Bruno Casali

Azienda Ospedaliera Santa Maria Nuova di Reggio Emilia, Reggio nell'Emilia, Emilia-Romagna, Italy

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Publications (70)268.88 Total impact

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    ABSTRACT: Objective: Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We performed whole exome sequencing in European-derived BD patients to investigate the role of rare variants in BD. Methods: Whole exome sequencing was performed in a discovery set comprised of 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in two additional independent sets of 49 and 129 European-derived BD patients from Germany and Italy, respectively. Genetic association analysis was then performed in BD patients and 503 European-derived controls. Functional effects of associated genetic variants were assessed using bioinformatic approaches. Results: We identified 77 rare variants (in 74 genes) with predicted protein-damaging effects in BD using whole exome sequencing. These variants were genotyped in 2 additional patient sets, and then analyzed to reveal significant BD-associations at two genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and NEIL1 (rs5745908), involved in base excision DNA repair (P=3.22x10(-4) and P=5.16x10(-4) , respectively). The LIMK2 association is a missense variant with predicted protein-damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni-corrected P=5.63x10(-14) , P=7.29x10(-6) , P=1.15x10(-5) , and P=6.40x10(-3) , respectively). The genetic association in NEIL1 is a predicted splice donor variant that may introduce a deleterious intron retention and result in a non-coding transcript variant. Conclusion: We used whole exome sequencing in BD for the first time, and identified two rare putative protein-damaging genetic variants associated with this disease. These genetic variants might influence cytoskeletal regulation and DNA repair mechanisms in BD and might provide further insight into increased leukocyte tissue infiltration and the role of oxidative stress in BD. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Arthritis and Rheumatology
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    ABSTRACT: There is increasing evidence that microRNAs (miRNAs) are deregulated in autoimmune and cardiovascular diseases. The present study aimed to identify if miRNAs are deregulated in giant cell arteritis (GCA), a vasculitis affecting large-sized and medium-sized arteries, and to determine if miRNA levels might allow to discriminate between patients with GCA and those without. 58 patients who had temporal artery biopsy (TAB) for suspected GCA were included in the study and divided into three groups: patients with TAB-positive GCA showing a transmural inflammation (n=27), patients with TAB-negative GCA (n=8) and TAB-negative non-GCA patients with a final diagnosis different from GCA (n=23). To identify candidate miRNAs deregulated in GCA, we profiled the expression of 1209 miRNAs in inflamed TABs and normal TABs. Selected miRNAs were then validated by real-time PCRs and in situ hybridisation (ISH). MiR-146b-5p, -146a, -155, -150, -21 and -299-5p were significantly more expressed in inflamed TABs from patients with GCA. miRNAs were mainly deregulated at the tissue level because peripheral blood mononuclear cells and polymorphonuclear cells from the three groups of patients and age-matched healthy controls had similar levels of miRNAs. ISH showed that miR-21 was mainly expressed by cells in the medial and intimal layers of inflamed TABs. Patients with TAB-negative GCA had a miRNA profile similar to TAB-negative non-GCA patients. MiR-146b-5p, -146a, -21, -150, -155, -299-5p are overexpressed in the presence of inflammation in TABs from patients with GCA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Full-text · Article · Sep 2015 · Annals of the rheumatic diseases
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    ABSTRACT: The enzyme cyclooxygenase 2 is an inducible enzyme expressed at sites of inflammation and in a variety of malignant solid tumors such as endometrial cancer (EC). In EC patients, its over-expression is correlated with progressive disease and poor prognosis. The expression is encoded by a polymorphic gene, called PTGS2. The aim of the current study was to test the hypothesis that rs5275 polymorphism of PTGS2 influence the prognosis of EC patients. This paper is a retrospective cohort study. Clinical and pathological data were extrapolated and genotypes were assessed on formalin-fixed and paraffin-embedded non-tumor tissues. A total of 159 type I EC patients were included in the final analysis. Univariate analysis indicated that patients with rs5275 genotype CC have a lower risk to develop a grade (G) 2-3 endometrial cancer. rs5275 effect on EC grading was confirmed by multivariate analysis also after data adjusting for age, BMI, parity, hypertension, and diabetes. Adjusted odds ratio (OR) confirmed that patients with rs5275 genotype CC have a risk 80 % lower (OR = 0.20, P = 0.009) to develop a G2 and/or G3 EC in comparison with patients with TT or TC genotype. Differentiation of the type 1 EC is significantly and independently influenced by rs5275 polymorphism. rs5275 CC patients have a lower risk to present a G2-G3 EC.
    Full-text · Article · Apr 2015 · Tumor Biology
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    ABSTRACT: HNF1B (formerly known as TCF2) gene encodes for a transcription factor that regulates gene expression involved in normal mesodermal and endodermal developments. A close association between rs4430796 polymorphism of HNF1B gene and decreased endometrial cancer (EC) risk has been demonstrated. The aim of the current study was to test the hypothesis that rs4430796 polymorphism can influence the prognosis of EC patients. Retrospective cohort study. Clinical and pathological data were extrapolated and genotypes were assessed on formalin-fixed and paraffin-embedded non-tumour tissues. The influence of patients' genotype on overall survival and progression free survival were our main outcome measures. A total of 191 EC patients were included in the final analysis. Overall survival differed significantly (P = 0.003) among genotypes. At multivariate analysis, a significant (P < 0.05) effect on overall survival was detected for histology, myometrial invasion, FIGO stage, adjuvant therapy, and rs4430796 polymorphism of HNF1B gene. After grouping EC patients according to adjuvant treatment, rs4430796 polymorphism resulted significantly (P < 0.001) related to overall survival only (vs. radiotherapy alone) in subjects who received radiotherapy plus chemotherapy. A significant (P = 0.014) interaction between rs4430796 polymorphism and chemo-radiotherapy was also detected. Finally, only a trend (P = 0.090) towards significance was observed for rs4430796 polymorphism effect on progression free survival. rs4430796 polymorphism of HNF1B gene influences independently the prognosis of EC patients with a potential effect on tumor chemo-sensitivity.
    Full-text · Article · Apr 2015 · BMC Cancer
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    ABSTRACT: Background Chronic periaortitis (CP) is a rare disease characterised by a fibro-inflammatory reaction that arises from the adventitia of the abdominal aorta and common iliac arteries in the retro-peritoneum.It often entrapsadjacent structures, such as ureters and the inferior vena cava. CP includes non-aneurysmal (idiopathic retroperitoneal fibrosis, IRF) and aneurysmal forms (inflammatory abdominal aortic aneurysm, IAAA) [1]. These have common clinical and histopathological features, which suggests that they represent different manifestations of the same disease. It has been reported that variants in Toll-like receptor 4 (TLR4) are associated with inflammatory diseases, and also that VEGF polymorphisms are associated with various productions and clinical expressions of VEGF in autoimmune disease [2,3]. Objectives To investigate whether TLR4 and VEGF polymorphisms are associated with a susceptibility to, and the clinical features of, CP or its subsets, IRF and IAAA. Methods Using polymerase chain reaction and allele-specific oligonucleotide techniques, 102 CP patients and 200 healthy controls were genotyped for the TLR4 Asp299Gly (+896 A/G; rs4986790), for 936 C/T and 634 C/G mutations and for an 18 bp insertion/deletion (I/D) polymorphism in the VEGF promoter region polymorphisms. The patients were sub-grouped according to their type of CP (IRF/IAAA) and to the presence of established atherosclerotic disease (ischemic heart disease, cerebrovascular disease, peripheral arterial disease). Results There was no significant difference in allele frequency or genotype of TLR4 (+896 A/G) between CP patients and controls (P=1.00). No differences in carriage rates of the alleles I, –634C and +936T of VEGF polymorphisms were found between patients with CP and healthy controls [P=0.108, OR 1.51 (95% CI 0.92–2.48) and P=0.304, OR 1.33 (95% CI 0.79–2.23), respectively].The frequency of carriage rate T of 936 VEGF polymorphism was significantly lower in patients with CP with IAAA than in those with IRF (5.3% vs 26.5%, p=0.046, OR 6.49, 95% CI 0.82–51.54). Carrying the I allele (II+ID) was significantly associated with ureteral obstruction in comparison with non-carrying patients (74% vs. 44%; P=0.006). Moreover, those patients homozygous for the inserted version (II) had a significantly increased frequency of thrombosis compared to those without (43% vs. 19.00 P=0.031). Conclusions Our findings demonstrate that, amongst Italian patients, carrying (II +ID) polymorphism in the VEGF is associated with an increased susceptibility to the development of ureteral obstruction, and those patients homozygous for the inserted version (II) had an increased risk of thrombosis. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives: The single nucleotide polymorphism (SNP) of TIRAP (Serine 180 leucine, S180L) that is shown to be associated with Behçet's disease (BD) in a European-derived cohort, but not in Middle Eastern patients is investigated in two other populations. Methods: Two cohorts of BD patients and controls from Turkey (n=797) and Italy (n=633) were genotyped by sequence specific primer-polymerase chain reaction (SSP-PCR) or TaqMan q-PCR assays. Results: Genotype and allele frequencies in TIRAP S180L (rs8177374) were not different between BD patients and controls in either ethnicity. Furthermore, a meta-analysis between the Turkish and the Italian BD cohorts did not reveal an association between this non-synonymous SNP in TIRAP and BD (meta-analysis OR=0.94, meta-analysis p=0.61, Q statistic heterogeneity p=0.11). Conclusions: TIRAP S180L gene polymorphism, which was previously shown to be associated with BD in a Caucasian population, has been replicated in either Turkish or Italian population in our study.
    No preview · Article · Sep 2013 · Clinical and experimental rheumatology
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    ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14+1G>A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician's decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1G>A mutations.
    Full-text · Article · Apr 2013 · Internal and Emergency Medicine
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    ABSTRACT: Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 μM, trypan blue exclusion assay). At a lower range (25 μM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 μM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.
    Full-text · Article · Mar 2013 · International Journal of Cancer
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    ABSTRACT: Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10(-26)), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10(-14)) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10(-18)) were also identified and replicated.
    Full-text · Article · Feb 2013 · Nature Genetics
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    ABSTRACT: The mechanisms of excess aldosterone secretion in primary aldosteronism (PA) remain poorly understood, although a role for circulating factors has been hypothesized for decades. Agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) are detectable in malignant hypertension and preeclampsia and might play a role in PA. Moreover, if they were elevated in aldosterone-producing adenoma (APA) and not in idiopathic hyperaldosteronism (IHA), they might be useful for discriminating between these conditions. To test these hypotheses, we measured the titer of AT1AA in serum of 46 patients with PA (26 with APA, 20 with IHA), 62 with primary hypertension (PH), 13 preeclamptic women, and 45 healthy normotensive blood donors. We found that the AT1AA titer was higher (P<0.05) in both PA and PH patients (2.65±1.55 and 1.86±0.63, respectively) than in normotensive subjects (1.00±0.20). In APA, it was 2-fold higher than in IHA patients (3.43±1.20 versus 1.64±1.39, respectively, P<0.001), despite similar blood pressure values. Of note, it allowed effective discrimination of APA from either PH or IHA, as shown by Receiver Operator Characteristics curve analysis. Moreover, after captopril challenge, plasma aldosterone concentration fell more in AT1AA-positive than in AT1AA-negative PA patients (-32.4% [21.1-42.9] versus 0.0% [0.0-22.6], P=0.015), suggesting an agonistic role for these autoantibodies. Thus, a higher serum AT1AA titer in patients with APA than in IHA and PH patients can be useful in differentiating APA patients from either PH or IHA, and thus in selecting PA patients to be submitted to adrenal vein sampling.
    Full-text · Article · Dec 2012 · Hypertension
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    ABSTRACT: Haptoglobin (H) is a glycoprotein that regulates the immune response. Serum haptoglobin levels are significantly higher in patients with advanced epithelial ovarian cancer (EOC) with poor survival. Different isoforms of haptoglobin have been found in the serum of patients with EOC. We studied the genetic susceptibility and outcome of patients with EOC correlated to H phenotypes. Analyses of the H phenotypes were performed on sera from patients stored at -70°C. A modified method based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of sera was used, followed by western blotting. Seventy-nine consecutive patients with EOC and 63 healthy women were enrolled. Their mean (±S.D.) age was 58.9±12.46 years. Overall survival was 66 months (95% confidence interval=37.7-94.2). Similar distribution of haptoglobin phenotypes was observed in EOC and in healthy women. No significant correlation was found between haptoglobin phenotype, overall survival and time-to-progression. Fewer G3 tumors were found in patients with H2-2 compared with those with H1-2 (84.2% and 90.6%, respectively, p<0.04). No significant correlation was found between H phenotype and tumor markers or number of relapses. Although ours is a preliminary study based on a small population with scant significant findings, we hypothesize that patients with EOC with haptoglobin 2-2, might have a better prognosis because they present fewer G3 tumors and they may present a stronger immune response than patients with 1-1 and 1-2 phenotypes. Larger studies should be performed to assess the predictive value of haptoglobin phenotype in patients with EOC.
    No preview · Article · Oct 2012 · Anticancer research
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    ABSTRACT: Objectives To evaluate the potential role of CC chemokine receptor 5 (CCR5)Δ32 polymorphism in the susceptibility to giant cell arteritis (GCA) in a cohort of Italian patients. Methods 176 consecutive Italian patients with biopsy-proven GCA and 180 healthy age- and sex-matched blood donors were molecularly genotyped for the CCR5Δ32 polymorphism. Results No statistically significant difference in the Δ32CCR5 allele frequency between GCA patients (5.1 %) and controls (2.8 %) was observed (p = 0.109). Carriers of the CCR5Δ32 allele (Δ32/Δ32 + CCR5/Δ32) were similarly represented in the two groups. Conclusions Our results do not support a role for the CCR5Δ32 polymorphism in determining susceptibility to GCA.
    No preview · Article · Sep 2012 · Modern Rheumatology
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    ABSTRACT: Objective: To evaluate the potential role of CC chemokine receptor 5 (CCR5)Δ32 polymorphism in the susceptibility to and clinical expression of Behçet's disease (BD) in a cohort of Italian patients. Methods: One hundred and ninety-six consecutive Italian patients satisfying the ISG criteria for BD were followed up for 8 years, and 180 healthy age- and sex-matched blood donors were molecularly genotyped for the CCR5Δ32 polymorphism. A standard microlymphocytotoxicity technique was used to serotype HLA-B51. The patients were subgrouped on the basis of the presence or absence of clinical manifestations. Results: The distribution of the CCR5Δ32 genotype differed between BD patients and controls (P = 0.02). The CCR5Δ32 allele was more common in BD patients than in controls [P = 0.02, odds ratio (OR) 2.28 (95% CI 1.1, 4.8)]. Carriers of the CCR5Δ32 allele (Δ32/Δ32 + CCR5/Δ32) were significantly more common in BD patients than in controls [P = 0.02, OR 2.37 (95% CI 1.1, 5.1)]. Population-attributable risk was 7.1%. In categorizing patients according to gender, the association between CCR5Δ32 polymorphism and BD was similar in females and males (ORs 2.76 and 2.0, respectively). No significant differences were found when the frequencies of clinical manifestations were compared between CC5RΔ32 allele carriers and non-carriers. Conclusion: CCR5Δ32 polymorphism is associated with an increased susceptibility to develop BD. Chemokines may have a role in the pathophysiology of BD.
    Preview · Article · Sep 2012 · Rheumatology (Oxford, England)
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    ABSTRACT: To investigate the genetic variability of IL-17A, IL17-RA, IL-23A and IL-23R genes on an in-depth phenotypically characterized northern Italian Psoriatic arthritis (PsA) case–control cohort, in search for associations specific to different PsA clinical sub-phenotypes. We examined 118 patients with PsA according to CASPAR criteria (mean age 57 ± 13, female 38.4 %, mean disease duration 13.9 ± 8.6 years, peripheral disease 83.8 %, axial manifestations 34.5 %, radiological erosive disease 49 %) compared with 248 controls of the same ethnic origin matched for age and sex. The presence of axial disease was defined by the clinical axial involvement and/or the presence of radiological alteration consistent with spondyloarthropathy according to New York criteria. The presence of peripheral disease (arthritis and/or enthesitis) was defined only on clinical basis. A total of 40 SNPs, mapping within the genes mentioned above, were genotyped in both groups and used to perform association analyses by subdividing the PsA sample into subgroups according to different clinical manifestations on the basis of axial and peripheral involvements. No differences between patients and controls were found in the distribution of the IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants. Comparing patients with axial disease versus those without, we found that axial manifestations were significantly associated with the presence of IL-23R rs12401432 GG homozygosity (26.8 % vs. 5.3 %, p corr = 0.019, OR 2.63 [95 % CI 1.13–6.16]). No differences in distribution of the allelic variants were found comparing patients with versus those without peripheral disease or patients with versus without radiological peripheral erosions. In PA patients of northern Italian origin, IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants are not associated with disease susceptibility. However, a strong association with the IL-23RA rs12401432 GG genotype is associated with axial involvement of the disease.
    No preview · Article · Sep 2012 · Rheumatology International
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    ABSTRACT: Introduction. There is growing evidence that Hypertension in pregnancy is linked to immunological and the renin-angiotensin system dysfunction. An autoantibody (class IgG), has been proposed as a circulating factor able to begin the disease process. The objective of this study was to evaluate the serum concentration of anti-AT1 receptor antibody agonist of angiotensin II (AAb anti AT1R), in patients with pregnancy complicated by hypertension. Materials and methods. We analysed three groups of patients: 13 patients with gestational hypertension, 9 with chronic hypertension in pregnancy and 10 controls (physiological pregnancies). Peptide corresponding to amino acid sequence of the second extracellular loop AT1 receptor has been used as antigen for evaluating AAb anti AT1R plasma concentration. Results. Patients with gestational hypertension have a concentration of anti AAb AT1R higher than controls (2.1±0.5 vs 1.5±0.5 IU / ml, p=0.029). Between the group of patients affected by chronic hypertension and controls was not observed any significant difference. Conclusions. The concentration of AAb anti AT1R is increased in gestational hypertension. These preliminary results highlight new immunological aspects of gestational hypertension. Monitoring these autoantibodies in pregnancy at risk could play an important role in the diagnosis and treatment of this disease.
    No preview · Article · Sep 2012 · Giornale Italiano di Ostetricia e Ginecologia
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    ABSTRACT: Spastic paraplegia 3A is the second most common form of hereditary autosomal dominant spastic paraplegia. This form is mainly associated with an early age of onset and pure phenotype, although recently complicated forms were reported. We describe a patient carrying a new C>T P344S>CT mutation in exon 10 of the spastic paraplegia 3A gene with unusual, complicated, and extremely severe phenotype. At the last neurologic examination performed at 17 years of life, the patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy, cognitive and cranial nerve impairment, mild pes cavus, and distal amyotrophy.
    No preview · Article · Feb 2012 · Journal of child neurology
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    ABSTRACT: Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet's disease. We undertook this study to establish the genetic effect within the UBAC2 gene, in the course of which we replicated this genetic association and identified a functional variant within this locus. We studied a total of 676 Behçet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls from Turkey and 144 patients and 560 controls from Italy. Genotyping of 14 single-nucleotide polymorphisms (SNPs) within and around UBAC2 was performed using TaqMan SNP genotyping assays. The genetic association between Behçet's disease and UBAC2 was established, replicated, and confirmed (meta-analysis odds ratio 1.84, P = 1.69 × 10(-7) ). Haplotype analysis identified both a disease-risk haplotype and a protective haplotype (P = 0.00014 and P = 0.0075, respectively). Using conditional haplotype analysis, we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrated that rs7999348 tags a functional variant associated with increased messenger RNA expression of a UBAC2 transcript variant in peripheral blood mononuclear cells of individuals homozygous for the Behçet's disease-associated "G" allele. Further, our data suggested the possibility of multiple genetic effects that increase susceptibility to Behçet's disease in the UBAC2 locus. We established and confirmed the genetic association between UBAC2 and Behçet's disease in 3 independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.
    Full-text · Article · Nov 2011 · Arthritis & Rheumatology
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    ABSTRACT: To investigate potential associations between the PlA1/A2 polymorphism of the platelet glycoprotein receptor IIIA (GpIIIa) gene and venous thrombosis and other clinical manifestations in Italian patients with Behçet's disease (BD). Two hundred consecutive Italian patients satisfying the International Study Group criteria for BD who were followed up for seven years and 241 healthy Italian age- and gender-matched blood donors were molecularly genotyped for the PlA1/A2 polymorphism of the platelet GpIIIa gene; 118 and 117 of the 200 BD patients were also respectively genotyped for factor V Leiden and prothrombin gene G20210A polymorphisms. A standard microlymphocytotoxicity technique was used to type serological HLA class B51. The patients were grouped on the basis of the presence or absence of clinical manifestations. The diagnoses of deep vein thrombosis (DVT) and superficial thrombophlebitis were initially made clinically, and then confirmed by means of ultrasonography or contrast venography. The distribution of the PlA1/A2 genotype was investigated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The allele and genotype frequency of the PlA1/A2 polymorphism were not significantly different in the BD patients and controls, but the PlA2 allele was significantly more frequent in the BD patients with DVT than the controls (p=0.023; Pcorr=0.046; OR 2.0, 95% CI 1.1-3.7). There were no associations between thrombotic events and the PlA1/A2 polymorphism in the BD patients carrying factor V Leiden or prothrombin gene G20210A mutations. The PlA2 allele was significantly less frequent in the BD patients with genital genital ulcers than in those without (26.9% vs. 43.2%; p=0.022; P corr 0.044; OR 0.48, CI 0.27-0.88). The PlA1/A2 polymorphism of the GpIIIa gene was associated with DVT in our Italian BD patients, but does not seem to increase the risk of DVT due to factor V Leiden or prothrombin gene G20210A mutations. There was a negative association between the A2 allele and genital ulcers.
    No preview · Article · Jul 2011 · Clinical and experimental rheumatology
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    ABSTRACT: Chronic periaortitis (CP) is a rare disease characterized by a fibro-inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Δ32 polymorphism confers susceptibility to CP. One hundred CP patients and 180 healthy controls were genotyped for CCR5Δ32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). The distribution of the CCR5Δ32 genotype differed between CP patients and controls (P = 0.01). The CCR5Δ32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Δ32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Δ32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Δ32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Δ32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. The CCR5Δ32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP.
    Preview · Article · May 2011 · Rheumatology (Oxford, England)
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    ABSTRACT: Liddle's syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of-function mutation of the β subunit of the epithelial sodium channel (ENaC) (P617L) previously reported by our group in an apparently unrelated Sicilian patient presenting the typical phenotype of LS including hypokalemia; (ii) to determine whether an unknown biological relationship exists between the newly identified family and the family of the proband previously reported. Genetic analysis was performed in the present family, in the individual in which the βP617L mutation was first observed, and in his relatives. βP617L mutation was identified in the proband and in three maternal relatives. None of them showed hypokalemia. Mild to severe early onset hypertension and left ventricular hypertrophy were present in all of them. Analysis of mitochondrial DNA (mtDNA) and Y chromosome profiles in the present family and in the proband's family previously reported showed the absence of a relationship between them. The availability of only one carrier of the mutation in one of the two families meant that a genetic analysis able to assess a founder effect was not feasible. LS should be considered in all cases of early onset hypertension, independently of the plasma potassium concentration. The incidence of LS may be greater than is currently thought, because hypokalemia is not invariably present.
    No preview · Article · Apr 2011 · American Journal of Hypertension