Papers by Renato Polimanti
Journal of Alzheimers Disease, 2012
Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study w... more Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12-2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19-2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X 2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X 2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD.
Neuroscience Letters, 2012
Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A gen... more Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimer's Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P = 0.003; adjusted OR = 3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1 activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk.
International Journal of Alzheimer's Disease, 2011
we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most ... more we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WDcausing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P = .074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P = .028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.
Metal Dysfunction in Alzheimer’s Disease
Oxidative Stress in Applied Basic Research and Clinical Practice, 2013
ABSTRACT It has been recently established that oxidative stress plays a key role in neurodegenera... more ABSTRACT It has been recently established that oxidative stress plays a key role in neurodegeneration. Consequently, researchers have focused their attention on transition metals, as they are known to participate in biochemical reactions that produce free radicals. In Alzheimer’s disease (AD), in particular, in vitro and animal studies have uncovered the role of iron and copper in the disease’s pathogenesis, recently confirmed in clinical studies. However, the link between AD and metals has been mostly investigated with a focus on local accumulations in brain areas critical for AD. More recently, a wider view has emerged proposing a relationship between AD and systemic changes of metal metabolism, upon genetic variability. In this chapter, we describe the major functions of iron and copper in the body and summarize the reasons why we should closely monitor their dyshomeostases in AD.
Antioxidant Status in Vascular Dementia
Diet and Nutrition in Dementia and Cognitive Decline, 2015
ABSTRACT Vascular dementia (VaD) is the second most common form of dementia. Different studies ha... more ABSTRACT Vascular dementia (VaD) is the second most common form of dementia. Different studies have indicated that patients with VaD have increased levels of local and systemic oxidative stress markers. Furthermore, in vivo and clinical experiments have demonstrated that the administration of antioxidants via foods and/or supplementation therapies significantly reduces the pathological features of VaD, including cognitive decline. Here, we provide a survey of studies about the role of oxidative stress and antioxidants in VaD pathogenesis. Moreover, we suggest the potential approach that caregivers might use to verify the effectiveness of antioxidants to prevent VaD or treat VaD patients. Keywords: cerebrovascular disorders, oxidative stress, neurodegenerative diseases, Antioxidants, diet.
GSTM1 null genotype as risk factor for late-onset Alzheimer's disease in Italian patients
Journal of the Neurological Sciences, 2012
Alzheimer&amp... more Alzheimer's disease (AD) is the most common form of dementia in the elderly. The causes of AD are very complex but there is general agreement about the existence of a link between Alzheimer's disease and oxidative stress. The Glutathione S-transferases (GSTs) act to detoxify products of oxidation that cause damage to macromolecules. Particular attention has been focused on GST genes because polymorphisms are important determinants of disease risk. To evaluate if GSTA1, GSTM1, GSTP1, and GSTT1 genes are associated with LOAD we screened a case-control population (n=311). Differences in genotype distributions between AD patients and controls were found only for the GSTM1 null genotype (P<0.001). In addition, a logistic regression analysis also conferred a positive association between the GSTM1 null genotype and LOAD after adjustment for age and gender (OR=2.09; 95%CI=1.31-3.35). The GSTM1 enzyme detoxifies substances such as exogenous and endogenous metabolites and plays a regulatory role in cellular signaling. Previous studies have highlighted that GSTM1 has a role in neurodegenerative disorders, but no data have associated the GSTM1 gene with AD risk. Our outcome suggests that the GSTM1 null genotype is a risk factor for AD in Italian patients.
The Clinical Respiratory Journal, 2014
Background and Aims: Allergic rhinitis (AR) is one of the most common respiratory diseases among ... more 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 casecontrol 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. Please cite this paper as: Iorio A, Polimanti R, Piacentini S, Liumbruno GM, Manfellotto D and Fuciarelli M. Deletion polymorphism of GSTT1 gene as protective marker for allergic rhinitis. Clin Respir J 2014; ••: ••-••.
Amyloid, 2014
Introduction: Transthyretin (TTR)-related amyloidosis is characterized by autosomal transmission ... more 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.
Genetic diversity of disease-associated loci in Turkish population
Journal of Human Genetics, 2015
Many consortia and international projects have investigated the human genetic variation of a larg... more Many consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health-related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries.Journal of Human Genetics advance online publication, 26 February 2015; doi:10.1038/jhg.2015.8.
American Journal of Human Biology, 2014
Objectives: Glutathione S-transferases (GSTs) are enzymes involved in Phase II reactions. They pl... more Objectives: Glutathione S-transferases (GSTs) are enzymes involved in Phase II reactions. They play a key role in cellular detoxification. Various studies have shown that genes coding for the GST are highly polymorphic and some of these variants are directly associated with a decrease of enzyme activity making individuals more susceptible to different clinical phenotypes. The aim of this study is to investigate the genetic variability of GST genes among human populations. We have focused our attention on the polymorphic variants of the GSTA1, GSTM1, GSTO1, GSTO2, GSTP1, GSTT1, and GSTT2B genes.
Functional polymorphisms of GSTA1 and GSTO2 genes associated with asthma in Italian children
Clinical Chemistry and Laboratory Medicine, 2000
Asthma is an airway disorder characterized by bronchial inflammation. An imbalance between the ox... more Asthma is an airway disorder characterized by bronchial inflammation. An imbalance between the oxidative forces and the antioxidant defense systems has been implicated in the pathogenesis of asthma. Glutathione S-transferases (GSTs) play an important role in cellular protection against inflammation. Several studies have investigated the genetic variability of GSTM1, GSTP1 and GSTT1 enzymes in asthma development with conflicting results. Moreover, in our previous independent case-control study on GSTs and asthma, we have found that GSTA1 and GSTO2 gene polymorphisms are associated with asthma. The aim of the present study is to analyze if some functional polymorphisms of GSTA1, GSTM1, GSTP1, GSTO2 and GSTT1 are associated with asthma in pediatric patients from Chieti (Italy). In this study, we performed an association study on 127 asthmatic children and 126 controls. We screened single nucleotide polymorphisms at GSTA1, GSTO2 and GSTP1 loci. The effects of GSTM1 and GSTT1 null genotype were also investigated. The GSTA1*-69T and GSTO2*D142 variants are associated with the significant increased risk of asthma development in our study population, while GSTM1, GSTP1 and GSTT1 genotype distributions were nearly equal between the control group and asthmatics. Confirming our previous study, these findings suggest that the GSTA1 and the GSTO2 are asthma susceptible genes involved in increasing the risk of asthma development in the Italian population.
GSTM1 , GSTP1 , and GSTT1 genetic variability in Turkish and worldwide populations
American Journal of Human Biology, 2014
Glutathione S-transferase (GST) variants have been widely investigated to better understand their... more Glutathione S-transferase (GST) variants have been widely investigated to better understand their role in several pathologic conditions. To our knowledge, no data about these genetic polymorphisms within the Turkish population are currently available. The aim of this study was to analyze GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V (rs1695), and GSTP1*A114V (rs1138272) variants in the general Turkish population, to provide information about its genetic diversity, and predisposition to GST-related diseases. Genotyping was performed in 500 Turkish individuals using the Sequenom MassARRAY platform. A comparative analysis was executed using the data from the HapMap and Human Genome Diversity Projects (HGDP). Sequence variation was deeply explored using the Phase 1 data of the 1,000 Genomes Project. The variability of GSTM1, GSTT1, and GSTP1 polymorphisms in the Turkish population was similar to that observed in Central Asian, European, and Middle Eastern populations. The high linkage disequilibrium between GSTP1*I105V and GSTP1*A114V in these populations may have a confounding effect on GSTP1 genetic association studies. In analyzing GSTM1, GSTT1, and GSTP1 sequence variation, we observed other common functional variants that may be candidates for associated studies of diseases related to GST genes (e.g., cancer, cardiovascular disease, and allergy). This study provides novel data about GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V, and GSTP1*A114V variants in the Turkish population, and other functional variants that may affect GSTM1, GSTT1, and GSTP1 functions among worldwide populations. This information can assist in the design of future genetic association studies investigating oxidative stress-related diseases. Am. J. Hum. Biol., 2014. © 2014 Wiley Periodicals, Inc.
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, 2013
Heterogeneity in the genotype-phenotype correlation of transthyretin (TTR)-related amyloidosis ha... more 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. 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. 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 i...
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Papers by Renato Polimanti