (hypothetical) ECS test, while uptake rates for actual ECS offers ranged from 8% to 50%. The highest overall uptake was observed when ECS was offered to pregnant women (50%). By contrast, studies focusing on the preconception population reported lower overall uptake rates (8-34%) with the exception of one study where women were counseled preconception in preparation for IVF (68.7%).
WIDER IMPLICATIONS
Our findings suggest that there may be discrepancies between prospective parents' reported intentions to undergo ECS and their actual uptake, particularly during the preconception period. As ECS is a new and relatively unknown test for most future parents, the awareness and comprehension within the general population could be rather limited. Adequate pre- and post-test counseling services should be made available to couples offered ECS to ensure informed reproductive decision-making, together with guidelines for primary health care professionals. Due to restricted nature of the samples and methods of the underlying primary studies, some of the reported results might not be transferable to a broader population. More research is needed to see if the observed trends also apply to a broader and more diverse population.
Topics: Female; Genetic Carrier Screening; Genetic Counseling; Genetic Diseases, Inborn; Humans; Netherlands; Parents; Pregnancy; Prospective Studies; Reproduction
PubMed: 32099997
DOI: 10.1093/humupd/dmaa001 -
European Neuropsychopharmacology : the... Oct 2013There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced... (Meta-Analysis)
Meta-Analysis Review
There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83-1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12-0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.
Topics: Alleles; Antidepressive Agents; Brain; Depression; Drug Resistance; Evidence-Based Medicine; Genetic Association Studies; Genetic Variation; Humans; Nerve Tissue Proteins; Neurons; Randomized Controlled Trials as Topic; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 23265954
DOI: 10.1016/j.euroneuro.2012.12.001 -
Smoking and selected DNA repair gene polymorphisms in controls: systematic review and meta-analysis.Cancer Epidemiology, Biomarkers &... Dec 2010When the case-only study design is used to estimate statistical interaction between genetic (G) and environmental (E) exposures, G and E must be independent in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
When the case-only study design is used to estimate statistical interaction between genetic (G) and environmental (E) exposures, G and E must be independent in the underlying population, or the case-only estimate of interaction (COR) will be biased. Few studies have examined the occurrence of G-E association in published control group data.
METHODS
To examine the assumption of G-E independence in empirical data, we conducted a systematic review and meta-analysis of G-E associations in controls for frequently investigated DNA repair genes (XRCC1 Arg399Gln, Arg194Trp, or Arg280His, XPD Lys751Gln, and Asp312Asn, and XRCC3 Thr241Met), and smoking (ever/never smoking, current/not current smoker, smoking duration, smoking intensity, and pack-years).
RESULTS
Across the 55 included studies, single nucleotide polymorphisms SNP-smoking associations in controls (OR(z)) were not reliably at the null value of 1.0 for any SNP-smoking combinations. Two G-E combinations were too heterogeneous for summary estimates: XRCC1 399 and ever-never smoking (N = 21), and XPD 751 and pack-years (N = 12). OR(z) ranges for these combinations were: [OR(z) (95% confidence interval (CI)] 0.7 (0.4, 1.2)-1.9 (1.2, 2.8) and 0.8 (0.5, 1.3)-2.3 (0.8, 6.1), respectively). Estimates for studies considered homogeneous (Cochran's Q P-value <0.10) varied 2- to 5-fold. No study characteristics were identified that could explain heterogeneity.
CONCLUSIONS
We recommend the independence assumption be evaluated in the population underlying any potential case-only study, rather than in a proxy control group(s) or pooled controls.
IMPACT
These results suggest that G-E association in controls may be population-specific. Increased access to control data would improve evaluation of the independence assumption.
Topics: DNA Repair; DNA Repair Enzymes; Environmental Exposure; Humans; Neoplasms; Polymorphism, Single Nucleotide; Research Design; Smoking
PubMed: 20935063
DOI: 10.1158/1055-9965.EPI-10-0877 -
European Spine Journal : Official... Jan 2017To examine the association between Vitamin D receptor (VDR) gene polymorphisms and lumbar disc degeneration (LDD) predisposition. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To examine the association between Vitamin D receptor (VDR) gene polymorphisms and lumbar disc degeneration (LDD) predisposition.
METHODS
A comprehensive literature search was conducted to identify all the relevant studies. The allele/genotype frequencies were extracted from each study. We calculated the pooled odds ratios (ORs) and 95 % confidence intervals (CI) to assess the strength of the association between the VDR gene polymorphisms and LDD risk. Statistical analysis was performed using RevMan 5.31 software.
RESULTS
A total of 23 case-control studies (1835 cases and 1923 controls) were included in this systematic review. For the TaqI (rs731236), FokI (rs2228570) and ApaI (rs7975232) polymorphisms of VDR gene, nine studies, seven studies, and five studies, were eventually included in the meta-analysis, respectively. There was no evidence that the VDR gene polymorphisms (TaqI, FokI, ApaI) had significant associations with LDD risk.(for TaqI allelic comparison, OR = 1.07, 95 % CI 0.81-1.40, p = 0.64; for FokI allelic comparison, OR = 1.23, 95 % CI 0.83-1.82, p = 0.31; for ApaI allelic comparison, OR = 0.79, 95 % CI 0.55-1.14, p = 0.20). For stratified analyses by ethnicity and study design, no significant associations were found in Caucasian population and Asian population, as well as the population-based studies and hospital-based studies under all genetic models.
CONCLUSIONS
TaqI, FokI, and ApaI polymorphisms of VDR gene were not significantly associated with the predisposition of LDD. Large-scale and well-designed international studies are needed to further analyze this field.
Topics: Genetic Predisposition to Disease; Humans; Intervertebral Disc Degeneration; Polymorphism, Genetic; Receptors, Calcitriol
PubMed: 27613009
DOI: 10.1007/s00586-016-4771-2 -
Journal of the Association For Research... Feb 2024To assess the available evidence to support a genetic contribution and define the role of common and rare variants in tinnitus.
PURPOSE
To assess the available evidence to support a genetic contribution and define the role of common and rare variants in tinnitus.
METHODS
After a systematic search and quality assessment, 31 records including 383,063 patients were selected (14 epidemiological studies and 17 genetic association studies). General information on the sample size, age, sex, tinnitus prevalence, severe tinnitus distribution, and sensorineural hearing loss was retrieved. Studies that did not include data on hearing assessment were excluded. Relative frequencies were used for qualitative variables to compare different studies and to obtain average values. Genetic variants and genes were listed and clustered according to their potential role in tinnitus development.
RESULTS
The average prevalence of tinnitus estimated from population-based studies was 26.3% for any tinnitus, and 20% of patients with tinnitus reported it as an annoying symptom. One study has reported population-specific differences in the prevalence of tinnitus, the white ancestry being the population with a higher prevalence. Genome-wide association studies have identified and replicated two common variants in the Chinese population (rs2846071; rs4149577) in the intron of TNFRSF1A, associated with noise-induced tinnitus. Moreover, gene burden analyses in sequencing data from Spanish and Swede patients with severe tinnitus have identified and replicated ANK2, AKAP9, and TSC2 genes.
CONCLUSIONS
The genetic contribution to tinnitus is starting to be revealed and it shows population-specific effects in European and Asian populations. The common allelic variants associated with tinnitus that showed replication are associated with noise-induced tinnitus. Although severe tinnitus has been associated with rare variants with large effect, their role on hearing or hyperacusis has not been established.
Topics: Humans; Tinnitus; Genome-Wide Association Study; Hearing; Hearing Loss, Sensorineural; Hyperacusis
PubMed: 38334885
DOI: 10.1007/s10162-024-00925-6 -
Scientific Reports Jul 2020Translation of survival benefits observed in glioblastoma clinical trials to populations and to longer-term survival remains uncertain. We aimed to assess if... (Comparative Study)
Comparative Study Meta-Analysis
Translation of survival benefits observed in glioblastoma clinical trials to populations and to longer-term survival remains uncertain. We aimed to assess if ≥ 2-year survival has changed in relation to the trial of radiotherapy plus concomitant and adjuvant temozolomide published in 2005. We searched MEDLINE and Embase for population-based studies with ≥ 50 patients published after 2002 reporting survival at ≥ 2 years following glioblastoma diagnosis. Primary endpoints were survival at 2-, 3- and 5-years stratified by recruitment period. We meta-analysed survival estimates using a random effects model stratified according to whether recruitment ended before 2005 (earlier) or started during or after 2005 (later). PROSPERO registration number CRD42019130035. Twenty-three populations from 63 potentially eligible studies contributed to the meta-analyses. Pooled 2-year overall survival estimates for the earlier and later study periods were 9% (95% confidence interval [CI] 6-12%; n/N = 1,488/17,507) and 18% (95% CI 14-22%; n/N = 5,670/32,390), respectively. Similarly, pooled 3-year survival estimates increased from 4% (95% CI 2-6%; n/N = 325/10,556) to 11% (95% CI 9-14%; n/N = 1900/16,397). One study with a within-population comparison showed similar improvement in survival among the older population. Pooled 5-year survival estimates were 3% (95% CI 1-5%; n/N = 401/14,919) and 4% (95% CI 2-5%; n/N = 1,291/28,748) for the earlier and later periods, respectively. Meta-analyses of real-world data suggested a doubling of 2- and 3-year survival in glioblastoma patients since 2005. However, 5-year survival remains poor with no apparent improvement. Detailed clinically annotated population-based data and further molecular characterization of longer-term survivors may explain the unchanged survival beyond 5 years.
Topics: Brain Neoplasms; Cancer Survivors; Chemotherapy, Adjuvant; Disease-Free Survival; Glioblastoma; Humans; Risk; Temozolomide; Time Factors; Treatment Outcome
PubMed: 32669604
DOI: 10.1038/s41598-020-68011-4 -
Tumour Biology : the Journal of the... May 2014The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this... (Meta-Analysis)
Meta-Analysis Review
The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this meta-analysis was conducted to clarify the association between VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) and cancer risk. One hundred twenty-six studies were enrolled through PubMed. For VDR BsmI polymorphism, significantly increased cancer risks were observed in the overall analysis. In the further stratified analysis, increased risks were observed in colorectal and skin cancer, especially in Caucasian population. However, no significant associations were observed in other VDR polymorphisms in the overall analysis. In the further subgroup analysis, increased risks were found in oral, breast, and basal cell cancer while decreased risk was found in prostate cancer in t allele carriers of TaqI polymorphism. For VDR FokI polymorphism, increased risks were found in ovarian and skin cancer while decreased risk in glioma in f allele carriers. For VDR ApaI polymorphism, increased risk was observed in basal cell cancer, especially in Asian population in a allele carriers. In conclusion, these results indicated that b allele of BamI polymorphism was a risk factor for cancer susceptibility. Meanwhile, t allele of TaqI polymorphism was a risk factor for oral, breast, and basal cell cancer and a protective factor for prostate cancer. Moreover, f allele of FokI polymorphism was a risk factor for ovarian and skin cancer and a protective factor for glioma. Finally, a allele of ApaI polymorphism was a risk factor for basal cell cancer in Asian population.
Topics: Alleles; Deoxyribonucleases, Type II Site-Specific; Genetic Predisposition to Disease; Humans; Neoplasms; Polymorphism, Genetic; Publication Bias; Receptors, Calcitriol; Risk
PubMed: 24408013
DOI: 10.1007/s13277-013-1544-y -
Human Mutation Apr 2003Phenylketonuria (PKU) is heterogeneous. More than 400 different mutations in the phenylalanine hydroxylase (PAH) gene have been identified. In a systematic review of the... (Review)
Review
Phenylketonuria (PKU) is heterogeneous. More than 400 different mutations in the phenylalanine hydroxylase (PAH) gene have been identified. In a systematic review of the molecular genetics of PKU in Europe we identified 29 mutations that may be regarded as prevalent in European populations. Comprehensive regional data for these mutations were collated from all available studies. The spectrum of mutations found in individual regions results from a combination of factors including founder effect, range expansion and migration, genetic drift, and probably heterozygote advantage. Common mutations include R408W on a haplotype 2 background in Eastern Europe, IVS10-11G>A in the Mediterranean, IVS12+1G>A in Denmark and England, Y414C in Scandinavia, I65T in Western Europe, and R408W on haplotype 1 in the British Isles. Molecular data from mild hyperphenylalaninemia (MHP) patients are available from a number of countries, but it is currently not possible to calculate relative allele frequencies. The available data on PAH mutations are useful for the understanding of both the clinical features and the population genetics of PAH deficiency in Europe.
Topics: Europe; Genetics, Population; Humans; Mutation; Phenylketonurias
PubMed: 12655544
DOI: 10.1002/humu.10192 -
Journal of Clinical Pharmacy and... Jun 2018Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key... (Meta-Analysis)
Meta-Analysis Review
WHAT IS KNOWN AND OBJECTIVE
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key enzyme in PHT metabolism. The aim of this meta-analysis was to evaluate the association between CYP2C9*3 and PHT-induced SJS/TEN.
METHODS
An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE, PubMed, OVID and EBSCO. Studies exploring the relationship between CYP2C9*3 and PHT-induced SJS and TEN were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3).
RESULTS AND DISCUSSION
Four studies, with 117 PHT-induced SJS/TEN cases and 338 matched controls (PHT-tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP2C9*3 allele, comparing both matched controls (OR, 8.93; 95% CI, 2.63-30.36; P = .0005) with substantial heterogeneity (I = 46%) and population controls (OR, 8.88; 95% CI, 5.01-15.74; P < .00001).
WHAT IS NEW AND CONCLUSION
A significant association between CYP2C9*3 and PHT-induced SJS/TEN was identified, especially in a Thai population. CYP2C9*3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN. Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP2C*3 on blood levels of PHT and its metabolites, and their association with SJS/TEN.
Topics: Alleles; Anticonvulsants; Cytochrome P-450 CYP2C9; Genetic Markers; Humans; Phenytoin; Stevens-Johnson Syndrome
PubMed: 29274302
DOI: 10.1111/jcpt.12660