Publications by authors named "Cinzia Ciccacci"

54 Publications

Genetics, Epigenetics, and Gender Impact in Axial-Spondyloarthritis Susceptibility: An Update on Genetic Polymorphisms and Their Sex Related Associations.

Front Genet 2021 10;12:671976. Epub 2021 Aug 10.

Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Spondyloarthritis (SpA) is a group of chronic inflammatory rheumatic disease that can be divided into predominantly axial or predominantly peripheral involvement, with or without associated psoriasis, inflammatory bowel disease or previous infection. Axial SpA (axSpA) encompasses ankylosing spondylitis (AS) with radiological sacroiliitis, and a type without radiographic sacroiliitis, called "non-radiographic axial SpA" (nr-axSpA). Males and females show large differences in their susceptibility to SpA, such as distinctions in clinical patterns, phenotypes and in therapeutical response, particularly to TNF inhibitors (TNFi). Several studies indicate that AS women have doubled risk to failure TNFi compared with males. This diversity in drugs' efficacy among women and men may be caused by differences in the balance of sex hormones and in gene-specific expression likely triggered by X-chromosome instability and gene-specific epigenetic modifications. Evidence reported that polymorphisms in microRNAs on X- and other chromosomes, such as miR-146a, miR-155, miR-125a-5p, miR-151a-3p and miR-22-3p, miR-199a-5p could be involved in the different clinical presentation of SpA, as well as disease activity. In addition, association with non-response to TNFi treatment and presence of IRAK3 and CHUCK genes in SpA patients was recently detected. Finally, polymorphisms in genes involved in IL-23/IL-17 pathway, such as in drug pharmacodynamics and pharmacokinetics may have a role in response to TNFi, IL17i, and IL23i. A major understanding of genomic variability could help in the development of new therapeutic targets or in taking advantages of different mechanisms of action of biological drugs. Moving from the multifactorial etiology of disease, the present review aims at evaluating genetic and epigenetic factors and their relationship with sex and bDMARDs response, helping to investigate the different expression among males and females of genes on X- and other chromosomes, as well as mi-RNA, to highlight relationships between sex and occurrence of specific phenotypes and symptoms of the disease. Moreover, the role of the epigenetic modification in relation to immune-regulatory mechanisms will be evaluated.
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http://dx.doi.org/10.3389/fgene.2021.671976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383732PMC
August 2021

Emerging Role of microRNAs and Long Non-Coding RNAs in Sjögren's Syndrome.

Genes (Basel) 2021 06 11;12(6). Epub 2021 Jun 11.

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy.

Sjögren's Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies.
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http://dx.doi.org/10.3390/genes12060903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230573PMC
June 2021

mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

Lupus 2021 Jun 1;30(7):1086-1093. Epub 2021 Apr 1.

Department of Biomedicine & Prevention, Genetics Section, University of Rome "Tor Vergata", Rome, Italy.

Background: Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of transcripts is not fully understood. We investigated the mRNA expression of and and also analyzed possible splicing regulators (ESRP1 molecule and rs9666607 polymorphism) in a cohort of SLE patients compared to healthy controls.

Methods: This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing.

Results: mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of and mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of was associated with higher level of global mRNA (p = 0.04) but not with the variant isoforms.

Conclusions: In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of splicing in the disease, whose regulatory mechanisms require further investigation.
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http://dx.doi.org/10.1177/09612033211004725DOI Listing
June 2021

Altered expression of miR-142, miR-155, miR-499a and of their putative common target in systemic lupus erythematosus.

Epigenomics 2021 01 18;13(1):5-13. Epub 2020 Dec 18.

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome 00133, Italy.

To evaluate genetic and expression variability of three miRNAs potentially involved in systemic lupus erythematosus (SLE) and to identify any miRNA's target gene. Gene polymorphisms and expression levels of three miRNAs have been evaluated in a cohort of SLE patients and controls. miR-142 and miR-499a were significantly down-expressed in patients (p = 0.005 and p = 0.02, respectively). A trend for down-expression of miR-155 was also observed (p = 0.07). The lower expression of miR-142 was associated with the rs2632516 polymorphism variant allele (p = 0.002). Predictive analyses identified a target gene common to the three miRNAs, , whose higher expression was seen in patients compared with controls (p = 0.03). The three miRNAs and MDM2 might be involved in SLE.
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http://dx.doi.org/10.2217/epi-2020-0278DOI Listing
January 2021

CLEC4E (Mincle) genetic variation associates with pulmonary tuberculosis in Guinea-Bissau (West Africa).

Infect Genet Evol 2020 11 22;85:104560. Epub 2020 Sep 22.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Tuberculosis (TB) is the leading cause of death from a single infectious agent. According to the WHO, 85% of cases in 2018 were pulmonary tuberculosis (PTB), making it the most prevalent form of the disease. Although the bacillus responsible for disease, Mycobacterium tuberculosis (MTB), is estimated to infect 1.7 billion people worldwide, only a small portion of those infected (5-10%) will transition into active TB. Because such a small fraction of infected people develop active disease, we hypothesized that underlying host genetic variation associates with developing active pulmonary disease. Variation in CLEC4E has been of interest in previous association studies showing either no effect or protection from PTB. For our study we assessed 60 SNPs in 11 immune genes, including CLEC4E, using a case-control study from Guinea-Bissau. The 289 cases and 322 controls differed in age, sex, and ethnicity all of which were included in adjusted models. Initial association analysis with unadjusted logistic regression revealed putative association with seven SNPs (p < 0.05). All SNPs were then assessed in an adjusted model. Of the six SNPs that remained significant, three of them were assigned to the CLEC4E gene (rs12302046, rs10841847, and rs11046143). Of these, only rs10841847 passed FDR adjustment for multiple testing. Adjusted regression analyses showed that the minor allele at rs10841847 associated with higher risk of developing PTB (OR = 1.55, CI = 1.22-1.96, p-value = 0.00036). Based on these initial association tests, CLEC4E seemed to be the predictor of interest for PTB risk in this population. Haplotype analysis (2-SNP and 3-SNP windows) showed that minor alleles in segments including rs10841847 were the only ones to pass the threshold of global significance, compared to other haplotypes (p-value < 0.05). Linkage disequilibrium patterns showed that rs12302046 is in high LD with rs10841847 (r = 0.67), and all other SNPs lost significance when adjusted for rs10841847 effects. These findings indicate that rs10841847 in CLEC4E is the single best predictor of pulmonary tuberculosis risk in our study population. These results provide evidence for the hypothesis that genetic variation of CLEC4E influences risk to TB in Guinea-Bissau.
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http://dx.doi.org/10.1016/j.meegid.2020.104560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962542PMC
November 2020

The differential response to anti IL-6 treatment in COVID-19: the genetic counterpart.

Clin Exp Rheumatol 2020 May-Jun;38(3):580. Epub 2020 May 10.

Rheumatology Unit, Department of Medicine, University of Perugia, Italy.

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June 2020

Expression study of candidate miRNAs and evaluation of their potential use as biomarkers of diabetic neuropathy.

Epigenomics 2020 04 13;12(7):575-585. Epub 2020 May 13.

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy.

To evaluate the expression of candidate miRNAs in relation to diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). The expression of six candidate miRNAs has been evaluated in 49 Type 2 diabetes patients with neurological evaluation. A higher expression of miR-128a was seen in patients with DPN compared with those without DPN (p = 0.015). miR-155 and miR-499a seemed to be down-expressed in patients with DPN (p = 0.04 and p = 0.05, respectively). A lower expression of miR-155 (p = 0.05) was observed even in patients with CAN with respect to CAN-negative. A higher expression of miR-155 was associated with the rs767649 polymorphism variant allele compared with the wild-type allele (p = 0.03).  miR-128a, miR-155 and miR-499a might be involved in diabetic neuropathies development.
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http://dx.doi.org/10.2217/epi-2019-0242DOI Listing
April 2020

Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a Gene Polymorphism.

DNA Cell Biol 2020 Aug 20;39(8):1467-1472. Epub 2020 Apr 20.

Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy.

Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the . T2D patients show a decrease in the number of mtDNA copies compared to healthy controls ( = 2 × 10). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without ( = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of correlates with a decrease in the number of mtDNA copies, particularly in T2D patients ( = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.
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http://dx.doi.org/10.1089/dna.2019.5326DOI Listing
August 2020

miRNAs in drug response variability: potential utility as biomarkers for personalized medicine.

Pharmacogenomics 2019 09;20(14):1049-1059

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly.

MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. Almost all physiological conditions are probably modulated by miRNAs, including pharmacological response. Indeed, acting on the regulation of numerous genes involved in the pharmacokinetics and pharmacodynamics of drugs, differences in the levels of circulating miRNAs or genetic variants in the sequences of the miRNA genes can contribute to interindividual variability in drug response, both in terms of toxicity and efficacy. For their stability in body fluids and the easy availability and accurate quantification, miRNAs could be ideal biomarkers of individual response to drugs. This review aims to give an overview on the available studies that have investigated the relationship between miRNAs and response to drugs in different classes of diseases and considered their possible clinical application as therapy response predictive biomarkers. A comprehensive search was conducted from the international web database PubMed. We included papers that investigated the relationship between miRNAs and response to drugs, published before January 2019.
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http://dx.doi.org/10.2217/pgs-2019-0089DOI Listing
September 2019

The Heart Matters: Contribution of Genetic Factors in Recurrent Pericarditis.

Isr Med Assoc J 2019 Jul;21(7):487-490

Lupus Clinic, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy.

Background: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.
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July 2019

, , , and Polymorphisms in Sjögren's Syndrome: Association with Disease Susceptibility and Clinical Aspects.

J Immunol Res 2019 10;2019:7682827. Epub 2019 Feb 10.

Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Italy.

Sjögren's syndrome (SS) is a chronic autoimmune condition characterized by autoantibody production, sicca syndrome, and periepithelial lymphocytic lesions in target tissues. A predisposing genetic background is likely, and, to date, several polymorphisms in non-HLA genes have been explored with interesting results. We investigated the association between the , , , and polymorphisms and SS susceptibility and their possible role in the modulation of clinical and laboratory features. 195 consecutive patients with SS were enrolled and clinical and laboratory data were collected. 248 age- and sex-matched healthy subjects were used as controls. Genotyping was performed by allelic discrimination assays. A case-control association study and a phenotype-genotype correlation analysis were performed. A genetic risk profile was developed considering the risk alleles. Both the variant alleles of rs7574865 in the gene and rs3099844 in the gene were significantly more prevalent in patients than in controls (OR = 1.91 and OR = 2.44, respectively). The variant allele of rs3024505 of resulted to be a susceptibility allele (OR = 1.52), while the variant allele of rs1800872 seemed to confer a protective effect for the development of the disease (OR = 0.65). A risk genetic profile showed a higher probability to develop the disease in subjects with at least three risk alleles; subjects with 4 risk alleles were not observed in the controls. rs3099844 was associated with anti-SSA ( = 0.006, OR = 3.07) and anti-SSB ( = 0.005, OR = 2.66) antibodies, severity of focus score ( = 0.03, OR = 12), and lymphoma development ( = 0.002, OR = 7.23). Patients carrying the rs7574965 variant allele had a higher risk of monoclonal component and leukopenia ( = 0.002, OR = 7.6; = 0.048, OR = 2.01, respectively). We confirmed the association of SS with the and genes and we describe a novel association with . In particular, we describe an association of this specific SNP of not only with disease development but also with autoantibody production and focus score suggesting a potential contribution of this variant to a more severe phenotype.
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http://dx.doi.org/10.1155/2019/7682827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387711PMC
May 2019

A common polymorphism in MIR155 gene promoter region is associated with a lower risk to develop type 2 diabetes.

Acta Diabetol 2019 06 11;56(6):717-718. Epub 2019 Jan 11.

Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", 00133, Rome, Italy.

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http://dx.doi.org/10.1007/s00592-018-1277-xDOI Listing
June 2019

Discovering the genetic contribution to cardiovascular diseases in patients affected by autoimmune diseases.

Authors:
Cinzia Ciccacci

Ann Transl Med 2018 Nov;6(Suppl 1):S44

Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.21037/atm.2018.09.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291537PMC
November 2018

Pharmacogenomics in Parkinson's disease: which perspective for developing a personalized medicine?

Neural Regen Res 2019 Jan;14(1):75-76

Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.4103/1673-5374.243706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263000PMC
January 2019

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

Clin Pharmacol Ther 2019 06 17;105(6):1477-1491. Epub 2019 Feb 17.

Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.
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http://dx.doi.org/10.1002/cpt.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542461PMC
June 2019

A multivariate genetic analysis confirms rs5010528 in the human leucocyte antigen-C locus as a significant contributor to Stevens-Johnson syndrome/toxic epidermal necrolysis susceptibility in a Mozambique HIV population treated with nevirapine.

J Antimicrob Chemother 2018 08;73(8):2137-2140

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Objectives: Nevirapine is used in developing countries for the treatment of HIV infection, but its use is associated with rare serious adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, an association between rs5010528 in the human leucocyte antigen (HLA)-C locus and SJS/TEN susceptibility has been described in sub-Saharan populations. Our aim was to verify this association in a population of nevirapine-treated patients from Mozambique.

Methods: The rs5010528 SNP was analysed by direct sequencing in 27 patients who had developed SJS/TEN and 75 patients who did not develop adverse reactions after nevirapine treatment. A case-control association study was conducted. A multivariate analysis was performed in order to evaluate the role of HLA-C also in relation to other susceptibility genetic factors (CYP2B6, TRAF3IP2, HCP5, PSORS1C1 and GSTM1 genes).

Results: rs5010528 was significantly associated with a higher risk of developing SJS/TEN; the variant allele was more frequent in cases than in controls, conferring a high risk of developing this adverse reaction in carriers (OR = 5.72 and P = 0.0002 at genotype level, OR = 3.51 and P = 0.0002 at allelic level). The multivariate analysis showed that the HLA-C SNP, CYP2B6 (rs28399499), TRAF3IP2 (rs76228616) and GSTM1 (null genotype) can explain 25% of the susceptibility to this reaction, with the HLA-C SNP as the most significant contributor (P = 0.02 and OR = 5.64).

Conclusions: Our study confirmed the association of the rs5010528 SNP in the HLA-C region with susceptibility to developing SJS/TEN in a population from Mozambique, suggesting that it could be a good genomic biomarker for SJS/TEN susceptibility in different sub-Saharan populations.
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http://dx.doi.org/10.1093/jac/dky180DOI Listing
August 2018

Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants.

Oncotarget 2018 Jan 12;9(8):7812-7821. Epub 2017 Dec 12.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome, Italy.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants ( and ) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life.
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http://dx.doi.org/10.18632/oncotarget.23241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814260PMC
January 2018

Interaction between microbiome and host genetics in psoriatic arthritis.

Autoimmun Rev 2018 Mar 3;17(3):276-283. Epub 2018 Feb 3.

Rheumatology, Allergology and Clinical Immunology, Department of Medicina dei Sistemi, University of Rome Tor Vergata, Rome, Italy.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease, seen in combination with psoriasis. Both genetic and environmental factors are responsible for the development of PsA, however little is known about the different weight of these two distinctive components in the pathogenesis of the disease. Genomic variability in PsA is associated with the disease and/or some peculiar clinical phenotypes. Candidate genes involved are crucial in inflammation, immune system, and epithelial permeability. Moreover, the genesis and regulation of inflammation are influenced by the composition of the human intestinal microbiome that is able to modulate both mucosal and systemic immune system. It is possible that pro-inflammatory responses initiated in gut mucosa could contribute to the induction and progression of autoimmune conditions. Given such premises, the aim of this review is to summarize immune-mediated response and specific bacterial changes in the composition of fecal microbiota in PsA patients and to analyze the relationships between bacterial changes, immune system, and host genetic background.
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http://dx.doi.org/10.1016/j.autrev.2018.01.002DOI Listing
March 2018

Genetics and Treatment Response in Parkinson's Disease: An Update on Pharmacogenetic Studies.

Neuromolecular Med 2018 03 5;20(1):1-17. Epub 2018 Jan 5.

Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.
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http://dx.doi.org/10.1007/s12017-017-8473-7DOI Listing
March 2018

Association between a MIR499A polymorphism and diabetic neuropathy in type 2 diabetes.

J Diabetes Complications 2018 01 26;32(1):11-17. Epub 2017 Oct 26.

Department of Systems Medicine, Endocrinology, University of Rome "Tor Vergata", Italy.

Aims: Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) affect a large percentage of diabetic people and impact severely on quality of life. As it seems that miRNAs and their variations might play a role in these complications, we investigated whether the rs3746444 SNP in the MIR499A gene could be associated with susceptibility to DPN and/or CAN.

Methods: We analyzed 150 participants with type 2 diabetes. DNA was extracted from peripheral blood samples and genotyping was performed by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and thermal thresholds were used for CAN and DPN assessment. We performed a genotype-phenotype correlation analysis.

Results: We observed that the GG genotype was associated with a higher risk of developing CAN (P=0.002 and OR=16.08, P=0.0005 and OR=35.02, for early and confirmed CAN, respectively) and DPN (P=0.037 and OR=6.56), after correction for BMI, sex, age, HbA1c and disease duration. Moreover, the GG genotype was associated with worse values of MDNS (P=0.017), VPT (P=0.01), thermal thresholds (P=0.01), and CAN score (P<0.001). A logistic multivariate analysis confirmed that MIR499A GG genotype, disease duration and HbA1c contributed to early CAN (R=0.26), while the same variables and age contributed to DPN (R=0.21). With a multiple linear regression, we observed that GG genotype (P=0.001) and disease duration (P=0.035) were the main variables contributing to the CAN score (R=0.35).

Conclusions: We described for the first time that the MIR499A genetic variation could be involved in diabetic neuropathies susceptibility. In particular, patients carrying the rs3746444 GG genotype had a higher risk of CAN development, together with a more severe form of CAN.
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http://dx.doi.org/10.1016/j.jdiacomp.2017.10.011DOI Listing
January 2018

Polymorphisms in miRNA genes and their involvement in autoimmune diseases susceptibility.

Immunol Res 2017 08;65(4):811-827

Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy.

MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate the expression of multiple protein-encoding genes at the post-transcriptional level. MicroRNAs are involved in different pathways, such as cellular proliferation and differentiation, signal transduction and inflammation, and play crucial roles in the development of several diseases, such as cancer, diabetes, and cardiovascular diseases. They have recently been recognized to play a role also in the pathogenesis of autoimmune diseases. Although the majority of studies are focused on miRNA expression profiles investigation, a growing number of studies have been investigating the role of polymorphisms in miRNA genes in the autoimmune diseases development. Indeed, polymorphisms affecting the miRNA genes can modify the set of targets they regulate or the maturation efficiency. This review is aimed to give an overview about the available studies that have investigated the association of miRNA gene polymorphisms with the susceptibility to various autoimmune diseases and to their clinical phenotypes.
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http://dx.doi.org/10.1007/s12026-017-8937-8DOI Listing
August 2017

Impact of glutathione transferases genes polymorphisms in nevirapine adverse reactions: a possible role for GSTM1 in SJS/TEN susceptibility.

Eur J Clin Pharmacol 2017 Oct 8;73(10):1253-1259. Epub 2017 Jul 8.

Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

Purpose: Nevirapine (NVP) is used in developing countries as first-line treatment of HIV infection. Unfortunately, its use is associated with common serious adverse drug reactions, such as liver toxicity and the most severe and rare Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). GSTT1 and GSTM1 genes code for enzymes involved in the metabolism of a wide range of drugs. We hypothesized that this gene variability could be implicated in NVP adverse reactions.

Methods: We analyzed the GSTM1 and GSTT1 null genotypes by multiplex PCR in a population of 181 patients from Mozambique, treated with NVP. A case/control association study was performed. We also counted the number of risk alleles in SJS/TEN patients and in controls, including the GSTM1 null genotype and four previously identified risk alleles in CYP2B6, HCP5, and TRAF3IP2 genes.

Results: Among patients, 27 had developed SJS/TEN and 76 had developed hepatotoxicity during the treatment. The GSTM1 null genotype was more frequent in the cases with SJS/TEN than in the controls (OR = 2.94, P = 0.027). This association is also observed when other risk factors are taken into account, by a multivariate analysis (P = 0.024 and OR = 3.58). The risk allele counting analysis revealed a significantly higher risk for SJS/TEN in patients carrying three or four risk alleles. Moreover, all subjects with five or six risk alleles developed SJS/TEN, while subjects without any risk alleles were present only in the control group.

Conclusions: We observed an association between GSTM1 and SJS/TEN susceptibility. Moreover, GSTM1 contributes to the definition of a genetic risk profile for SJS/TEN susceptibility.
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http://dx.doi.org/10.1007/s00228-017-2295-2DOI Listing
October 2017

Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease.

Pharmacogenomics 2017 Jul 7;18(11):1095-1114. Epub 2017 Jul 7.

Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy.

Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
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http://dx.doi.org/10.2217/pgs-2017-0068DOI Listing
July 2017

Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis.

PLoS One 2017 20;12(1):e0169956. Epub 2017 Jan 20.

Clinic of Rheumatology, Allergology and Clinical Immunology, Department of "Medicina dei Sistemi", University of Rome Tor Vergata, Rome, Italy.

Objective: Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients.

Methods: In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)].

Results: STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients.

Conclusions: For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169956PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5249113PMC
August 2017

Polymorphisms in MIR122, MIR196A2, and MIR124A Genes are Associated with Clinical Phenotypes in Inflammatory Bowel Diseases.

Mol Diagn Ther 2017 02;21(1):107-114

Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", 00133, Rome, Italy.

Background: Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial disorders that result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. Recently, microRNAs (miRNAs) have been shown to be involved in the development of IBDs.

Aims: We investigated common variants in five miRNA genes in a cohort of Italian IBD patients, to evaluate their possible role in the disease's susceptibility and phenotype manifestations.

Methods: The analysis included 267 CD patients, 207 UC patients, and 298 matched healthy controls. Polymorphisms in the MIR122, MIR499, MIR146A, MIR196A2, and MIR124A genes were evaluated by allelic discrimination assay.

Results: We did not find associations between mir polymorphisms and IBD susceptibility. In both diseases, rs17669 and rs11614913 (MIR122 and MIR196A2) seem to contribute to clinical phenotypes: ileal location in CD (odds ratio [OR] = 1.82, p = 0.03; OR = 0.51, p = 0.01), and left-sided extent in UC (OR = 0.43, p = 0.05; OR = 0.28, p = 0.002). In CD, the MIR124A polymorphism (rs531564) contributed to colon location (p = 0.03, OR = 2.74). Finally, the variant allele of rs11614913 was associated with early age at onset in both diseases (p = 0.05 and p = 0.02).

Conclusions: We showed for the first time that polymorphisms in MIR122, MIR196A2, and MIR124A could play a role in clinical phenotype modulation in IBD.
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http://dx.doi.org/10.1007/s40291-016-0240-1DOI Listing
February 2017

Recent advances in exploring the genetic susceptibility to diabetic neuropathy.

Diabetes Res Clin Pract 2016 Oct 26;120:198-208. Epub 2016 Aug 26.

Department of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.

Diabetic polyneuropathy and cardiovascular autonomic neuropathy are common and disabling complications of diabetes. Although glycaemic control and cardiovascular risk factors are major contributory elements in its development, diabetic neuropathy recognizes a multifactorial influence and a multiplicity of pathogenetic mechanisms. Thus genetic and environmental factors may contribute to its susceptibility, each with a modest contribution, by targeting various metabolic and microvascular pathways whose alterations intervene in diabetic neuropathy pathogenesis. This review is aimed at describing major data from the available literature regarding genetic susceptibility to diabetic neuropathies. It provides an overview of the genes reported as associated with the development or progression of these complications, i.e. ACE, MTHFR, GST, GLO1, APOE, TCF7L2, VEGF, IL-4, GPX1, eNOS, ADRA2B, GFRA2, MIR146A, MIR128A. The identification of genetic susceptibility can help in both expanding the comprehension of the pathogenetic mechanisms of diabetic nerve damage and identifying biomarkers of risk prediction and response to therapeutic intervention.
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http://dx.doi.org/10.1016/j.diabres.2016.08.006DOI Listing
October 2016

Cannabinoid Poisoning by Hemp Seed Oil in a Child.

Pediatr Emerg Care 2017 May;33(5):344-345

From the *University of Trieste, Institute for Maternal and Child Health IRCCS 'Burlo Garofolo', Trieste; †Department of Pediatrics and Pediatric Hematology, S. Camillo-Forlanini Hospital; ‡Legal Medicine Department, Public Health Institute, Catholic University of the Sacred Heart; and §Department of Biomedicine and Prevention, Genetics Unit, University of Rome Tor Vergata, Rome, Italy.

We report a case of mild cannabinoid poisoning in a preschool child, after 3-week ingestion of hemp seed oil prescribed by his pediatrician to strengthen his immune system. The patient presented neurological symptoms that disappeared after intravenous hydration. A possible mild withdrawal syndrome was reported after discharge. The main metabolite of Δ-tetrahydrocannabinol was detected in urine, and very low concentration of Δ-tetrahydrocannabinol was detected in the ingested product. This is, as far as we know, the first report of cannabinoid poisoning after medical prescription of hemp seed oil in a preschool child.
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http://dx.doi.org/10.1097/PEC.0000000000000780DOI Listing
May 2017

Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype.

J Immunol Res 2015 21;2015:745647. Epub 2015 Dec 21.

Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, 00161 Rome, Italy.

Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association.
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http://dx.doi.org/10.1155/2015/745647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699011PMC
September 2016

Advances in Exploring the Role of Micrornas in Inflammatory Bowel Disease.

Microrna 2016 ;5(1):5-11

Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome "Tor Vergata", Rome, Italy.

Inflammatory bowel diseases, including Crohn's Disease and Ulcerative Colitis, result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. The list of genetic factors involved in the development of these diseases has considerably increased in last years. However, recently, new promising insights on inflammatory bowel diseases have been produced by studies on microRNAs. MicroRNAs are small non coding RNA molecules, that play a pivotal role in gene expression and regulation. They are involved in many biological processes, such as cellular proliferation and differentiation, signal transduction and, more recently, they have been recognized as also having a role in the innate and adaptative response. In this review we give an overview on the role of microRNAs in the pathogenesis of inflammatory bowel diseases.
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http://dx.doi.org/10.2174/2211536605666160111124812DOI Listing
June 2017

Stevens-Johnson syndrome and toxic epidermal necrolysis: an update on pharmacogenetics studies in drug-induced severe skin reaction.

Pharmacogenomics 2015 Nov 10;16(17):1989-2002. Epub 2015 Nov 10.

Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Italy.

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.
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http://dx.doi.org/10.2217/pgs.15.128DOI Listing
November 2015
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