Individual Genetic Association Studies Research Articles

LncRNA growth arrest-special 5 polymorphisms and predisposition to cancer: A meta-analysis.

The lncRNA growth arrest-special 5 (GAS5) is a critical tumor suppressor lncRNA, and its expression level has been found to be decreased in many types of cancers. So GAS5 polymorphisms are also likely to influence predisposition to many types of malignant diseases. Nevertheless, the relationships between GAS5 polymorphisms and cancer are still controversial. Thus, the authors designed this meta-analysis to get a more statistically reliable conclusion. The authors searched PubMed, Embase, and Web of Science for eligible studies. A total of 12 eligible studies involving 8693 cancer cases and 10,805 controls were pooled and analyzed in this meta-analysis. Among GAS5 polymorphisms, only GAS5 rs145204276 insertion/deletion polymorphism could be analyzed in a meta-analysis with regard to predisposition to cancer since no any other GAS5 polymorphisms were explored by at least two individual genetic association studies. All eligible studies were found to be of Asian origin. Although the overall pooled meta-analysis results did not show any significant associations between rs145204276 insertion/deletion polymorphism and a predisposition to cancer, rs145204276 insertion/deletion polymorphism was demonstrated to be significantly associated with a predisposition to gastric cancer (dominant comparison: P<0.0001; recessive comparison: P=0.005; over-dominant comparison: P=0.0003; over-dominant comparison: P<0.0001) in Asians in further subgroup analyses. This meta-analysis demonstrated that GAS5 rs145204276 insertion/deletion polymorphism was associated with a predisposition to gastric cancer in Asians. Nevertheless, considering that this positive finding was only based on three eligible studies from the same area, future studies with larger sample sizes in other populations are still warranted to test the robustness of our findings.

Update on Asthma Genetics: Results From Meta-Analyses of Candidate Gene Association Studies.

Several studies have investigated the risk factors associated with asthma. Both genetic and environmental factors are considered to contribute to asthma susceptibility. Individual genetic association studies usually suffer from small sample size leading to biased results. Meta-analysis is a powerful tool that has the potential to resolve this limitation by increasing the statistical power of analyses. The current review summarizes the recent knowledge concerning genetic factors involved in asthma predisposition based on meta-analyses. Using the keywords: asthma, meta-analysis, polymorphism, we searched Pubmed, Medline, Embase and Google Scholar databases for the associated articles. Genetic polymorphisms in twenty-three genes are associated with asthma risk in meta-analyses. However, polymorphisms in nine genes showed none significant association. These findings are used to assess the genetic risk factors and to understand the molecular pathways related to asthma.

Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis.

The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg's funnel plot and Egger's tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95% CI)=1.432 (1.213-1.691)] and Asians-pooled population [C vs. T: OR (95% CI)=1.583 (1.365-1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians.

Non-association of MMP-9 -1562C/T polymorphism with preeclampsia risk: evidence from a meta-analysis

Individual genetic association studies examining the relationship between the MMP-9 -1562C/T polymorphism (rs3918242) and preeclampsia risk have yielded inconsistent results. Objective: This study aims to evaluate the association between the MMP-9 - 1562C/T polymorphism and preeclampsia risk using meta-analysis. Materials and Methods: Relevant studies were identified by searching PubMed database. Data were extracted and statistical analysis was performed using STATA 12.0 software. A total of six publications involving 871 cases and 845 controls were included in this meta-analysis. Results: Combined analysis revealed no association between the MMP-9 -1562C/T polymorphism and preeclampsia risk (allelic model: OR = 1.10, 95% CI 0.86 - 1.41, Pheterogeneity= 0.07; recessive model: OR = 0.38, 95% CI 0.14-1.01, Pheterogeneity= 0.64; dominant model: OR = 1.09, 95% CI 0.70 - 1.69, Pheterogeneity = 0.01; homozygous model: OR = 0.41, 95% CI 0.15 - 1.09, Pheterogeneity = 0.67; heterozygous model: OR = 1.36, 95% CI 0.80 - 2.29, Pheterogeneity = 0.01). Similarly, subgroup analysis by ethnicity showed that MMP-9 -1562C/T polymorphism was not associated with preeclampsia risk in Brazilian (allelic model: OR = 1.37, 95% CI 0.92 - 2.05, Pheterogeneity= 0.61; recessive model: OR = 0.80, 95% CI 0.18 - 3.57, Pheterogeneity= 0.58; dominant model: OR = 1.12, 95%CI 0.60-2.10, Pheterogeneity= 0.03; homozygous model: OR = 0.87, 95%CI 0.19-3.94, Pheterogeneity = 0.62; heterozygous model: OR = 1.55, 95% CI 0.99 - 1.75, Pheterogeneity = 0.32). Conclusion: This meta-analysis indicated that MMP-9 -1562C/T polymorphism was not associated with preeclampsia risk. However, large welldesigned, multi-center epidemiological studies should be carried out in these and other ethnic populations to confirm our findings.

The ABCG2 gene Q141K polymorphism contributes to an increased risk of gout: A meta-analysis of 2185 cases

Objectives. Individual genetic association studies examining the relationship between the ABCG2 gene polymorphisms and gout have yielded inconsistent results. This study aims to evaluate the association between the ABCG2 gene variants and gout using meta-analysis.Materials and methods. Relevant studies were identified by searching databases extensively. The odds ratio (OR) was calculated using a random-effect or fixed-effect model. A Q statistic was used to evaluate homogeneity, and Egger's test and funnel plot were used to assess publication bias. Subgroup analyses on ethnicities and sex were also performed.Results. A total of 7 studies, including 2185 gout patients and 8028 controls from 5 countries or regions, were included and identified for the current meta-analysis. It was found that the A allele or AA genotype of the ABCG2 Q141K polymorphism (rs2231142) had an increased risk of gout in the general population (A allele, p < 0.00001 and AA genotype, p < 0.00001, respectively). On the contrary, CC homozygote played a protective role against the risk of gout (p < 0.00001). Similar results were found in subgroup analyses. However, there was a significant heterogeneity among studies.Conclusions. Existing evidence indicates that the Q141K polymorphism (rs2231142, the A allele and AA genotype) is associated with an increased risk of gout.

MTHFR genetic polymorphisms may contribute to the risk of chronic myelogenous leukemia in adults: a meta-analysis of 12 genetic association studies

Chronic myelogenous leukemia (CML) is a complex disease with a genetic basis. The genetic association studies (GASs) that have investigated the association between adult CML and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the association of these polymorphisms with adult CML risk. A literature search for eligible GAS published before September 15, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. All analyses were performed using the Stata software, version 12.0. Twelve case-control studies were included in this meta-analysis with a total of 932 CML patients and 3,465 healthy controls. For MTHFR C677T (dbSNP: rs1801133, C>T), though the pooled ORs were not significant in the overall population, all the ORs greater than 1 suggested an increased risk of CML for carriers of the risk allele. However, stratified analysis based on genotyping method revealed a significant association in the PCR-restriction fragment length polymorphism (RFLP) subgroup, possibly as a result of heterogeneity. For MTHFR A1298C (dbSNP: rs1801131, A>C), the combined results showed that carriers of the C allele may be associated with a decreased risk of adult CML. Stratified analysis showed that the magnitude of this effect was especially significant among Asians, indicating ethnicity differences in adult CML susceptibility. This meta-analysis shows that the C allele of MTHFR A1298C may be associated with a decreased risk in adult CML, especially among Asians, while MTHFR C677T may not be associated with adult CML risk. However, the development of adult CML may be the result of gene-gene and gene-environment interactions, which should be considered in future individual GAS and subsequent meta-analyses.

Genetics in rheumatoid arthritis beyond HLA genes: What meta-analyses have shown?

ObjectiveRheumatoid arthritis (RA) is a complex disorder with many genetic and environmental factors to account for disease susceptibility. Individual genetic association studies usually suffer from small sample size leading to biased results of polymorphisms association with RA liability. Therefore, meta-analyses seem to resolve this limitation, up to a point, increasing the power of statistical analyses. In this review, we summarize the current knowledge of non-HLA genetic factors contributing to RA predisposition based on meta-analyses. MethodsUsing the key words: rheumatoid arthritis, meta-analysis, and polymorphism, we searched the PubMed database for the associated articles. Up to the middle of November 2012, seventy-nine articles fulfilled the criteria and highlighted the current findings on the genetic factors contributing to RA susceptibility. ResultsThe association with RA was confirmed for 32 gene polymorphisms, being population specific in some cases. However, meta-analyses did not confirm an association in case of 16 gene variants, previously studied in individual studies for their association with RA. ConclusionsThe use of bioinformatics tools and functional studies of the summarized implicated genes in RA pathogenesis could shed light on the molecular pathways related to the disorder, helping to the development of new drug targets for a better treatment of RA.

PON Gene Polymorphisms and Ischaemic Stroke: A Systematic Review and Meta Analysis

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. This study aimed to evaluate the association between the paraoxonase gene variants and ischaemic stroke using systematic review with meta-analysis. 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. 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. 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.

Association of 5-HTT gene polymorphisms with migraine: A systematic review and meta-analysis

Background/aims Serotonin is known to play an important role in the pathogenesis of migraine, but individual genetic association studies that examine the relationship between polymorphisms of serotonin transporter (5-HTT) gene and migraine have yielded inconsistent results. This study aimed to evaluate the association between 5-HTT gene variants (including 5-HTTLPR, VNTR and SNP) and migraine 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 (OR) was calculated using a random-effects or fixed-effects model. Q statistic was used to evaluate homogeneity, and Egger's test and Funnel plot were used to assess publication bias. For family-based association studies, a descriptive analysis was carried out. Results A total of 15 studies were identified for meta-analysis. It was found that the 5-HTT VNTR Stin2.12 allele or 12/12 genotype had an increased risk for migraine in the general population (Stin2.12 allele: OR, 95% CI: 1.34, 1.09–1.64, p = 0.006; 12/12 genotype: OR, 95% CI: 1.55, 1.17–2.05, p = 0.002), but there was no significant association between migraine and 5-HTTLPR or SNP rs2020942. Conclusions Existing evidence indicates that the 5-HTT VNTR polymorphism (mainly the STin2.12 genotype) is associated with an increased risk of migraine in the general population. Future studies with larger sample sizes will be necessary to confirm the present results.

Impact of Hardy–Weinberg equilibrium deviation on allele-based risk effect of genetic association studies and meta-analysis

Deviations from Hardy-Weinberg equilibrium (HWE) in control subjects may bias the estimates of genetic effects in genetic association studies (GAS) and meta-analysis. A large empirical evaluation was carried out to evaluate the impact of HWE deviation and explore the effect of variance adjustment for the allele-based odds ratio in 833 individual GAS and 72 meta-analyses. In individual GAS, the variance adjustment for any deviation from HWE resulted in stronger associations, and 10 GAS (1%) became significant (P < 0.05). One hundred sixteen GAS (14%) showed significant deviation from HWE (P (HWE) < 0.05); however, only 37 GAS (4%) had more than 90% power to detect significant deviation from HWE at the 5% level. In meta-analyses, adjustment for any deviation from HWE improved the significance in 53 meta-analyses (74%). Then, a formal statistical significance (P < 0.05) was revealed for one previously negative meta-analyses whereas one meta-analysis lost its significance. Between-study heterogeneity was enhanced in 50 meta-analyses (69%). None of the meta-analyses lost the significance of heterogeneity (P ( Q ) < 0.10) whereas in one meta-analysis, the non significant heterogeneity became significant. Sensitivity analysis for studies not conforming to HWE (P (HWE) < 0.05) was applied to 45 meta-analyses (69%). Then, the significance of association was increased in 26 the meta-analyses (58%) and one meta-analysis became significant (P < 0.05) whereas seven meta-analyses (16%) were no longer significant. Adjustment for HWE deviation could be an effective strategy for dealing with HWE violations in GAS and meta-analyses.

Synopsis and data synthesis of genetic association studies in hypertension for the adrenergic receptor family genes: the CUMAGAS-HYPERT database.

The adrenergic receptor (adrenoceptor) family genes have been extensively studied as candidate genes in hypertension but the results of individual genetic association studies (GAS) are controversial and inconclusive. To clarify these data, a systematic assessment of GAS for adrenoceptor family genes in hypertension was conducted. Data from 163 GAS involving 7 genes and 37 distinct genetic variants were analyzed and cataloged in CUMAGAS-HYPERT (Cumulative Meta-analysis of Genetic Association Studies-HYPERTension; a web-based information system, which allows the retrieval and synthesis of data from GAS in hypertension, available at http://biomath.med.uth.gr). Data from genome-wide association studies involving the adrenoceptor family genes were also systematically searched. Individual GAS reported inconsistent associations and had limited power to detect modest genetic effects, with only 1.2% having power >80%. Thirteen variants were investigated by three or more studies and their results were subject to meta-analysis. In the main meta-analyses, significant results were shown for five variants (ADRB1 p.Arg389Gly, ADRB1 p.Ser49Gly, ADRB2 g.9368308A>G, ADRB3 p.Trp64Arg, and ADRA1A p.Cys347Arg) under the allelic contrast and/or the dominant model. Subgroup analyses by ethnicity and gender detected significant associations for three variants (ADRB1 p.Arg389Gly in east Asians, ADRB2 p.Gln27Glu in whites, and ADRB3 p.Trp64Arg in whites and in males). Heterogeneity ranged from none to high. No significant associations were recorded from genome-wide studies. There is evidence to implicate adrenoceptor genes in hypertension, although future studies designed to investigate epistatic and gene-environment interactions would allow more solid conclusions to be drawn about the role of these genes in hypertension.

The ANKK1 Kinase Gene and Psychiatric Disorders

The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue.