Evaluation of MMP1 and MMP3 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma

Purpose: To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients. Methods: A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1-1607 1G/2G (rs1799750) and MMP3-1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression. Results: The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03-2.10]), since after correction for multiple comparisons, this association was no longer statistically significant. Conclusions: Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients

Synopsis and meta-analysis of genetic association studies in osteoporosis for the focal adhesion family genes: the CUMAGAS-OSTEOporosis information system

<p>Abstract</p> <p>Background</p> <p>Focal adhesion (FA) family genes have been studied as candidate genes for osteoporosis, but the results of genetic association studies (GASs) are controversial. To clarify these data, a systematic assessment of GASs for FA genes in osteoporosis was conducted.</p> <p>Methods</p> <p>We developed Cumulative Meta-Analysis of GAS-OSTEOporosis (CUMAGAS-OSTEOporosis), a web-based information system that allows the retrieval, analysis and meta-analysis (for allele contrast, recessive, dominant, additive and codominant models) of data from GASs on osteoporosis with the capability of update. GASs were identified by searching the PubMed and HuGE PubLit databases.</p> <p>Results</p> <p>Data from 72 studies involving 13 variants of 6 genes were analyzed and catalogued in CUMAGAS-OSTEOporosis. Twenty-two studies produced significant associations with osteoporosis risk under any genetic model. All studies were underpowered (<50%). In four studies, the controls deviated from the Hardy-Weinberg equilibrium. Eight variants were chosen for meta-analysis, and significance was shown for the variants collagen, type I, α₁(<it>COL1A1</it>) G2046T (all genetic models), <it>COL1A1 </it>G-1997T (allele contrast and dominant model) and integrin β-chain β₃(<it>ITGB3</it>) T176C (recessive and additive models). In <it>COL1A1 </it>G2046T, subgroup analysis has shown significant associations for Caucasians, adults, females, males and postmenopausal women. A differential magnitude of effect in large versus small studies (that is, indication of publication bias) was detected for the variant <it>COL1A1 </it>G2046T.</p> <p>Conclusion</p> <p>There is evidence of an implication of FA family genes in osteoporosis. CUMAGAS-OSTEOporosis could be a useful tool for current genomic epidemiology research in the field of osteoporosis.</p

The role of MTHFR gene in multiple myeloma

Case-control studies investigating associations between multiple myeloma (MM) and the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) have provided controversial results. In an attempt to interpret these results, a meta-analysis of all available studies was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using fixed effects (FE) and random effects (RE) models. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. The meta-analysis revealed non-significant heterogeneity between studies (P-q &gt;= 0.65). The dominant model for the effect of 677T allele produced significant association overall [FE OR = 1.23 (1.04-1.47)] and in Caucasians [FE OR = 1.54 (1.14-2.08)], but not in East Asians [FE OR = 1.05 (0.82-1.34)]. Although the cumulative meta-analysis for the dominant model of 677T allele showed a downward trend of RE OR for the period 2000-2007, the association still remained significant. Analysis of the A1298C polymorphisms revealed lack of association both in Caucasians and in East Asians. There is an indication of potential bias: a differential magnitude of effect in large versus small studies emerged. In conclusion, the accumulated evidence indicated an association between MTHFR C677T polymorphism and MM in Caucasians under a dominant model

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia

A meta-analysis of case-control studies that investigated the association between the C677T and/or A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and acute lymphoblastic leukemia (ALL) was carried out. Pooled odds ratios (OR) of various genetic contrasts of each polymorphism were estimated using random (RE) and fixed effects (FE) models. Pooled ORs for combined genotypes and haplotypes were estimated after adjustment for study effect using a log-linear model and the expectation-maximization algorithm in combination with log-linear modeling, respectively. The recessive model for allele 1298C produced a rather marginal association: RE OR: 0.67; 95% confidence interval (CI): 0.46-0.99 and FE OR: 0.64; 95% CI: 0.49-0.84. In Caucasians, the results of the recessive model for allele 1298C was consisted with a protective effect of ALL development: FE OR: 0.63; 95% CI: 0.46-0.87. In childhood ALL, according to the results of the allele contrast and the recessive model for 677T allele it was conceivable that a protective effect exist: RE OR = 0.74; 95% CI: 0.57-0.96 and RE OR: 0.69; 95% CI: 0.51-0.94, respectively. The combined genotypes produced significant pooled OR for the 677CC/1298CC relative to 677CC/1298AA (OR: 0.54; 95% CI: 0.36-0.80). The haplotype 677C/1298C might be more protective to ALL relative to haplotype 677C/1298A (OR: 0.77; 95% CI: 0.61-0.97). When studies not in Hardy-Weinberg equilibrium (HWE) were corrected to account for departures from HWE, then, the pattern of results remained the same. Overall, there is high heterogeneity between the studies in both polymorphisms. A differential magnitude of effect in large versus small studies and alteration of early extremes effects existed

Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: A synthesis of genetic association studies

Background: Acute lymphoblastic leukemia (ALL) is a complex disease with genetic background. The genetic association studies (GAS) that investigated the association between ALL and the MTHFR C677T and A1298C gene variants have produced contradictory or inconclusive results. Materials and methods: In order to decrease the uncertainty of estimated genetic risk effects, a meticulous meta-analysis of published GAS related the variants in the MTFHR gene with susceptibility to ALL was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (ORG). Cumulative and recursive cumulative meta-analyses were also performed. Results: The analysis showed marginal significant association for the C677T variant, overall [OR = 0.91 (0.82-1.00) and ORG = 0.89 (0.79-1.01)], and in Whites [OR = 0.88 (0.77-0.99) and ORG = 0.85 (0.73-0.99)]. The A1298C variant produced non-significant results. For both variants, the cumulative meta-analysis did not show a trend of association as evidence accumulates and the recursive cumulative meta-analysis indicated lack of sufficient evidence for denying or claiming an association. Conclusion: The current evidence is not sufficient to draw definite conclusions regarding the association of MTHFR variants and development of ALL. (C) 2011 Elsevier Ltd. All rights reserved

Field Synopsis and Synthesis of Genetic Association Studies in Osteoarthritis: The CUMAGAS-OSTEO Information System

A comprehensive and systematic assessment of the current status of genetic association studies (GAS) for osteoarthntis was conducted. Data from 327 GAS involving 187 distinct genetic variants were analyzed and cataloged in CUMAGAS-OSTEO, a Web-based information system (http.//biomath.med uth.gr) that allows the retrieval and synthesis of data from GAS on osteoarthritis In individual studies, 66 variants (mostly single nucleotide polymorphisms) showed significant associations with osteoarthntis risk. For 19 variants, the association was significant at P < 0.01, with an increased risk greater than 30%. Only 2 4% of studies had statistical power greater than 50% to detect a modest genetic effect. Nineteen variants were investigated by 4 or more studies, and their results were subjected to meta-analysis Significant associations were derived for 2 variants (GDF5 rs143383, LRCH1 rs912428) in the main meta-analysis and for 2 other variants (TXNDC3 rs4720262, ESR1 rs2234693) in subgroup analysis by ethnicity or osteoarthntic body site. Heterogeneity ranged from none to high In general, there was consistency of genetic effects across ethnic groups and body sites, and there was no differential magnitude of effect in large studies versus small studies CUMAGAS-OSTEO may be a useful tool for identifying pertinent gene-osteoarthritis associations and providing an updated summary of risk effect

Variants of the Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP) Gene and Risk of Stroke: A HuGE Gene-Disease Association Review and Meta-Analysis

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been implicated as a risk factor for stroke. However, genetic association studies that have examined the association between ALOX5AP gene variants (HapA haplotype, HapB haplotype, and SG polymorphisms) and stroke have produced conflicting results. Therefore, the authors performed a meta-analysis of all studies with ALOX5AP genotyping (5,194 stroke cases and 4,566 controls). The meta-analysis showed significant heterogeneity among studies (P(Q) = 0.03, I(2) = 63%) and a nonsignificant association between the HapA haplotype (SG13S25G-SG13S114T-SG13S89G-SG13S32A) and stroke risk (random-effects (RE) odds ratio (OR) = 1.13, 95% confidence interval (CI): 0.88, 1.45). Regarding the HapB haplotype (SG13S377A-SG13S114A-SG13S41A-SG13S35G), there was no association with stroke risk (RE OR = 1.03, 95% CI: 0.77, 1.37). The SG13S114, SG13S89, SG13S25, SG13S32, SG13S35, and SG13S42 polymorphisms were not associated with stroke. The SG13S106 and SG13S377 polymorphisms revealed evidence of marginal association (RE OR = 1.23 (95% CI: 1.03, 1.46) and RE OR = 1.25 (95% CI: 1.04, 1.50), respectively). However, cumulative meta-analysis for the HapA haplotype showed a downward trend of odds ratios over time, and recursive cumulative meta-analysis indicated insufficient evidence for claiming or denying an association. Tests for bias revealed no evidence of biases. Rigorous genetic association studies investigating gene-gene-environment interactions may generate more conclusive claims about the genetics of stroke

Assessing the relative effectiveness and tolerability of treatments in small cell lung cancer: A network meta-analysis

Background: The combination of Cisplatin plus Etoposide (EP) is currently the standard treatment for small cell lung cancer (SCLC). However, a large number of alternative treatments (monotherapies and combinations) have been studied in randomized controlled trials (RCTs) to identify more effective treatments. Aim of the present study was to assess the relative effectiveness and tolerability of these treatments. Methods: PubMed, EMBASE and Cochrane Central Register of Controlled Trials were systematically searched to identify all RCTs that compared treatments for SCLC. Then, effectiveness of the treatments relative to the combination of Cisplatin plus Etoposide, reference treatment) was estimated by performing a network of treatments analysis. The analysis evaluated two efficacy outcomes (complete response - CR and objective response rate - ORR) and two tolerability outcomes (neutropenia and febrile neutropenia). All RCTs that provided data for calculating the odds ratios (OR) for the selected outcomes were considered. The network analysis involved direct and indirect analyses. Results: We identified 71 articles eligible for inclusion, involving 91 different treatments. In total, 16,026 patients were included in the analysis. In the direct analysis the combination of Cisplatin plus Cyclophosphamide plus Etoposide plus Epirubicin showed better response than EP for the ORR outcome, but with worse tolerability (presence of neutropenia). The indirect analysis revealed that the combination of Cisplatin plus Doxorubicin plus Etoposide (plus Vincrisitine) showed better response that EP for the ORR outcome. Conclusions: No therapy shows better response for the two efficacy outcomes (CR and ORR); though, Cisplatin plus Doxorubicin plus Etoposide plus Vincrisitine might be a promising therapy for SCLC. The results should be interpreted with caution because the network was dominated by indirect comparisons. Large scale head-to-head RCTs are needed to confirm the present findings. (C) 2013 Elsevier Ltd. All rights reserved