The etiology of sporadic Parkinson's disease is (PD) still not understood but it is believed that a complex interplay between environmental and genetic factors could trigger the pathology. ...Pro-inflammatory TNF-α is released by activated microglia and is up-regulated in the brain and cerebrospinal fluid of PD patients; TNF-α modulates neuroinflammation and can activate the molecular mechanisms that lead to neurotoxicity and neuronal death. We analyzed two functional SNPs within the TNF-α gene promoter (rs361525 and rs1800629) in 354 Italian PD patients and 443 healthy controls (HC). In our cohort of patients, no significant associations could be observed between rs361525 and rs1800629 SNPs and either PD onset risk or PD-associated clinical parameters including age at onset of fluctuations, UPDRS-ME (Unified Parkinson Disease Rating Scale-Motor Examination), Schwab & England, Hohen & Yahr stage scale, and MMSE (Mini-Mental State Examination) score. Conflicting results on the role played by TNF-α rs1800629 SNP on PD onset risk are present in the literature. We could not find any association between TNF-α rs361525 and rs1800629 and PD.
•Chronic inflammation and microglia activation is present in Parkinson's disease.•TNF-α is up-regulated in the brain and cerebrospinal fluid of PD patients.•rs1800629 and rs361525 TNF-α promoter SNPs confer stronger transcriptional activity.•We analyzed rs1800629 and rs361525 SNP in a cohort of Italian PD patients.•We found no association between rs1800629 and rs361525 SNPs with PD in our cohort.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was ...to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and
functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in
, a gene coding for a protein of an unknown function (
< 10
). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (
= 0.0093 and
= 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (
= 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (
= 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.
Background. Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder. Rate of decline and functional restoration in AD greatly depend on the capacity for neural plasticity within ...residual neural tissues; this is at least partially influenced by polymorphisms in genes that determine neural plasticity, including Apolipoprotein E4 (ApoE4) and synaptosomal-associated protein of 25 kDa (SNAP-25). Objective. We investigated whether correlations could be detected between polymorphisms of ApoE4 and SNAP-25 and the outcome of a multidimensional rehabilitative approach, based on cognitive stimulation, behavioral, and functional therapy (multidimensional stimulation therapy MST). Methods. Fifty-eight individuals with mild-to-moderate AD underwent MST for 10 weeks. Neuro-psychological functional and behavioral evaluations were performed blindly by a neuropsychologist at baseline and after 10 weeks of therapy using Mini-Mental State Examination (MMSE), Functional Living Skill Assessment (FLSA), and Neuropsychiatric Inventory (NPI) scales. Molecular genotyping of ApoE4 and SNAP-25 rs363050, rs363039, rs363043 was performed. Results were correlated with ΔMMSE, ΔNPI and ΔFLSA scores by multinomial logistic regression analysis. Results. Polymorphisms in both genes correlated with the outcome of MST for MMSE and NPI scores. Thus, higher overall MMSE scores after rehabilitation were detected in ApoE4 negative compared to ApoE4 positive patients, whereas the SNAP-25 rs363050(G) and rs363039(A) alleles correlated with significant improvements in behavioural parameters. Conclusions. Polymorphisms in genes known to modulate neural plasticity might predict the outcome of a multistructured rehabilitation protocol in patients with AD. These data, although needing confirmation on larger case studies, could help optimizing the clinical management of individuals with AD, for example defining a more intensive treatment in those subjects with a lower likelihood of success.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Vitamin D is a seco-sterol produced endogenously in the skin or obtained from certain foods. It exerts its action through binding to intracellular vitamin D receptor (VDR). Lately, the role of ...vitamin D has been revised regarding its potential advantage on delaying the process of aging. The aim of this study was to assess the contribution of VDR gene polymorphisms in healthy aging and longevity. We evaluated the frequency of four polymorphisms of the VDR gene (
Fok
I,
Bsm
I,
Apa
I, and
Taq
I) in centenarians (102 subjects, mean age: 102.3 ± 0.3 years), compared to septuagenarians (163 subjects, mean age: 73.0 ± 0.6 years) and we analyzed a variety of pathophysiologically relevant functions in centenarians.
Bsm
I and
Apa
I provided a significant association with longevity: there was a highly significant difference in the frequency of
Bsm
I genotypes (
p
= 0.037),
Apa
I genotypes (
p
= 0.022), and
Apa
I alleles (
p
= 0.050) in centenarians versus septuagenarians. Furthermore, we found a significant correlation of all the VDR gene polymorphisms in centenarians with some measured variables such as hand grip strength, body mass index, blood pressure, HDL cholesterol, and mini-mental state examination. We also found a correlation with the prevalence of medical history of hypertension, acute myocardial infarction, angina, venous insufficiency, dementia, chronic obstructive pulmonary disease, and arthrosis. In conclusion, this study proposes a new scenario in which the variability of the VDR gene is relevant in the aging process and emphasizes the role of VDR genetic background in determining healthy aging.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's ...disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD.
Abstract Killer Immunoglobulin-like Receptor (KIR) genes may affect both resistance and susceptibility to autoimmune disorders, but their role in the pathogenesis of Multiple Sclerosis (MS) is still ...unclear. To evaluate the involvement of KIRs and their HLA ligands in the development of MS we performed genotyping of HLA -A, -B, -Cw, -DRB1 and KIRs loci in 121 RRMS patients and 103 healthy controls (HC). Results evidenced a possible protective role of the activating KIR2DS1 gene (py = 0.001; OR:0.38), enhanced in the presence of its ligand group HLA-C2 (py = 0.0001; OR:0.23). Our data suggest that the presence of functional compounds of activating KIR receptors together with their HLA ligands, allowing the immunomodulatory function of NK cells, may have a protective role against the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Association studies have implicated common variants in the 12q14.1 region containing CYP27B1 in multiple sclerosis (MS). Rare CYP27B1 mutations cause autosomal recessive vitamin D–dependent rickets ...type 1, and it has recently been reported that heterozygous CYP27B1 mutations are associated with increased MS susceptibility and lower active vitamin D levels. By sequencing CYP27B1 in 134 multiplex families and genotyping the most common variant R389H in 2,608 MS patients and 1,987 controls from Italy and Belgium (a total of 4,729 individuals), we were unable to replicate these observations. These results provide evidence against a major role for CYP27B1 mutations in MS. ANN NEUROL 2013;73:433–437
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). ...Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3′ untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders.
The link between Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) and Kaposi's sarcoma has been proven, but the transmission routes, especially in the heterosexual population, ...are not yet completely understood. To assess the intrafamilial patterns of transmission among first-degree relatives of Italian classic Kaposi's sarcoma (cKS) patients, KSHV seroprevalence and the presence of viral DNA in blood and saliva were evaluated in 18 families (32 cKS patients and 35 family members), comparing the results with those obtained in 200 elderly healthy controls without known exposure to KSHV. The KSHV genotype of variable region VR1 of the hypervariable ORF K1 gene was subsequently analysed in all KSHV-positive samples. The results showed that KSHV infection was significantly higher in relatives of cKS patients (11/35 cases) than in healthy controls (17/200 cases; P=0.001). The 11 infected relatives included spouses (n=3), siblings (n=2) and offspring (n=6) of the cKS patients; the same KSHV genotype was shared within the same family in the majority of cases (85%), indicating the presence of person-to-person transmission within families. Viral DNA was mostly observed in the saliva of infected relatives (45.4%); detection of DNA in blood was less frequent (27.3%). Notably, KSHV DNA was present in saliva and/or blood of three KSHV-infected relatives with indeterminate or negative serostatus. Thus, the risk of KSHV infection is greatly enhanced within families of cKS patients, where close contacts (horizontal and/or sexual) can contribute to the spread of KSHV.
Progressive multifocal leukoencephalopathy (PML) usually is a rapid and fatal demyelinating disease of the central nervous system (CNS), caused by JC virus (JCV). After the introduction of Highly ...active antiretroviral therapy (HAART), its prognosis has been modified in some cases but remains a relevant cause of morbidity in human immunodeficiency virus-seropositive (HIV+) patients. The authors report here two cases of PML, followed over time, sharing a benign course and a JCV antigen-specific T-cell response, but with different cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and clinical features. In both cases, JCV DNA detection in brain biopsies samples and specific antigenic response preceded its isolation in the CSF by several months. In one patient, during the first stage of the disease, the presence of CSF and MRI inflammatory findings, associated with the lack of JCV detection in the CSF, made the diagnosis more challenging. Given that to date a reformation of the laboratory parameters for PML diagnosis is strongly needed, this report highlights the following considerations: (a) indications for performing brain biopsy in HIV-related leukoencephalopathies of uncertain origin, and (b) the role of JCV immunologically specific T-cell response as an additional marker for PML diagnosis and indicator for good prognosis of the disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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