Estimating the mode of inheritance in genetic association studies of qualitative traits based on the degree of dominance index

<p>Abstract</p> <p>Background</p> <p>The biological justification for the choice of the genetic mode in genetic association studies (GAS) is seldom available. Then, the mode of inheritance is approximated by investigating a number of non-orthogonal genetic contrasts making the interpretation of results difficult.</p> <p>Methods</p> <p>We propose to define the mode of inheritance by the significance of the deviance of the co-dominant contrast and the degree of dominance (<it>h</it>), which is a function of two orthogonal contrasts (the co-dominant and additive). Non-dominance exists when the co-dominant contrast is non-significant and, hence, the risk effect of heterozygotes lies in the middle of the risk of the two homozygotes. Otherwise, dominance (including over- and under-dominance) is present and the direction of dominance depends on the value of <it>h</it>.</p> <p>Results</p> <p>Simulations show that <it>h </it>may capture the real mode of inheritance and it is affected by deviations from Hardy-Weinberg equilibrium (HWE). In addition, power for detecting significance of <it>h </it>when the study conforms to HWE rule increases with the degree of dominance and to some extent is related to the mutant allele frequency.</p> <p>Conclusion</p> <p>The introduction of the degree of dominance provides useful insights into the mode of inheritance in GAS.</p

An NOS3 Haplotype is Protective against Hypertension in a Caucasian Population

The endothelial nitric oxide synthase gene (NOS3) has been implicated in the development of hypertension, although the specific role of variants and haplotypes has not been clarified. In this study, the association of three polymorphisms (promoter T786C, intronic 4a/b, and nonsynonymous G894T) was tested in a case-control sample of 230 patients with essential hypertension and 306 healthy controls. Haplotype analysis was also performed. The mutant allele a∗ of the 4a/b polymorphism showed a protective effect against hypertension under a dominant model (odds ratio = 0.64, 95% confidence interval (0.44–0.93)), although this effect was not significant after the adjustment for covariates (P = 0.06). The estimated frequency of the haplotype composed of the T786∗, 4a∗, and G894∗ alleles was significantly higher in controls (5.5%) compared to cases (2%). These results indicate that although individual NOS3 polymorphisms are not associated with hypertension, a rare haplotype of the gene might be protective against the development of hypertension

Reporting quality of randomized controlled trials in Restless Legs Syndrome based on the CONSORT statement

Randomized Controlled Trials (RCTs) are the cornerstone of modern medical research and their reporting may not always be optimal. The CONSORT (CONsolidated Standards of Reporting Trials) statement is an evidence-based means of improving and assessing the quality of these trials. The aim of the present study was to assess the reporting quality of published RCTs on the Restless Legs Syndrome (RLS) based on a checklist stemming from the CONSORT statement. RCTs involving patients with RLS were searched for into medical electronic databases. Inclusion criteria were English language of publication and the randomization of RLS patients in a minimum of two treatment cohorts of different medicinal orientations. The reporting quality was evaluated by the means of the aforementioned 38-item CONSORT checklist and the articles were divided into three 6-year periods. Descriptive statistics were used to make the comparisons. Fifty four (54) eligible trials were found, published in 21 different scientific journals. The average CONSORT compliance score was 56.6% (23.68%-84.21%). CONSORT-endorsing journals had a mean CONSORT compliance of 58.47%, whereas non-endorsing journals 50.4%. The median CONSORT compliance for articles published in low (IF7) ranked journals was 52.63%, 56.57% and 59.21% respectively. Throughout the whole 1998-2016 period, 14 items (36.8%) were reported in >75% of the articles. This study shows that the reporting of RLS-related RCTs is suboptimal, regardless of the time period, the quality of the publishing journal and the endorsing or not of the CONSORT statement

Erosive Hand Osteoarthritis is Associated with Subclinical Atherosclerosis and Endothelial Dysfunction

Chronic inflammatory disorders have been associated with accelerated atherosclerosis and increased cardiovascular (CV) risk. Recent evidence suggests that erosive hand osteoarthritis (EOA) has considerable inflammation; therefore, we examined the presence of subclinical atherosclerosis and endothelial dysfunction in EOA. Twenty-four patients with EOA and 24 age- and sex-matched healthy individuals without clinical OA were included in the study. No subject had a history of CV disease. Intima-media thickness (IMT) and atheromatous plaques in the common carotid and common femoral arteries were measured by Doppler ultrasonography. The endothelium-dependent, flow-mediated dilatation (FMD) and endothelium-independent, sublingual glyceryl trinitrate (NTG)-induced dilatation (NMD) of the brachial artery were assessed. The EOA patients had significantly elevated systolic and diastolic blood pressure (p\u3c0.001 for both). The 10-year risk of general CV disease, as predicted with the Framingham Risk Score, was similar in patients and controls (p=0.18). IMT of both common carotid and common femoral artery were increased in EOA (p=0.01 and p\u3c0.01, respectively), but the frequency of atherosclerotic plaques was not increased. There was no difference in FMD and NMD between the two groups, but the difference between FMD and NMD was increased in EOA. In conclusion, this small controlled study showed an association between EOA and subclinical atherosclerosis that cannot be fully attributed to traditional CV risk factors, as assessed by the Framingham score. These results suggest that chronic, low-grade inflammation is implicated in atherosclerosis in EOA

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

Selfishness versus functional cooperation in a stochastic protocell model

How to design an "evolvable" artificial system capable to increase in complexity? Although Darwin's theory of evolution by natural selection obviously offers a firm foundation, little hope of success seems to be expected from the explanatory adequacy of modern evolutionary theory, which does a good job at explaining what has already happened but remains practically helpless at predicting what will occur. However, the study of the major transitions in evolution clearly suggests that increases in complexity have occurred on those occasions when the conflicting interests between competing individuals were partly subjugated. This immediately raises the issue about "levels of selection" in evolutionary biology, and the idea that multi-level selection scenarios are required for complexity to emerge. After analyzing the dynamical behaviour of competing replicators within compartments, we show here that a proliferation of differentiated catalysts and/or improvement of catalytic efficiency of ribozymes can potentially evolve in properly designed artificial cells. Experimental evolution in these systems will likely stand as beautiful examples of artificial adaptive systems, and will provide new insights to understand possible evolutionary paths to the evolution of metabolic complexity

Preservative-free versus preserved latanoprost eye drops for reducing intraocular pressure: a non-inferiority phase III randomized, multi-center, single-blind, parallel-group controlled trial

Background: The aim of this study was to test the non-inferiority of preservative-free (PF) latanoprost 50 μg/mL multi-dose ophthalmic solution versus the marketed benzalkonium chloride (BAK)-preserved latanoprost 50 μg/mL ophthalmic solution in patients with open-angle glaucoma and patients with ocular hypertension. Methods: This was a prospective, national, randomized, multi-center, observer-blind, parallel-group controlled clinical trial. Patients were randomized to receive either PF or BAK-preserved latanoprost once daily for 12 weeks. The primary endpoint was the change in intraocular pressure (IOP) at 8:00 AM in the affected eye between the end of the treatment (week 12) and the baseline (week 0). Secondary measurements were taken at weeks 2 and 6, with IOP being recorded at 8:00 AM, 12:00 PM, and 4:00 PM. Results: A total of 158 patients were included in the per protocol (PP) population (77 in the PF latanoprost treatment arm and 81 patients in the BAK-preserved latanoprost treatment arm). PF latanoprost was non-inferior to BAK-preserved latanoprost in reducing IOP at 8:00 AM in the study eye from the baseline (week 0) to the end of the treatment (week 12). The point estimate of the between-treatment difference was 0.1 mmHg (95% confidence interval: -0.646, 0.847). Mean between-group differences in IOP reduction from the baseline to each of the secondary measurements were also similar between the two treatment arms. The two treatments were well tolerated and had comparable adverse event profiles. Conclusions: PF latanoprost was non-inferior to BAK-preserved latanoprost in reducing IOP in patients with open-angle glaucoma or ocular hypertension. Both treatments were well tolerated

Polymorphisms of the endothelial nitric oxide synthase (NOS3) gene in preeclampsia: a candidate-gene association study

<p>Abstract</p> <p>Background</p> <p>The endothelial nitric oxide synthase gene (<it>NOS3</it>) has been proposed as a candidate gene for preeclampsia. However, studies so far have produced conflicting results. This study examines the specific role of variants and haplotypes of the <it>NOS3 </it>gene in a population of Caucasian origin.</p> <p>Methods</p> <p>We examined the association of three common variants of the <it>NOS3 </it>gene (4b/a, T-786C and G894T) and their haplotypes in a case-control sample of 102 patients with preeclampsia and 176 women with a history of uncomplicated pregnancies. Genotyping for the <it>NOS3 </it>variants was performed and odds ratios and 95% confidence intervals were obtained to evaluate the association between <it>NOS3 </it>polymorphisms and preeclampsia.</p> <p>Results</p> <p>The single locus analysis for the three variants using various genetic models and a model-free approach revealed no significant association in relation to clinical status. The analysis of haplotypes also showed lack of significant association.</p> <p>Conclusions</p> <p>Given the limitations of the candidate-gene approach in investigating complex traits, the evidence of our study does not support the major contributory role of these common <it>NOS3 </it>variants in preeclampsia. Future larger studies may help in elucidating the genetics of preeclampsia further.</p

Non-inferiority evaluation of preservative-free latanoprost/timolol eye drops solution versus preserved latanoprost/timolol eye drops in patients with high intraocular pressure and open-angle glaucoma

Background: This study aimed to evaluate the non-inferiority and safety of a newly developed preservative-free (PF) multi-dose latanoprost/timolol ophthalmic solution, compared with the benzalkonium chloride (BAK)-preserved fixed combination, in patients with open-angle glaucoma and ocular hypertension.Methods: A Phase III randomized multi-center observer-blind parallel-group clinical trial was conducted. A total of 210 adult patients (aged over 18 years) were randomly treated with the PF- or the BAK-preserved latanoprost/timolol solution once daily in the affected eye(s) for 12 weeks. Follow-up visits were scheduled at weeks 2, 6, and 12; intraocular pressure (IOP) was recorded at 8:00 AM, 12:00 PM, and 4:00 PM. The primary efficacy endpoint to prove non-inferiority was the IOP change at 8:00 AM (± 1 hour) from the baseline to the end of treatment (week 12) in the studied eye. Safety parameters were also assessed.Results: In total, 196 patients completed the study. The pressure-lowering effect of the PF eye drops was comparable to that of the preserved formulation at all time points. Latanoprost/timolol PF formulation was non-inferior to the BAK-preserved solution as shown by the change in IOP from day 0 to week 12. The point estimate of the inter-treatment difference was 0.624 mmHg (95% CI: -0.094, 1.341). Both treatments were well-tolerated during the study, and they had similar adverse event profiles.Conclusions: PF-latanoprost/timolol combination was found to be non-inferior to the BAK-preserved formulation based on the efficacy at all times, with similar local tolerance

Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations