Association between SMAD3 gene polymorphisms and osteoarthritis risk: a systematic review and meta-analysis.
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ABSTRACT: Objective
Several studies have been performed to investigate the association between SMAD3 gene polymorphism and osteoarthritis (OA), but the results were inconclusive. This study aims to determine whether SMAD3 polymorphism is associated with risk of OA.Method
A comprehensive literature search in PubMed, Embase, and ISI Web of Science for relevant studies was performed. After extracting data from eligible studies, we chose the fixed or random effect model according to the heterogeneity test. Estimation of publication bias and sensitivity analysis were conducted to confirm the stability of this meta-analysis.Results
In total, 10 studies from 6 articles with 5093 OA patients and 5699 controls were enrolled in this meta-analysis. The combined results revealed significant association between SMAD3 rs12901499 polymorphism and the risk of OA (allele model: OR 1.21, 95% CI 1.07-1.38). Subgroup analysis revealed that G allele increased the risk of OA in Caucasians, but not in Asians (allele model: Caucasians: OR 1.31, 95% CI 1.18-1.44; Asians: OR 1.24, 95% CI 0.95-1.61). And the pooled results revealed significant association between SMAD3 rs12901499 polymorphism and both knee and hip OA (knee OA: OR 1.18, 95% CI 1.04-1.34; hip OA: OR 1.31, 95% CI 1.18-1.44).Conclusion
The current meta-analysis revealed that the G variant of SMAD3 rs12901499 polymorphism increased the risk of OA in Caucasians. Further well-designed studies with larger sample size in different ethnic populations are required to confirm these results.
SUBMITTER: Hong JQ
PROVIDER: S-EPMC6134766 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose:This study was conducted to assess and synthesize the current evidence on the association between rs12901499 polymorphism in SMAD3 gene and risk of osteoarthritis (OA). Materials and methods:Four electronic databases, including PubMed, Embase, ISI Web of Science, and CENTRAL were systematically searched for potential studies. Summary odds ratio and corresponding 95% CI were calculated to evaluate the association. Risk of bias was assessed through the Newcastle-Ottawa Scale. Subgroups and sensitivity analyses were performed using the RevMan 5.3 software. Publication bias was evaluated by Egger's and Begg's tests. Power analysis was conducted using the Power and Sample Size Calculation program. Results:Eight case-control studies containing 5,625 patients with OA and 5,600 healthy controls were obtained for the meta-analysis. After excluding cohorts with inadequate power, the pooled data supported that G allele carriers of rs12901499 had a significantly increased risk of OA (odds ratio 1.31, 95% CI: 1.21 to 1.43, P<0.00001). When stratified by OA site and ethnicity, the association remained statistically significant. Conclusion:The combined results evidently supported that rs12901499 polymorphism in SMAD3 gene is significantly associated with OA vulnerability across both Caucasian and Asian populations.
| S-EPMC5960251 | biostudies-literature
Project description:BACKGROUND Toll-like receptor 4 (TLR4) plays a pivotal role in the innate immune response and is hyperactivated in preeclampsia (PE). Several researchers have published conflicting evidence for TLR4 rs4986790 and rs4986791 single nucleotide polymorphisms (SNPs) as risk factors for PE. The present meta-analysis was conducted to obtain a more definitive conclusion about the effects of these SNPs on PE susceptibility. MATERIAL AND METHODS To determine the correlation between rs4986790 and rs4986791 polymorphisms in the TLR4 gene and susceptibility to PE, the PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure, and Chinese WANFANG databases were searched for eligible articles. Statistical analysis was performed with STATA software, version 12.0. Pooled odds ratios with corresponding 95% confidence intervals (CIs) were extracted for assessment of correlation strength. RESULTS We identified 5 studies including 578 cases and 631 controls for the rs4986790 SNP and 4 studies including 469 cases and 457 controls for the rs4986791 SNP, mainly from a White population. The pooled analyses showed no statistical relationship between the polymorphisms rs4986790 and rs4986791 and PE susceptibility in 5 genetic models (all P>0.05). Moreover, the allelic and dominant gene models of rs4986790 and the allelic, heterozygous, and dominant gene models of rs4986791 had high heterogeneity. The sensitivity analysis explored potential sources of heterogeneity and confirmed the findings of this meta-analysis. CONCLUSIONS TLR4 rs4986790 and rs4986791 polymorphisms may not be implicated in PE susceptibility, primarily in a White population. More high-quality studies of genetic associations with PE are warranted.
| S-EPMC8343538 | biostudies-literature
Project description:INTRODUCTION:The role of genetic factors influencing osteoarthritis (OA) susceptibility is well documented and several candidate genes have been identified to be associated with it. Among these genes are Bone Morphogenetic Protein 5 (BMP5) and Smad family member 3 (SMAD3), all involved in Transforming Growth Factor (TGF) signaling pathway. The knee is the commonly affected joint, and knee OA has an especially high prevalence in Asian population. AIM:To investigate associations between Single Nucleotide Polymorphisms (SNPs) rs12901499 in SMAD3 and rs921126 in the BMP5 gene with knee OA susceptibility in and around Lucknow, Uttar Pradesh, India. MATERIALS AND METHODS:SNPs rs12901499 in SMAD3 and rs921126 in BMP5 were genotyped in patients with knee OA and age- sex matched OA-free controls from our population. A total of 450 patients with knee OA and 458 controls were enrolled in the study. Venous blood samples were obtained from all cases as well as controls for PCR-RFLP (Polymerase Chain Reaction- Restriction Fragment Length Polymorphism). Data was collected and entered in excel sheets. Statistical analyses of the data were performed using statistical software package SPSS version 16.0. Chi-square, Student's t-test and logistic regression tests were used to analyse the data. RESULTS:GA and GG genotypes of both SNPs (rs12901499 and rs921126), and variant G, were associated with a significantly increased risk of knee OA. A significantly increased risk of knee OA was associated with the genotype GG and GA of rs12901499 (p < 0.03 and p <0.004 respectively) and rs921126 (p< 0.0001 and p<0.001 respectively) compared with the AA genotype. In addition, those bearing at least one G allele (GG + GA) had a significantly increased risk of knee OA compared with those without the G allele (AA) in rs921126 (p< 0.0001). However, in rs12901499, significant association with the risk of knee OA was not found (p<0.4). On age and gender based stratification, the association between the risk of OA and rs921126 GG mutant compared with AA homozygotes was strong in both gender (adjusted OR= 2.93 for male and 2.25 for female) and in those aged >55 years (adjusted OR= 3.4), similarly in rs12901499, GG mutant compared with AA homozygote was strong in female (adjusted OR= 1.5) and in those aged >55 years (adjusted OR= 1.5). CONCLUSION:The results showed that both in SMAD3 rs12901499 and BMP5 921126, G allele is significantly associated with knee OA. A to G change and variant G genotype may contribute to knee OA risk in our study population of Lucknow.
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Project description:BACKGROUND: Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association. METHODS: We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software. RESULTS: We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08-1.68), P = .008), rs13181 (OR = 1.18 (1.06-1.31), P = .002), and rs25487 (OR = 1.12 (1.03-1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68-0.89), P = .0004) and rs12917 (OR = 0.84 (0.73-0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed. CONCLUSION: This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.
| S-EPMC4022225 | biostudies-literature
Project description:Though numerous studies have been conducted to investigate the associations between five 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) and prostate cancer (PCa) risk, the available results remained contradictory. Therefore, we performed a comprehensive meta-analysis to derive a precise estimation of such associations. We searched electronic databases PubMed, EMBASE, Web of Science and Wan Fang for the relevant available studies up to February 1st, 2017, and 39 articles were ultimately adopted in this meta-analysis. All data were extracted independently by two investigators and recorded in a unified form. The strength of association between 8q24 polymorphisms and PCa susceptibility was evaluated by the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analysis was conducted based on ethnicity, source of controls and genotypic method. Overall, a total of 39 articles containing 80 studies were adopted in this meta-analysis. The results of this meta-analysis indicated that five 8q24 polymorphisms above were all related to PCa susceptibility. Besides, in the subgroup analysis by ethnicity, all selected 8q24 polymorphisms were significantly associated with PCa risk in Asian population. In addition, stratification analysis by source of controls showed that significant results were mostly concentrated in the studies' controls from general population. Moreover, when stratified by genotypic method, significant increased PCa risks were found by TaqMan method. Therefore, this meta-analysis demonstrated that 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) were associated with the susceptibility to PCa, which held the potential biomarkers for PCa risk.
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Project description:Current studies have explored the correlation between the single nucleotide polymorphisms (SNPs) of pregnane X receptor (PXR) and cancer risk. However, the findings were conflicting. Hence, we performed a comprehensive review and meta-analysis for these researches to determine the effect of PXR polymorphisms on the risk of cancer. Eligible publications were collected based on a series of rigorous inclusion and exclusion criteria. In consequence, a total of eight case-control studies (from seven citations) covering 11143 cases and 12170 controls were involved in a meta-analysis of ten prevalent PXR SNPs (rs10504191 G/A, rs3814058 C/T, rs6785049 A/G, rs1464603 A/G, rs1523127 A/C, rs2276706 G/A, rs2276707 C/T, rs3732360 C/T, rs3814055 C/T, rs3814057 A/C). The correlations between PXR SNPs and cancer risk were estimated by odds ratios (ORs) with their 95% confidence intervals (95%CIs). The findings demonstrated that rs3814058 polymorphism (CT compared with CC: pooled OR = 1.280, P=6.36E-05; TT compared with CC: pooled OR = 1.663, P=2.40E-04; dominant model: pooled OR = 1.382, P=2.58E-08; recessive model: pooled OR = 1.422, P=0.002; T compared with C: pooled OR = 1.292, P=6.35E-05) and rs3814057 polymorphism (AC compared with AA: pooled OR = 1.170, P=0.036; dominant model: pooled OR = 1.162, P=0.037) were associated with the risk of overall cancer. In stratified analyses, rs3814058 polymorphism was revealed to increase the cancer risk in lung cancer subgroup. In summary, this meta-analysis indicates that the rs3814057 and rs3814058 polymorphisms of PXR gene play crucial roles in the pathogenesis of cancer and may be novel biomarkers for cancer-forewarning in overall population or in some particular subgroups.
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Project description:BACKGROUND:Asthma is a common complex chronic, inflammatory polygenic disease with heterogeneous manifestations, affecting individuals of all age groups and posing an immense burden on healthcare resources. A number of studies have identified the association between a disintegrin and metalloprotease 33 (ADAM33) polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of ADAM33 variants in asthma susceptibility. METHODS:Eligible case-control studies published between January 2000 and June 2018 was searched and retrieved from online electronic databases. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect. RESULTS:A total of 63 case-control studies were finally screened out, including 13,280 asthma patients and 13,340 controls. Eleven SNPs of ADAM33 gene were identified. Our results detected a significant association between ADAM33 T2, Q1, F?+?1 and AA genotype of T?+?1 polymorphisms and asthma risk in total population. Subgroup analysis by ethnicities showed that the alleles and genotypes of T2, Q1 and F?+?1 polymorphisms were associated with asthma susceptibility among Asian populations, while V4 polymorphism was associated with asthma among Caucasian populations. Subgroup analysis by ages showed that T2, F?+?1 and ST?+?4 polymorphisms were associated with childhood asthma, while Q1 and V4 polymorphisms were associated with asthma risk in adults. Subgroup analysis by asthma severity showed that only the G allele of ADAM33 T1 polymorphism was associated with the severity of asthma when compared with the controls. In addition, T2, Q1 and F?+?1 polymorphisms of ADAM33 were significantly associated with increased the asthma risk in Chinese asthma patients. CONCLUSIONS:Our results found that T2, Q1 and F?+?1 polymorphisms of ADAM33 gene might contribute to asthma risk. Future well-designed case-control studies with large population and more ethnicities are still needed to estimate the association.
| S-EPMC6385425 | biostudies-literature
Project description:OBJECTIVE:Studies have assessed the association between aspartic acid (D)-repeat polymorphism in the gene encoding Asporin (ASPN) and knee osteoarthritis (KOA) risk, but the results were inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between ASPN gene D-repeat polymorphism and KOA risk. METHODS:Eligible studies were identified by searching several electronic databases for relevant reports published before September 2016. The pooled odds ratios (ORs) for the association between ASPN polymorphism and KOA and their corresponding 95% confidence intervals (CIs) were estimated using the random- or fixed-effect model. RESULTS:A total of eleven case-control studies in ten publications with 4610 KOA cases and 3621 controls were included for the ASPN D-repeat polymorphism. Overall, no significant association was detected for D14 allele carrier (D14 vs. D13: OR = 1.10, 95% CI = 0.90-1.36, p = 0.32). Meta-analysis of D14 vs. other alleles and D13 vs. other alleles showed the same pattern of KOA association as the D14 vs. D13 (OR = 1.30, 95% CI = 1.00-1.70, p = 0.06; OR = 0.93, 95% CI = 0.82-1.06, p = 0.33, respectively). Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of KOA was found in the European and Asians populations (OR = 1.05, 95% CI = 0.91-1.21, p = 0.49; OR = 0.98, 95% CI = 0.78-1.23, p = 0.88, respectively). CONCLUSIONS:The present meta-analysis suggests that the ASPN D-repeat polymorphism is not associated with an increased KOA risk. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings. LEVEL OF EVIDENCE:Level III diagnostic study.
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Project description:Estrogen receptor-alpha (ER-α) gene PvuII (T/C) and XbaI (A/G) polymorphisms have been hypothesized to be associated with osteoarthritis (OA) risk by several epidemiological studies, however, the available results were inconclusive and conflicting. We conducted a meta-analysis of 10 case-control studies that included 3328 osteoarthritis cases and 6390 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). This meta-analysis showed that the ER-α PvuII and XbaI polymorphisms were not associated with OA risk in overall population. For the PvuII (T/C) polymorphism, however, in the subgroup analysis by country, a significantly reduced risk was observed among Chinese (TC vs. CC: OR = 0.73, 95% CI 0.54-0.99, I (2) = 0%, P heterogeneity = 0.498; dominant model, OR = 0.73, 95% CI = 0.55-0.98, I (2) = 0%, P heterogeneity = 0.555). For the XbaI (A/G) polymorphism, when stratifying by sample size, a significantly elevated risk was found in sample size ≤ 500 (AA vs. GG: OR = 2.60, 95% CI 1.10-6.18, I (2) = 42.9%, P heterogeneity = 0.135; dominant model: OR = 2.04, 95% CI 1.12-3.71, I (2) = 11.4%, P heterogeneity = 0.341; and recessive model: OR = 1.69, 95% CI 1.12-2.55, I (2) = 40.2%, P heterogeneity = 0.154). No publication bias was found in the present study. This meta-analysis suggests that ER-α PvuII (T/C) polymorphism may be associated with a reduced OA risk among Chinese and the XbaI (A/G) polymorphism may not be associated with OA risk, while the observed increase in OA risk for XbaI polymorphism may be due to small-study bias.
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Project description:Transforming growth factor/Smad family member 3 (TGF)-?/Smad3 signalling is essential for maintaining articular cartilage. A relationship between the genetic variants of TGF-? itself, TGF-? signalling and binding molecules, and osteoarthritis (OA) has been reported. Although variants of candidate genes have become prime targets for genetic analysis, their detailed interplay has not been documented. Our goal was to establish whether single nucleotide polymorphisms (SNPs) of TGF-?1, TGF-?RI, Smad3 and tissue inhibitor of metalloproteinases 3 (TIMP3), and their interactions, are associated with knee OA.We performed a case-control association study and genotyped 518 knee patients with OA and 468 healthy controls. All participants were genotyped for TGF-?1 (rs1800469C/T), TGF-?RI (rs1590A/G), Smad3 (rs12901499A/G and rs6494629T/C), and TIMP3 (rs715572G/A and rs1962223G/C) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions.Significant associations were observed for TIMP3 rs715572G/A polymorphisms in knee patients with OA and healthy individuals. The GA heterozygote in TIMP3 (rs715572G/A) was significantly associated with OA (p=0.007). Patient stratification using the Kellgren-Lawrence grading scale showed significant differences in TIMP3 rs715572G/A genotypes between grade 4 knee OA and controls. By MDR analysis, a two-locus model (Smad3 rs6494629T/C and TIMP3 rs715572G/A) of gene-gene interaction was the best for predicting knee OA risk, and its maximum testing accuracy was 57.55% and maximum cross-validation consistency was 10/10.TIMP3 rs715572G/A is a candidate protective gene for severe knee OA. Gene-gene interactions between Smad3 rs6494629T/C and TIMP3 rs715572G/A polymorphisms may play more important protective roles in knee OA.
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