Publications by authors named "Dario Manfellotto"

47 Publications

Acute cardiovascular events in patients with community acquired pneumonia: results from the observational prospective FADOI-ICECAP study.

BMC Infect Dis 2021 Jan 25;21(1):116. Epub 2021 Jan 25.

Medical Department, Hospital "Buon Consiglio-Fatebenefratelli", Naples, Italy.

Background: The burden of cardiovascular (CV) complications in patients hospitalised for community-acquired pneumonia (CAP) is still uncertain. Available studies used different designs and different criteria to define CV complications. We assessed the cumulative incidence of acute of CV complications during hospitalisation for CAP in Internal Medicine Units (IMUs).

Methods: This was a prospective study carried out in 26 IMUs, enrolling patients consecutively hospitalised for CAP. Defined CV complications were: newly diagnosed heart failure, acute coronary syndrome, new onset of supraventricular or ventricular arrhythmias, new onset hemorrhagic or ischemic stroke or transient ischemic attack. Outcome measures were: in-hospital and 30-day mortality, length of hospital stay and rate of 30-day re-hospitalisation.

Results: A total of 1266 patients were enrolled, of these 23.8% experienced at least a CV event, the majority (15.5%) represented by newly diagnosed decompensated heart failure, and 75% occurring within 3 days. Female gender, a history of CV disease, and more severe pneumonia were predictors of CV events. In-hospital (12.2% vs 4.7%, p < 0.0001) and 30-day (16.3% vs 8.9%, p = 0.0001) mortality was higher in patients with CV events, as well as the re-hospitalisation rate (13.3% vs 9.3%, p = 0.002), and mean hospital stay was 11.4 ± 6.9 vs 9.5 ± 5.6 days (p < 0.0001). The occurrence of CV events during hospitalisation significantly increased the risk of 30-day mortality (HR 1.69, 95% CI 1.14-2.51; p = 0.009).

Conclusion: Cardiovascular events are frequent in CAP, and their occurrence adversely affects outcome. A strict monitoring might be useful to intercept in-hospital CV complications for those patients with higher risk profile.

Trial Registration: NCT03798457 Registered 10 January 2019 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12879-021-05781-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830042PMC
January 2021

The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism.

Int J Cardiol Hypertens 2020 Jun 15;5:100029. Epub 2020 Apr 15.

Clinica dell'Ipertensione Arteriosa, Department of Medicine - DIMED, University of Padua, Italy.

Background And Aim: Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensionlogists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism.

Methods: To identify the most relevant studies, the authors utilized a systematic literature review in international databases by applying the PICO strategy, and then they were required to make use of only those meeting predefined quality criteria. For studies of diagnostic tests, only those that fulfilled the Standards for Reporting of Diagnostic Accuracy recommendations were considered.

Results: Each section was jointly prepared by at least two co-authors, who provided Class of Recommendation and Level of Evidence following the American Heart Association methodology. The guidelines were sponsored by the Italian Society of Arterial Hypertension and underwent two rounds of revision, eventually reexamined by an External Committee. They were presented and thoroughly discussed in two face-to-face meetings with all co-authors and then presented on occasion of the 36th Italian Society of Arterial Hypertension meeting in order to gather further feedbacks by all members. The text amended according to these feedbacks was subjected to a further peer review.

Conclusions: After this process, substantial updated information was generated, which could simplify the diagnosis of primary aldosteronism and assist practicing physicians in optimizing treatment and follow-up of patients with one of the most common curable causes of arterial hypertension.
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http://dx.doi.org/10.1016/j.ijchy.2020.100029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803025PMC
June 2020

Lessons learned from COVID-19 for clinical research operations in Italy: what have we learned and what can we apply in the future?

Tumori 2021 Feb 9;107(1):6-11. Epub 2020 Dec 9.

Clinical Research Department, "Centro Studi" FADOI, Milan, Italy.

The coronavirus disease 2019 (COVID-19) pandemic has stressed the importance of health research as never before. In the specific domain of clinical research, the effort to rapidly find responses to health challenges and therapeutic hypotheses has highlighted the need for efficient, timely, ethically correct research. The guidelines published by the Agenzia Italiana del Farmaco have shown that some useful changes are feasible: simple and rapid methods have been implemented to conduct clinical research in the emergency conditions of the pandemic, maintaining high levels of quality. In this perspective, four Italian scientific associations operating in clinical research have worked together to evaluate which measures, among the ones implemented during the pandemic, have been particularly significant and potentially effective under normal conditions or in case of emergencies, and that therefore will be useful in the future as well.
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http://dx.doi.org/10.1177/0300891620977916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726625PMC
February 2021

Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis.

Clin Epigenetics 2020 11 17;12(1):176. Epub 2020 Nov 17.

Department of Psychiatry, Yale University School of Medicine, VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT, USA.

Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = -0.60, p = 6.26 × 10). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer's disease (KEGG hsa05010, q = 2.2 × 10). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = -2.18, p = 3.34 × 10). Cg13139646 showed co-methylation with cg19203115 (Pearson's r = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = -0.56, p = 8.6 × 10). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.
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http://dx.doi.org/10.1186/s13148-020-00967-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672937PMC
November 2020

COVID-19 pandemic and Internal Medicine Units in Italy: a precious effort on the front line.

Intern Emerg Med 2020 11 31;15(8):1595-1597. Epub 2020 Jul 31.

Department of Internal Medicine, Hospital "Fatebenefratelli-AFaR", Rome, Italy.

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http://dx.doi.org/10.1007/s11739-020-02454-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394267PMC
November 2020

Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses.

Hum Genet 2019 Dec 29;138(11-12):1331-1340. Epub 2019 Oct 29.

Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.

Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of wild-type transthyretin amyloidosis (ATTRwt). To understand the genetics of ATTRm and ATTRwt, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and ATTRwt such as chronic ischaemic heart disease (rs140226130, p = 2.00 × 10), heart failure (rs73956431, p = 2.74 × 10), atrial fibrillation (rs10163755, p = 4.63 × 10), dysphagia (rs2949506, p = 3.95 × 10), intestine diseases (rs970866, p = 7.14 × 10) and anxiety (rs554521234, p = 8.85 × 10). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p = 6.41 × 10) and mononeuropathies of upper limbs (p = 1.22 × 10). Sex differences were also observed in line with ATTRm and ATTRwt epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.
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http://dx.doi.org/10.1007/s00439-019-02078-6DOI Listing
December 2019

What Quality and Safety of Care for Patients Admitted to Clinically Inappropriate Wards: a Systematic Review.

J Gen Intern Med 2019 07 22;34(7):1314-1321. Epub 2019 Apr 22.

Dipartimento di Medicina Clinica e Sperimentale, Università dell'Insubria, Varese, Italy.

Background: In countries with public health system, hospital bed reductions and increasing social and medical frailty have led to the phenomenon of "outliers" or "outlying hospital in-patients." They are often medical patients who, because of unavailability of beds in their clinically appropriate ward, are admitted wherever unoccupied beds are. The present work is aimed to systematically review literature about quality and safety of care for patients admitted to clinically inappropriate wards.

Methods: We performed a systematic review of studies investigating outliers, published in peer-reviewed journals with no time restrictions. Search and screening were conducted by two independent researchers (MLR and ER). Studies were considered potentially eligible for this systematic review if aimed to assess the quality and/or the safety of care for patients admitted to clinically inappropriate units. Our search was supplemented by a hand search of references of included studies. Given the heterogeneity of studies, results were analyzed thematically. We used PRISMA guidelines to report our findings.

Results: We collected 17 eligible papers and grouped them into six thematic categories. Despite their methodological limits, the included studies show increased trends in mortality and readmissions among outliers. Quality of care and patient safety are compromised as patients and health professionals declare and risk analysis displays. Reported solutions are often multicomponent, stress early discharge but have not been investigated in the control group.

Conclusions: Published literature cannot definitely conclude on the quality and safety of care for patients admitted to clinically inappropriate wards. As they may represent a serious threat for quality and safety, and moreover often neglected and under valued, well-designed and powered prospective studies are urgently needed.
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http://dx.doi.org/10.1007/s11606-019-05008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614225PMC
July 2019

Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes.

Diabetes Res Clin Pract 2018 Apr 13;138:158-168. Epub 2018 Feb 13.

Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita Fatebenefratelli Hospital, Dept. of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Aims: An increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance.

Methods: A hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness.

Results: GSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene.

Conclusions: Therefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation. Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.
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http://dx.doi.org/10.1016/j.diabres.2018.02.006DOI Listing
April 2018

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis.

Eur J Hum Genet 2017 09 21;25(9):1055-1060. Epub 2017 Jun 21.

Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.
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http://dx.doi.org/10.1038/ejhg.2017.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558178PMC
September 2017

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis.

BMC Genomics 2017 03 23;18(1):254. Epub 2017 Mar 23.

Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT, 06516, USA.

Background: Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project.

Results: We observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10; Left Ventricle p = 6.54*10).

Conclusions: Genetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.
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http://dx.doi.org/10.1186/s12864-017-3646-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364715PMC
March 2017

E-learning in order to improve drug prescription for hospitalized older patients: a cluster-randomized controlled study.

Br J Clin Pharmacol 2016 07 5;82(1):53-63. Epub 2016 Apr 5.

Laboratory for Quality Assessment of Geriatric Therapies and Services, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

Aims: The aim of the study was to evaluate the effect of an e-learning educational program meant to foster the quality of drug prescription in hospitalized elderly patients.

Methods: Twenty geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control (basic geriatric pharmacology notions). Logistic regression analysis was used in order to assess the effect of the intervention on the use of potentially inappropriate medication (PIM, primary outcome) at hospital discharge. Secondary outcomes were a reduced prevalence of at least one potential drug-drug interaction (DDI) and potentially severe DDI at discharge. Mortality rate and incidence of re-hospitalizations were other secondary outcomes assessed at the 12-month follow-up.

Results: A total of 697 patients (347 in the intervention and 350 in the control arms) were enrolled. No difference in the prevalence of PIM at discharge was found between arms (OR 1.29 95%CI 0.87-1.91). We also found no decrease in the prevalence of DDI (OR 0.67 95%CI 0.34-1.28) and potentially severe DDI (OR 0.86 95%CI 0.63-1.15) at discharge, nor in mortality rates and incidence of re-hospitalization at 12-month follow-up.

Conclusions: This e-learning educational program had no clear effect on the quality of drug prescription and clinical outcomes in hospitalized elderly patients. Given the high prevalence of PIMs and potential DDIs recorded in the frame of this study, other approaches should be developed in order to improve the quality of drug prescription in this population.
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http://dx.doi.org/10.1111/bcp.12922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917810PMC
July 2016

GPX1*Pro198Leu AND GPX3 rs2070593 as genetic risk markers for Italian asthmatic patients.

Clin Exp Pharmacol Physiol 2016 Feb;43(2):277-9

Department of Biology, University of Rome "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1111/1440-1681.12522DOI Listing
February 2016

GSTA1 gene variation associated with gestational hypertension and its involvement in pregnancy-related pathogenic conditions.

Eur J Obstet Gynecol Reprod Biol 2015 Nov 17;194:34-7. Epub 2015 Aug 17.

Department of Biology, University of Rome "Tor Vergata", Rome, Italy. Electronic address:

Objective(s): Glutathione S-transferases (GSTs) are the main phase II enzymes involved in the cellular detoxification. Through phase I and phase II detoxification reactions, the cell is able to detoxify endogenous and exogenous toxic compounds. In this study, we focused our attention on the GSTA1*-69C/T gene polymorphism (rs3957357) in order to explore its involvement in the genetic predisposition to gestational hypertension (GH).

Study Design: The case-control population consists of 195 subjects. The genotyping of the GSTA1*-69C/T was performed by using an RFLP-PCR technique. We calculated odds ratios (ORs), adjusted for the confounding variables, to estimate the association between GSTA1 and GH.

Results: Significant allelic differences in GSTA1*-69C/T are present between GH women and pregnant women without cardiovascular complications (p<0.05). Specifically, we observed that the dominant genetic model best explains the observed genetic association, according to the Akaike information criterion and the Bayesian information criterion.

Conclusion(s): Our study highlighted a significant association between the GSTA1 gene and the risk of GH in Italian patients. In particular, the -69C/T variant was significantly associated with disease risk. Since previous studies indicated that this GSTA1 polymorphism is associated with different pregnancy-related conditions, our finding supports the notion that GSTA1 may play a key role during pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2015.08.006DOI Listing
November 2015

Explorative genetic association study of GSTT2B copy number variant in complex disease risks.

Ann Hum Biol 2016 May 24;43(3):279-84. Epub 2015 Jul 24.

a Department of Biology , University of Rome 'Tor Vergata' , Rome , Italy .

Background: Glutathione S-transferases (GSTs) are the main phase II enzymes involved in cellular detoxification. Through phase I and phase II detoxification reactions, the cell is able to detoxify endogenous and exogenous toxic compounds.

Aims: This study focused attention on the GSTT2B copy number variant (CNV) in order to explore its involvement in the genetic pre-disposition to asthma, Alzheimer's disease (AD), allergic rhinitis (AR), essential hypertension (EH), hypothyroidism and recurrent miscarriage (RM).

Methods: The study population consists of 1225 individuals divided into six case-control groups. The genotyping of the GSTT2B CNV was performed by using a duplex-PCR. Odds Ratios (ORs) were calculated, adjusting for the confounding variables, to estimate the association between GSTT2B CNV and the disease status.

Results: The χ(2)-test and ORs did not show any association between this genetic marker and pathological phenotypes.

Conclusion: The data highlights that GSTT2B CNV is not associated with the investigated complex diseases in Italian patients. However, further investigations are necessary to replicate these findings in larger sample sizes and to explore other health-related phenotypes.
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http://dx.doi.org/10.3109/03014460.2015.1049206DOI Listing
May 2016

Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation.

Amyloid 2015 16;22(2):73-8. Epub 2014 Dec 16.

Department of Biology, University of Rome "Tor Vergata" , Rome , Italy .

Introduction: Transthyretin (TTR)-related amyloidosis is characterized by autosomal transmission of amyloidogenic mutated TTR. Val30Met is one of the most common amyloidogenic TTR mutations, showing a worldwide distribution with phenotypic heterogeneity among human populations. Multiple founder mutations for Val30Met foci have been hypothesized and the different origins may explain the phenotypic variability. The aim of our study is to determine the origin of Italian Val30Met and to analyze the genetic relationship of other Val30Met foci.

Methods: We analyzed the origin of Italian Val30Met through 11 microsatellite markers around the TTR gene in 29 patients and 34 healthy controls.

Results: Our genetic analysis showed an estimated age of origin of 34-36 generations ago for the Italian Val30Met. Comparing Italian Val30Met haplotypes with those from Sweden and Portugal highlights relevant differences that seem to be consistent with an independent origin of Italian Val30Met mutation. This genetic evidence agrees with the disease phenotypic variation in these populations.

Discussion And Conclusions: Italian Val30Met mutation should have originated before the Portuguese and Swedish Val30Met ones (which arose through independent mutational events). This indicates a genetic diversity in the surrounding regions of three different Val30Met mutations, supporting the hypothesis that TTR non-coding regions may contribute to phenotypic heterogeneity.
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http://dx.doi.org/10.3109/13506129.2014.994597DOI Listing
April 2016

Deletion polymorphism of GSTT1 gene as protective marker for allergic rhinitis.

Clin Respir J 2015 Oct 1;9(4):481-6. Epub 2014 Jul 1.

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.

Background And Aims: Allergic rhinitis (AR) is one of the most common respiratory diseases among human populations. Strong evidence suggests that genetic predisposition and environmental factors could contribute to the development of this complex disease. Glutathione S-transferases (GSTs) are biomarkers of inflammation and oxidative stress. These phase II enzymes play a significant role in detoxifying xenobiotic compounds. To analyze the role of GST gene polymorphisms in AR pathogenesis in a case-control population of 103 patients affected by AR and 200 healthy non-allergic subjects.

Methods: We screened genomic DNA extracted from buccal cells for GSTM1 positive/null, GSTP1*I105V (rs1695) and GSTT1 positive/null polymorphisms. The X(2) -test, odds ratio (OR) and logistic regression were used as statistical analyses.

Results: Significant differences in null genotype distribution between AR patients (13%) and healthy controls (30%) were found for the GSTT1 null genotype (OR = 0.30, 95% confidence interval = 0.14-0.65; P = 0.001). GSTM1 and GSTP1 polymorphisms did not show any significant results.

Conclusion: Our data indicated that GSTT1 may be a susceptibility locus for AR. Specifically, the positive/null polymorphism of GSTT1 may be involved in an oxidative stress-related mechanism that may enhance pathogenic pathways related to AR. Moreover, beside GSTT1, this deletion polymorphism affects also another gene potentially related to AR phenotype, LOC391322. This gene belongs to MIF (macrophage migration inhibitory factor) gene family and several studies indicated the role of this gene in several immunology-related phenotypes. Therefore, two different scenarios may explain the observed genetic association.
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http://dx.doi.org/10.1111/crj.12170DOI Listing
October 2015

In silico analysis of TTR gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis.

Amyloid 2014 Sep 29;21(3):154-62. Epub 2014 Apr 29.

Department of Biology, University of Rome "Tor Vergata" , Rome , Italy and.

Introduction: Transthyretin (TTR)-related amyloidosis is a life-threatening disease. Currently, several questions about the pathogenic mechanisms of TTR-related amyloidosis remain unanswered.

Methods: We have investigated various TTR-related issues using different in silico approaches.

Results: Using an amino acid similarity-based analysis, we have indicated the most relevant TTR secondary structures in determining mutation impact. Our amyloidogenic propensity analysis of TTR missense substitutions has highlighted a similar pattern for wild-type and mutated TTR amino β acid sequences. However, some mutations present differences with respect to the general distribution. We have identified non-coding variants in cis-regulatory elements of the TTR gene, and our analysis on V122I-related haplotypes has indicated differences in non-coding regulatory variants, suggesting differences among V122I carriers. The analysis of methylation status indicated CpG sites that may affect TTR expression. Finally, our interactive network analysis revealed functional partners of TTR that may play a modifier role in the pathogenesis of TTR-related amyloidosis.

Discussion And Conclusion: Our data provided new insights into the pathogenesis of TTR-related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve our understanding of the disease.
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http://dx.doi.org/10.3109/13506129.2014.900487DOI Listing
September 2014

GSTA1*-69C/T and GSTO2*N142D as asthma- and allergy-related risk factors in Italian adult patients.

Clin Exp Pharmacol Physiol 2014 Mar;41(3):180-4

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.

1. Asthma and allergies are characterized by variable and subjective symptoms influenced by many genes, molecular mechanisms and environmental factors. The presence of inflammation and oxidative stress in the airways are important biochemical features of asthma and respiratory allergies. Glutathione S-transferase (GSTs) enzymes play an important role in cellular protection against inflammation, and functional genetic polymorphisms in GST genes show a significant association with asthma and allergy risk. Specifically, our previous study on asthmatic children highlighted GSTA1 and GSTO2 as novel susceptibility loci for asthma. 2. In the present study we focused our attention on GSTA1*-69C/T (rs3957357) and GSTO2*N142D (rs156697) polymorphisms to confirm our previous results in an independent adult study population and to clarify whether GSTA1 and GSTO2 gene polymorphisms are involved in a non-discriminative pathway towards asthma and respiratory allergy. 3. To accomplish this, we recruited 103 patients with respiratory allergies, 199 patients with asthma and 200 healthy controls. Genomic DNA extracted from buccal cells was screened for GSTA1*-69C/T and GSTO2*N142D single nucleotide polymorphisms. 4. The GSTA1*-69T and GSTO2*D142 variants are both associated with a significantly increased risk of asthma, whereas only GSTA1*-69C/T is significantly associated with allergies. These outcomes confirm the involvement of GSTO2 loci in asthma and suggest that GSTA1 is a common risk factor for asthma and allergies.
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http://dx.doi.org/10.1111/1440-1681.12201DOI Listing
March 2014

Uterine junctional zone at three-dimensional transvaginal ultrasonography in patients with recurrent miscarriage: a new diagnostic tool?

Eur J Obstet Gynecol Reprod Biol 2014 Mar 30;174:128-32. Epub 2013 Dec 30.

Department of Obstetrics and Gynecology, University of Siena , Siena, Italy.

Objective: To evaluate the characteristics of the uterine junctional zone (JZ) by three-dimensional (3D) transvaginal sonography (TVS) in women with recurrent miscarriage (RM) as compared to normal fertile controls.

Study Design: The thickness and the morphology of the JZ were evaluated in 75 women with a history of RM due to different causes and in 20 fertile women without a history of miscarriages or pelvic disease. All patients included in the study were selected among those who attended the outpatient clinic of "Tor Vergata" University. The JZ characteristics were evaluated in the midluteal phase of the cycle on the uterine coronal section obtained by 3D TVS.

Results: Patients with RM showed a JZ maximum thickness significantly increased when compared to that observed in control group (5.8±0.7 vs. 5.0±1.1mm). When grouped according to the different causes of RM, all groups of patients with RM showed an increased JZ thickness when compared to fertile women, with the exception of those with anti-phospholipid antibody syndrome, probably due to the small number of cases with this pathology.

Conclusions: A thickened JZ could be an independent indicator of the risk of miscarriage and may represent an important contributing factor to some causes of RM. These observations may offer new perspectives for the screening and treatment of patients with RM. Although further studies are needed to ascertain if the reduction of the JZ thickness can determine a better pregnancy outcome, 3D TVS evaluation of the JZ could provide the opportunity to identify women in which appropriate therapeutic protocols can improve the possibility of successful pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2013.12.014DOI Listing
March 2014

Human pharmacogenomic variation of antihypertensive drugs: from population genetics to personalized medicine.

Pharmacogenomics 2014 Feb;15(2):157-67

Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, Rome, Italy.

Aim: To investigate the human pharmacogenetic variation related to antihypertensive drugs, providing a survey of functional interpopulation differences in hypertension pharmacogenes.

Materials & Methods: The study was divided into two stages. In the first stage, we analyzed 1249 variants located in 57 hypertension pharmacogenes. This first-stage analysis confirmed that geographic origin strongly affects hypertension pharmacogenomic variation and that 31 pharmacogenes are geographically differentiated. In the second stage, we focused our attention on the ethnic-differentiated pharmacogenes, investigating 55,521 genetic variants. In silico analyses were performed to predict the effect of genetic variation.

Results: Our analyses indicated functional interpopulation differences, suggesting insight into the mechanisms of antihypertensive drug response. Moreover, our data suggested that rare variants mainly determine the functionality of genes related to antihypertensive drugs.

Conclusion: Our study provided important knowledge about the genetics of the antihypertensive drug response, suggesting that next-generation sequencing technologies may develop reliable pharmacogenetic tests for antihypertensive drugs.
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http://dx.doi.org/10.2217/pgs.13.231DOI Listing
February 2014

GSTO1 uncommon genetic variants are associated with recurrent miscarriage risk.

Fertil Steril 2014 Mar 10;101(3):735-9. Epub 2014 Jan 10.

Department of Biology, University of Rome "Tor Vergata," Rome, Italy. Electronic address:

Objective: To explore the role of the GSTO1 gene in the pathogenesis of recurrent miscarriage (RM).

Design: Genetic association study.

Setting: Rome, Italy.

Patient(s): 123 women with RM and 130 women without pregnancy complications.

Intervention(s): None.

Main Outcome Measure(s): Genotyping of two single nucleotide polymorphisms (A140D and E208K) and a 3-bp deletion (E155del) of the GSTO1 gene.

Result(s): We found a statistically significant association between GSTO1*E208K variants and RM risk. Specifically, we identified this uncommon genetic variant only in women with RM. None of the women with physiologic pregnancies were carriers of K208 allele.

Conclusion(s): GSTO1 has a role in detoxification metabolism, and we hypothesize that a functional variation of GSTO1 is a RM risk factor that interacts with environmental conditions.
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http://dx.doi.org/10.1016/j.fertnstert.2013.12.010DOI Listing
March 2014

Functional variation of the transthyretin gene among human populations and its correlation with amyloidosis phenotypes.

Amyloid 2013 Dec 10;20(4):256-62. Epub 2013 Oct 10.

Department of Biology, University of Rome "Tor Vergata" , Rome , Italy and.

Introduction: Heterogeneity in the genotype-phenotype correlation of transthyretin (TTR)-related amyloidosis has been reported, suggesting that other factors may interact with disease-causing mutations. Additional genetic variants in the TTR gene and its surrounding regions may influence disease phenotype. To explore this hypothesis, we analyzed the TTR variation among human populations to identify functional inter-ethnic differences that could influence the TTR-related amyloidosis.

Methods: Using the 1000 Genomes Project database, we analyzed a 20 kb region in 1092 apparently healthy individuals who belonged to 14 human populations. In silico analyses were performed to determine the functional impact of genetic variants.

Results: These analyses showed that significant ethnic differences are present in the TTR gene, and some differences may affect TTR gene function. Specifically, the non-coding variants potentially associated with regulatory function showed a significant diversity between African and non-African individuals.

Discussion And Conclusions: Our results highlighted that cis-regulatory variants may contribute to the cardiac TTR-related amyloidosis observed in patients carrier of Val122Ile mutation, the most common in population with African origin. Indeed, non-coding variants differentiated in Africans are, in some cases, located in binding sites of transcription factors involved in cardiac development and function (i.e. E2F3_2, REST, and TEAD).
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http://dx.doi.org/10.3109/13506129.2013.844689DOI Listing
December 2013

Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study).

Trials 2013 Jan 23;14:22. Epub 2013 Jan 23.

Department of Cardiology, IRCCS Ospedale San Luca, Istituto Auxologico Italiano, Milano, Italy.

Background: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated.

Methods/design: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome).

Discussion: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients.

Trial Registration: Clinical Trials.gov: NCT01541566.
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http://dx.doi.org/10.1186/1745-6215-14-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576326PMC
January 2013

Glutathione S-transferase polymorphisms, asthma susceptibility and confounding variables: a meta-analysis.

Mol Biol Rep 2013 Apr 10;40(4):3299-313. Epub 2013 Jan 10.

Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.

Oxidative stress is one of the main risk factors for asthma development. Glutathione S-transferases play an important role in antioxidant defences and may influence asthma susceptibility. In particular, GSTM1 and GSTT1 positive/null genotypes and the GSTP1 Ile105 Val polymorphism have been analyzed in a number of genetic association studies, with conflicting outcomes. Two previous meta-analyses have attempted to clarify the associations between GST genes and asthma, but these studies have also showed contrasting results. Our aim was to perform a meta-analysis that included independent genetic association studies on GSTM1, GSTP1, and GSTT1, evaluating also the effect of potential confounding variables (i.e. ethnicity, population age, and urbanization). Systematic review and meta-analysis of the effects of GST genes on asthma were conducted. The meta-analyses were performed using a fixed or, where appropriate, random effects model. The meta-analysis of the GSTM1 (n = 35), GSTT1 (n = 31) and GSTP1 (n = 28) studies suggests that no significant associations with asthma susceptibility were observed for GSTM1 and GSTP1 gene polymorphisms, whereas a significant outcome was detected for the GSTT1 positive/null genotype (pooled OR = 1.33, 95 %CI = 1.10-1.60). However, high between-study heterogeneity was identified in all the general analyses (p heterogenetity < 0.05). The stratification analysis seems to explain the heterogeneity only in few cases. This picture is probably due to the interactive process of genetics and environment that characterizes disease pathogenesis. Further studies on interactions of GST genes with the potential oxidative stress sources and with other antioxidant genes are needed to explain the role of GST enzymes in asthma.
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http://dx.doi.org/10.1007/s11033-012-2405-2DOI Listing
April 2013

Human genetic variation of CYP450 superfamily: analysis of functional diversity in worldwide populations.

Pharmacogenomics 2012 Dec;13(16):1951-60

Department of Biology, University of Rome, Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.

Aim: The present study aimed to investigate the human genetic diversity of the CYP450 superfamily in order to identify functional interethnic differences and analyze the role of CYP450 enzymes in human adaptation.

Materials & Methods: A computational analysis of genetic and functional differences of the 57 CYP450 genes was performed using the Human Genome Diversity Project and HapMap data; comprising approximately 1694 individuals belonging to 62 human populations.

Results: Twenty-six CYP450 SNPs with F-statistics significantly different than the general distribution were identified. Some showed high differentiation among human populations, suggesting that functional interethnic differences may be present. Indeed, some of these are significantly associated with drug response or disease risk. Furthermore, our data highlighted that TBXAS1 and genes in CYP3A cluster may have a role in some processes of human adaptation.

Conclusion: Our study provided an analysis of genetic diversity of CYP450 superfamily, identifying functional differences among ethnic groups and their related clinical phenotypes.
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http://dx.doi.org/10.2217/pgs.12.163DOI Listing
December 2012

GSTO2*N142D gene polymorphism associated with hypothyroidism in Italian patients.

Mol Biol Rep 2013 Feb 19;40(2):1967-71. Epub 2012 Oct 19.

Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.

Hypothyroidism is a multifactorial endocrinal disease characterized by abnormally low thyroid hormone production. Thyroiditis is one of the primary causes of hypothyroidism, as it is an increasing level of inflammation in the thyroid gland that could be due to a failure of the anti-inflammatory response. Glutathione S-transferases are biomarkers of inflammation and oxidative stress. These phase II enzymes play a relevant role in detoxifying xenobiotic compounds. Particular attention has been focused on GSTA1, GSTM1, GSTO2, GSTP1, and GSTT1 genes to evaluate if GST gene polymorphisms are associated with hypothyroidism. We screened a case-control population (patients with hypothyroidism n = 110, controls n = 122) to analyze GST gene polymorphisms. GST SNPs were determined using the PCR-RFLP method, while GST null polymorphisms were determined using a Multiplex PCR. In this study, we found differences in genotype distribution between hypothyroid individuals and controls only for the GSTO2*N142D polymorphism. Logistic regression analysis, after adjustment for age and sex, confirmed this positive association (OR = 4.56; 95 % CI 1.22-17.00; p = 0.009). The GSTO2 enzyme can catalyze several reactions important for countering oxidative stress: subjects with the D142 allele may have a deficiency in the antioxidant enzymatic system. A decrease in antioxidant capacity may trigger increased oxidative stress. Previous studies have highlighted the role of GST enzymes in inflammation disorders, but no data are available on their role in hypothyroidism. Our results suggest that GSTO2 could increase disease risk susceptibility and could act as a risk factor for hypothyroidism in Italian patients.
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http://dx.doi.org/10.1007/s11033-012-2253-0DOI Listing
February 2013