The −670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis

Objective:To evaluate the role of the single-nucleotide polymorphism (SNP) at position −670 in the FAS gene promoter (FAS−670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc).Methods:350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS−670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA.Results:A significant difference in FAS−670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS−670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS−670A allele was found in dcSSc. The FAS−670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS−670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS−670AA genotype compared with those carrying the FAS−670GG genotype (p = 0.003 in SSc, p = 0.004 in controls).Conclusion:The FAS−670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.

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Coexistence of Gilbert syndrome with hereditary haemolytic anaemias

Journal of Clinical Pathology ◽

10.1136/jclinpath-2011-200580 ◽

2012 ◽

Vol 65 (7) ◽

pp. 663-665 ◽

Cited By ~ 3

Author(s):

Katarzyna Rawa ◽

Anna Adamowicz-Salach ◽

Michał Matysiak ◽

Anna Trzemecka ◽

Beata Burzynska

Keyword(s):

Genetic Defect ◽

Gene Promoter ◽

Promoter Polymorphism ◽

Control Group ◽

Genotype Distribution ◽

Inherited Disease ◽

Healthy Individuals ◽

Gilbert Syndrome ◽

Significant Difference ◽

Glucose 6 Phosphate Dehydrogenase

BackgroundGilbert syndrome is an inherited disease characterised by mild unconjugated hyperbilirubinaemia caused by mutations in UGT1A1 gene which lead to decreased activity of UDP-glucuronosyltransferase 1A1. The most frequent genetic defect is a homozygous TA dinucleotide insertion in the regulatory TATA box in the UGT1A1 gene promoter.Methods and results182 Polish healthy individuals and 256 patients with different types of hereditary haemolytic anaemias were examined for the A(TA)nTAA motif. PCR was performed using sense primer labelled by 6-Fam and capillary electrophoresis was carried out in an ABI 3730 DNA analyser. The frequency of the (TA)7/(TA)7 genotype in the control group was estimated at 18.13%, (TA)6/(TA)7 at 45.05% and (TA)6/(TA)6 at 36.26%. There was a statistically significant difference in the (TA)6/(TA)6 genotype distribution between healthy individuals and patients with glucose-6-phosphate dehydrogenase deficiency (p=0.041). Additionally, uncommon genotypes, (TA)5/(TA)6, (TA)5/(TA)7 and (TA)7/(TA)8 of the promoter polymorphism, were discovered.ConclusionGenotyping of the UGT1A1 gene showed distinct distribution of the common A(TA)nTAA polymorphism relative to other European populations. Because of a greater risk of hyperbilirubinaemia due to hereditary haemolytic anaemia, the diagnosis of Gilbert syndrome in this group of patients is very important.

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Association between a stromal cell-derived factor 1 (SDF-1/CXCL12) gene polymorphism and microvascular disease in systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.098277 ◽

2008 ◽

Vol 68 (3) ◽

pp. 408-411 ◽

Cited By ~ 19

Author(s):

M Manetti ◽

V Liakouli ◽

C Fatini ◽

P Cipriani ◽

C Bonino ◽

...

Keyword(s):

Systemic Sclerosis ◽

Microvascular Disease ◽

Scleroderma Renal Crisis ◽

Genotype Distribution ◽

Skin Ulcers ◽

Genotype Frequencies ◽

Pcr Rflp ◽

Pulmonary Arterial ◽

Stromal Cell Derived Factor ◽

And Gender

Objective:To investigate the possible implication of SDF1-3′ polymorphism in systemic sclerosis (SSc) susceptibility or clinical phenotype, or both.Methods:150 patients with SSc and 150 controls were enrolled. Skin involvement, autoantibodies, interstitial lung disease, pulmonary arterial hypertension (PAH), scleroderma renal crisis, past and/or current skin ulcers were assessed. Genotyping was performed by PCR-RFLP.Results:Genotype distribution and allele frequency were similar in SSc and controls. SDF1-3′A allele and SDF1-3′GA/AA genotype frequencies were significantly higher in SSc-PAH than in SSc-non-PAH (33.3% vs 18.3%, p = 0.01) and in SSc with skin ulcers than in SSc without ulcers (27.3% vs 16.9%, p = 0.03). The SDF1-3′A allele influenced the predisposition to SSc-related PAH (OR = 2.52, 95% CI 1.11 to 5.69, p = 0.02) and skin ulcers (OR = 2.31, 95% CI 1.18 to 4.52, p = 0.01). After adjustment for age and gender, the SDF1-3′A allele remained a susceptibility factor for the SSc-related vascular manifestations (PAH: OR = 2.37, 95% CI 1.04 to 5.42, p = 0.04; ulcers: OR = 2.33, 95% CI 1.78 to 4.62, p = 0.01).Conclusion:The SDF1-3′A allele is significantly associated with microvascular involvement in SSc.

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AB0557 CO-EXISTENCE OF SYSTEMIC SCLEROSIS HALLMARK AUTOANTIBODIES ASSOCIATES WITH DISTINCT CLINICAL PHENOTYPE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3500 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1575.2-1575

Author(s):

C. Campochiaro ◽

K. Clark ◽

L. Host ◽

A. Sari ◽

S. Nihtyanova ◽

...

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Clinical Features ◽

Topoisomerase I ◽

Clinical Phenotype ◽

Rna Polymerase Iii ◽

Scleroderma Renal Crisis ◽

Fisher Exact Test ◽

Pulmonary Arterial

Background:Systemic sclerosis (SSc) is typically manifests with distinct SSc-specific antibodies (SSc-Abs): anti-topoisomerase I (ATA), anti-centromere (ACA), anti-RNA polymerase III (ARA), anti-U3RNP (u3RNP), anti-U1RNP (U1RNP), anti-PmScl (PmScl), anti-Ku (Ku) and anti-Th/T0 (Th/T0), each being characterised by different clinical features and prognosis. The presence of >1 SSc-Abs is rare with minimum data about these patients’ clinical phenotype.Objectives:To describe and compare the clinical features of SSc patients with >1 SSc-AbMethods:The autoantibody profiles of 2799 SSc patients from February 2001 to June 2017 were retrospectively reviewed. Patients with >1 SSc-Abs were identified. Clinical features were collected and compared to historical cohorts of SSc patients with single SSc-Ab positivity. Patients were excluded if treated prior to their immunology test with rituximab, iv immunoglobulins or stem cell transplantation. Statistical analysis was performed using Fisher exact test.Results:72 patients (2.6%) with >1 SSc-Ab were identified. Full clinical data were available for 63 patients. 60 patients (2.1%) had double Ab positivity and 3 patients had triple Ab positivity (0.1%). 13 Ab combinations were present. U1RNP and ATA was the most frequent combination (35%), patients were significantly younger (51.38 years) than both U1RNP (58.64 years, p=0.050) and ATA (62.03 years, p=0.002) patients and more commonly of diffuse subset (dcSSc) (p=0.001 and p=0.041 respectively). Compared to ATA patients overlap features were more frequent (43% vs 15%, p=0.004) including inflammatory arthritis (p=0.025) and myositis (p=0.013) (Table 1). U1RNP and ACA had a significantly higher prevalence of pulmonary arterial hypertension compared to U1RNP (p=0.039) and ACA (p=0.022) patients, and compared to ACA patients they were younger (57.88 vs 68.75, p=0.015) with a higher incidence of myositis (p=0.001). U1RNP and ARA patients were more frequently dcSSc subtype compared to U1RNP patients (75% vs 21%, p=0.040). U1RNP and PmScl patients had a higher prevalence of myositis compared to U1RNP patients (p=0.006). ATA and ACA patients behaved similarly to ATA patients with a significantly higher prevalence of lung fibrosis (p=0.006) and myositis (p=0.041) compared to ACA. ACA and PmScl (7%) had higher prevalence of myositis compared to ACA patients (p=0.04).Table 1. Frequency of clinical features in some of the double antibody group combinations, compared to our cohort of patients with only one of the SSc specific antibody. Significant p values (<0.05) highlighted in bold. ILD (interstitial lung disease), PAH (pulmonary arterial hypertension), SRC (scleroderma renal crisis).Conclusion:Coexistence of hallmark autoantibodies is exceedingly rare in SSc patients. When combined, both SSc-Abs have the potential to synergistically interact and modify the clinical phenotype.Disclosure of Interests:Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Kristina Clark: None declared, Lauren Host: None declared, Alper Sari: None declared, Svetlana Nihtyanova: None declared, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Voon Ong: None declared

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Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Disease Markers ◽

10.1155/2016/6064830 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Andréa Tavares Dantas ◽

Sayonara Maria Calado Gonçalves ◽

Anderson Rodrigues de Almeida ◽

Rafaela Silva Guimarães Gonçalves ◽

Maria Clara Pinheiro Duarte Sampaio ◽

...

Keyword(s):

Systemic Sclerosis ◽

Clinical Manifestations ◽

Serum Levels ◽

Vascular Involvement ◽

Digital Ulcers ◽

Serum Samples ◽

Peripheral Blood Mononuclear ◽

Pbmc Culture ◽

Significant Difference ◽

Skin Biopsies

Objective. To determine active TGF-β1 (aTGF-β1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients.Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-β1 by PBMC. The aTGF-β1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR.Results. TGF-β1 serum levels were significantly higher in SSc patients than in HC (p< 0.0001). Patients with increased TGF-β1 serum levels were more likely to have diffuse subset (p= 0.02), digital ulcers (p= 0.02), lung fibrosis (p< 0.0001), positive antitopoisomerase I (p= 0.03), and higher modified Rodnan score (p= 0.046). Most of our culture supernatant samples had undetectable levels of TGF-β1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin.Conclusion. Raised active TGF-β1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.

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French recommendations for the management of systemic sclerosis

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01844-y ◽

2021 ◽

Vol 16 (S2) ◽

Author(s):

Eric Hachulla ◽

Christian Agard ◽

Yannick Allanore ◽

Jerome Avouac ◽

Brigitte Bader-Meunier ◽

...

Keyword(s):

Systemic Sclerosis ◽

Proximal Region ◽

Scleroderma Renal Crisis ◽

Cardiac Damage ◽

Favorable Prognosis ◽

Causes Of Mortality ◽

Cutaneous Form ◽

Pulmonary Arterial ◽

Renal Crisis ◽

Severe Pulmonary Arterial Hypertension

AbstractSystemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis.

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Vascular Complications of Systemic Sclerosis during Pregnancy

International Journal of Rheumatology ◽

10.1155/2010/287248 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 14

Author(s):

Eliza F. Chakravarty

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Pregnancy Outcomes ◽

Vascular Complications ◽

Autoimmune Disorder ◽

Morbidity And Mortality ◽

Scleroderma Renal Crisis ◽

Hemodynamic Changes ◽

Pulmonary Arterial ◽

Renal Crisis

Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by progressive fibrosis of the skin and visceral tissues as well as a noninflammatory vasculopathy. Vascular disease in systemic sclerosis is a major cause of morbidity and mortality among nonpregnant patients with SSc and is even a bigger concern in the pregnant SSc patient, as the underlying vasculopathy may prevent the required hemodynamic changes necessary to support a growing pregnancy. Vascular manifestations including scleroderma renal crisis and pulmonary arterial hypertension should be considered relative contraindications against pregnancy due to the high associations of both maternal and fetal morbidity and mortality. In contrast, Raynaud's phenomenon may actually improve somewhat during pregnancy. Women with SSc who are considering a pregnancy or discover they are pregnant require evaluation for the presence and extent of underlying vasculopathy. In the absence of significant visceral vasculopathy, most women with SSc can expect to have reasonable pregnancy outcomes.

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Analysing CYP2D6*4 Allele frequency in Patients with Schizophrenia

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.314 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S101-S102

Author(s):

V. Djordjevic ◽

T. Jevtovic Stoimenov

Keyword(s):

Allele Frequency ◽

Plasma Concentrations ◽

Clinical Severity ◽

Genotype Distribution ◽

Healthy Individuals ◽

Wild Type ◽

Specific Pcr ◽

Significant Difference ◽

Schizophrenic Patients ◽

The Right

IntroductionSchizophrenia is treated with antipsychotics and other psychotropic medications, many of which are substrates for the highly polymorphic CYP2D6 enzyme. The most frequent variant allele is CYP2D6*4- leading cause of poor metabolism (PM) phenotype. PM causes the reduction of therapeutic response, increase the risk of adverse drug reactions and increase the plasma concentration of both drug and its metabolites above the levels of toxicity.The AimAnalysing CYP2D6*4 allele frequency among schizophrenic patients for further individualisation and rationalisation of therapy.Patients and methodsResearch was conducted on 38 schizophrenic patients and 110 healthy individuals. CYP2D6*4 allele was detected with allele specific PCR.ResultsBoth wild type allele carriers are 55% of the schizophrenic patients, 45% are wild type/*4heterozygous, and *4/*4 homozygous are not identified. There is a statistically significant difference in the genotype distribution (P < 0.05) between schizophrenic patients and healthy individuals. Significantly higher *4 allele frequency (37%) comparing to healthy individuals (P < 0.0001) indicates the necessary caution in administration of CYP2D6 substrates. A lower frequency of PMs in schizophrenic patients than in healthy individuals could be explained with CYP2D6 neuroactive substrate metabolism. Forty-five percent of the schizophrenic patients are intermediate metabolisers carrying the higher risk of adverse response to CYP2D6 substrates comparing to wild type homozygous. As none of the analyzed patients was PM, exceeded plasma concentrations of medications above toxic levels are not expected when administrating the right dosage.ConclusionAltered CYP2D6 metabolism may contribute to the vulnerability, clinical severity and treatment outcome of schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Evaluation of PECAM-1 Gene Polymorphism in Patients with Periodontal Disease and Healthy Individuals

ISRN Dentistry ◽

10.5402/2012/751920 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5

Author(s):

Mahdi Kdkhodazadeh ◽

Mehrdad Hajilooi ◽

Behzad Houshmand ◽

Sara Khazaei ◽

Leila Gholami ◽

...

Keyword(s):

Chronic Periodontitis ◽

Aggressive Periodontitis ◽

Genotype Distribution ◽

Nucleotide Polymorphisms ◽

Healthy Individuals ◽

Single Nucleotide ◽

Genotypic Distribution ◽

Genotype Frequencies ◽

Significant Difference ◽

Polymerase Chain

Objective. Our aim in this paper was to investigate the possible genetic association between three Ser563Asn, Leu125Val and Arg670Gly polymorphisms of the PECAM-1 gene and periodontitis. Methods. Genomic DNA was isolated from whole blood of 105 periodontal patient (52 with chronic periodontitis and 53 with aggressive periodontitis) and 101 healthy individuals. Samples were genotyped and analyzed for the three single-nucleotide polymorphisms (SNPs) of PECAM-1 using polymerase chain reaction with sequence-specific primers (PCR-SSPs). Results. A statistically significant difference was found between the genotypic distribution of the Ser563Asn polymorphism in patients with periodontitis compared to controls (P=0.02). But there were no statistically significant difference between the allele frequencies in the different groups (P=0.05). The other two polymorphisms did not show a statistically significant difference in their allele and genotype frequencies between the groups. There was no statistically significant difference found for any of the polymorphisms allele and genotype distribution in aggressive and chronic periodontitis either. Conclusions. No significant association was found between the polymorphism tested and the subgroups of periodontitis, further research is still necessary to determine whether this polymorphism can be used as a genetic marker of periodontitis.

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Circulating Tissue Inhibitor of Matrix Metalloproteinase-4 (TIMP-4) in Systemic Sclerosis Patients with Elevated Pulmonary Arterial Pressure

Mediators of Inflammation ◽

10.1155/2008/164134 ◽

2008 ◽

Vol 2008 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Gialafos J. Elias ◽

Moyssakis Ioannis ◽

Psaltopoulou Theodora ◽

Papadopoulos P. Dimitrios ◽

Perea Despoina ◽

...

Keyword(s):

Systemic Sclerosis ◽

Lung Fibrosis ◽

Pulmonary Function Tests ◽

Systolic Pressure ◽

Serum Levels ◽

Cross Sectional Study ◽

Pulmonary Artery Systolic Pressure ◽

Cross Sectional ◽

Skin Sclerosis ◽

Pulmonary Arterial

Decreased levels of matrix metalloproteinases (MMPs) or excess levels of their tissue inhibitors (TIMPs) may contribute to dysregulation of extracellular matrix turnover in systemic sclerosis (SSc). In a cross-sectional study of 106 SSc patients, we measured serum levels of TIMP-4 which is preferentially expressed in cardiovascular structures and searched for correlations with simultaneously performed echocardiography measurements of pulmonary artery systolic pressure (PASP), myocardial performance, and pulmonary function tests. TIMP-4, but not MMP-9, levels were significantly raised in patients with SSc than controls. However, in the subgroup of patients with PASP measurements lower to 40 mmHg (n=69), TIMP-4 levels were comparable to controls irrespective of the presence of diffuse or limited skin involvement, or lung fibrosis. Individual PASP measurements suggestive of pulmonary hypertension were associated with increased TIMP-4 serum levels (P=.03), independently of age, extent of skin sclerosis, or lung fibrosis, suggesting a cardiopulmonary vasculature-specific role of TIMP-4 activation in SSc.

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Bile acids serum levels in patients with nonalcoholic fatty liver disease

Kazan medical journal ◽

10.17750/kmj2015-354 ◽

2015 ◽

Vol 96 (3) ◽

pp. 354-358 ◽

Cited By ~ 1

Author(s):

Z Sh Minnullina ◽

S V Kiyashko ◽

O V Ryzhkova ◽

R G Sayfutdinov

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Bile Acids ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Serum Levels ◽

Healthy Individuals ◽

Alcoholic Fatty Liver ◽

Significant Difference ◽

Alcoholic Fatty Liver Disease

Aim. To estimate the blood levels of primary, secondary, tertiary and unconjugated bile acids in patients with non-alcoholic fatty liver disease.Methods. The study included 74 patients with non-alcoholic fatty liver disease (males - 30, females - 44) and 51 healthy individuals (males - 14, females - 37). All patients underwent anthropometry and complete clinical, biochemical and instrumental examination (measuring the subcutaneous fat layer). 64 patients had hepatic steatosis, 10 - steatohepatitis. Serum levels of bile acids (primary: cholic, chenodeoxycholic; secondary: lithocholic, deoxycholic and tertiary: ursodeoxycholic) were measured by gas-liquid chromatography on «Chromos GC-1000» (Russia) scanner.Results. Unconjugated primary, secondary and tertiary bile acids were detected in the blood of healthy individuals and patients with non-alcoholic fatty liver disease. In healthy individuals, there were no gender differences found in the bile acids levels. Patients with non-alcoholic fatty liver disease had higher level of bile acids compared to healthy controls. There was a significant difference in the concentrations of secondary and tertiary bile acids in patients with hepatic steatosis and steatohepatitis.Conclusion. Blood bile acids levels were significantly higher in patients with non-alcoholic fatty liver disease than in healthy individuals. At steatohepatitis, females had higher levels of cholic, chenodeoxycholic and deoxycholic acids and lower levels of lithocholic and ursodeoxycholic acids compared to males. Significant difference in patients with hepatic steatosis and steatohepatitis was revealed only in levels of secondary and tertiary bile acids.

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