Glutathione S-transferase genotypes and numerical chromosomal aberrations in myeloid neoplasms

The aim of the present study was to detect the frequency of monosomy 7 and trisomy 8 in myeloid disorders (acute myeloblastic leukemia (AML), myelodysplastic syndrome (MDS)), their association with GSTT1 and GSTM1 null genotypes, and their prognostic impact. The study included 50 patients with AML and MDS; monosomy 7 and trisomy 8 detection was done by interphase fluorescence in situ hybridization, and glutathione S-transferase (GST) genotyping was done by multiplex PCR. Monosomy 7 was present in 13–30 % of AML and MDS, respectively. A statistically significant relation was found between monosomy 7 and remission failure. Trisomy 8 was found in 10–15 % of AML and MDS. No significant association was found between response to treatment and trisomy 8. There was significant correlation between GSTT1 null/GSTM1 null genotype and poor response to treatment (p < 0.005). There was positive correlation between complete remission and both wild GST genotypes. In the whole patient group, a statistically significant association was found between GSTT null genotypes and monosomy 7 (p = 0.003). No significant association was found between trisomy 8 and specific GST genotypic polymorphism.     

The association of HLA-B8 with visceral disease in systemic sclerosis.

Seventy-one patients with systemic sclerosis (SS) were typed for twenty-seven HLA alleles of the A and B loci, and the findings were related to both the extent of visceral disease and tests of cellular immune competence in a subgroup of fifty-two of these patients. Nineteen pa;ients with widespread visceral involvement and more rapidly progressive disease had an increased frequency of HLA-B8 (relative risk = 4.14; P less than 0.05) when compared to thirty-three less severely affected patients and 3000 controls. Patients with severe and progressive disease also had defective cell-mediated immunity with reductions in both the numbers of circulating thymus-dependent (T) lymphocytes and in the lymphocyte transformation response to phytohaemagglutinin. These findings suggest that a genetic factor, such as an abnormal immune response gene, may be involved in the progression of the disease.     

Risk factors for severity and manifestations in systemic sclerosis and prediction of disease course

Systemic sclerosis (SSc, or scleroderma) is a rheumatic disease with distinct features that encompass autoimmunity, vascular lesions (vasculopathy) and tissue fibrosis. The disease has a high morbidity and mortality compared with other rheumatic diseases. This review discusses risk factors and markers that predict the disease course and the occurrence of disease manifestations, with an emphasis on major organ involvement. In addition, risk factors will be described that are associated with mortality in SSc patients. The review addresses the impact of recent developments on screening, diagnosis and risk stratification as well as the need for further research where data are lacking.     

Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: associations with organ manifestations, immunolaboratory markers and disease activity indices

BACKGROUND: Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. OBJECTIVES: We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. METHODS: TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. RESULTS: There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. CONCLUSION: The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.     

Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: Associations with organ manifestations,immunolaboratory markers and disease activity indices

BackgroundSome tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis.ObjectivesWe assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement.MethodsTAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively.ResultsThere were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6 ± 1.7 vs 1.8 ± 1.4 mg/l) and CA15-3 (22.9 ± 1.8 vs 18.6 ± 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls.ConclusionThe concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.     

Prevalence of ocular manifestations in systemic sclerosis patients

Introduction

Systemic sclerosis (scleroderma, SSc) is a severe chronic connective tissue disease caused by immune system disorders and changes in the structure and functions of blood vessels, which consequently leads to enhanced tissue fibrosis. The aim of the study was to evaluate changes in the organ of vision in systemic sclerosis patients.

Material and methods

Overall the study involved 27 patients with systemic sclerosis. The control group comprised 27 age- and gender-matched healthy individuals. All the study subjects underwent complete ophthalmological examination that in systemic sclerosis patients additionally involved fluorescein angiography.

Results

Ophthalmological examination revealed higher incidence of the following abnormalities in the study group, compared to the control: symptoms of dry eye syndrome (19 eyes, p < 0.02), astigmatism(in 30 eyes, p < 0.01), posterior subcapsular cataract (10 eyes, p < 0.05), increased intraocular pressure (> 21 mm Hg were observed in 11 eyes, p < 0.002) and vascular abnormalities within fundus in fluorescein angiography (20 eyes).

Conclusions

In patients with systemic sclerosis numerous abnormalities within the vision of organ may be found. Regular ophthalmological examinations are essential among the mentioned group. The examination should be particularly focused on the presence of retinal vascular abnormalities.     

Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease

Two authors were     

Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.     

Prevalence and clinical association of the presence of anti-neutrophilic cytoplasmic antibody in systemic sclerosis

IntroductionAnti-neutrophilic cytoplasmic antibody (ANCA) has been reported in systemic sclerosis (SSc). Some clinical features of SSc can also be presented with ANCA-associated vasculitis. Objectives were to determine the prevalence and clinical associations with ANCA among Thais with SSc.Material and methodsA cross-sectional study of Thai adult SSc patients was conducted. According to the sample size calculation, 185 patients were included. Clinical and laboratory tests for serology and others for evaluation of the clinical association with ANCA were done simultaneously on the study date.ResultsThe female to male ratio was 2 : 1. The majority had the diffuse SSc subset (71.2%). The respective prevalence of having a) at least 1 serological test for ANCA (viz., perinuclear ANCA, cytoplasmic ANCA, anti-myeloperoxidase, or anti-proteinase3), b) positive for either p-ANCA or c-ANCA, c) positive for either anti-MPO or anti-PR3, d) p-ANCA and anti-MPO and e) c-ANCA and anti-PR3 was 21.6% (95% CI: 15.9–28.3), 11.9% (95% CI: 7.6–17.4) and 13.0% (95% CI: 8.5–18.7) and 1% (95% CI: 0.1–3.9). By multivariate analysis, the erythrocyte sedimentation rate elevation was significantly associated with the presence of the antibody (OR = 11.36, 95% CI: 1.44–83.65), while elevation of high sensitivity cardiac troponin-T (hs-cTnT) was significantly associated with the presence of either p-ANCA or c-ANCA (OR = 4.25, 95% CI: 1.41–15.34). None of the patients had clinical features of systemic vasculitis.ConclusionsAround one-fifth of SSc patients have detectible ANCA without any features of vasculitis. The presence of ANCA is associated with inflammation and myocardial injury. ANCA is not antibody specific for vasculitis in SSc.     

The association of systemic sclerosis with malignant neoplasms]

The rate of concomitance of systemic sclerosis and malignant neoplasm is not still ascertained. Therefore we reviewed 8,327 patients who were diagnosed with systemic sclerosis and received public financial aid from the Ministry of Health, Labour and Welfare of Japan in 1999. The concomitance rate was 3.1% of all patients, however, it was more frequent among men than among women (5.4% for men and 2.8% for women, respectively, P<0.01), and the mean age of patients with complicated malignant neoplasms was significantly higher than that of patients without malignancy (P<0.01). For comparison with the Japanese general population, O/E ratios (ratio of observed-to-expected malignant neoplasms) were calculated, and it was found that both men and women had significantly higher O/E ratios (O/E ratio 2.31, 95% confidence interval [CI] 1.68-2.94, P<0.001 for men and O/E ratio 1.64, 95% CI 1.41-1.86, P<0.001 for women). In addition we also assessed laboratory findings including autoantibodies and respiratory function tests for patients with malignant neoplasms by logistic regression analysis adjusted for sex and age. Decreased DLco (pulmonary CO diffusing capacity) appeared to be a risk factor for the concomitant malignant neoplasms among patients with systemic sclerosis (odds ratio 2.00 for DLco < or = 70%, CI 1.06-3.74, P=0.032). These results may help to elucidate the etiology of systemic sclerosis.     

The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome

Thrombocytopenia is frequently found in patients with the antiphospholipid syndrome (APS), yet data concerning clinical associations of thrombocytopenia in patients with APS are still scarce. We evaluated possible associations between thrombocytopenia and various APS-related manifestations in a large group of APS patients. Three hundred and seven APS patients were retrospectively evaluated, 259 women and 48 men. Most patients had primary APS (PAPS) (n=173, 56.1%). APS was associated with systemic lupus erythematosus (SLE) in 104 patients (33.9%). All patients underwent detailed medical interview and routine physical examination. Further data were obtained from patients' medical files regarding the expression of various clinical manifestations of the disease. There were 90 patients with thrombocytopenia (29.3%), the rate was significantly higher in SLE compared to PAPS patients (41.9% vs. 23.1%, p=0.001). Similar rates of thrombocytopenia were found in male (29.2%) and female (29.3%) patients. Significant associations were found between thrombocytopenia and cardiac valves thickening and dysfunction, epilepsy, chorea, arthritis, livedo reticularis and skin ulcerations. In contrast, the rates of thrombotic episodes as well as obstetric complications were similar in patients with and without thrombocytopenia. Our data suggest the presence of thrombocytopenia may be a risk factor for cardiac, neurological, articular and cutaneous complications in APS.     

Metabolic mediators determine the association of antinuclear antibody subtypes with specific clinical symptoms in systemic sclerosis

PurposeThe aim of this study was to investigate the possible link between different types of systemic sclerosis-specific antinuclear antibodies, adipokines and endothelial molecules which were recently found to have a pathogenic significance in systemic sclerosis.Materials/methodsSerum concentration of adiponectin, resistin, leptin, endothelin-1, fractalkine and galectin-3 were determined in the sera of patients with systemic sclerosis (n ​= ​100) and healthy controls (n ​= ​20) using ELISA.ResultsThe following associations between antinuclear antibodies and increased serum concentrations were identified: anticentromere antibodies with endothelin-1 (p ​< ​0.0001; mean level in patients 2.21 vs control group 1.31 ​pg/ml), anti-topoisomerase I antibodies with fractalkine (p ​< ​0.0001; 3.68 vs 1.68 ​ng/ml) and galectin-3 (p ​= ​0.0010, 6.39 vs 3.26 ​ng/ml). Anti-RNA polymerase III antibodies were associated with increased resistin (p ​< ​0.0001; 15.13 vs 8.54 ​ng/ml) and decreased adiponectin (p ​< ​0.0001; 2894 vs 8847 ​ng/ml).ConclusionIn systemic sclerosis metabolic and vascular factors may serve as mediators between immunological abnormalities and non-immune driven clinical symptoms.     

Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

Systemic sclerosis (SSc; scleroderma) is a connective tissue disease, characterized by fibrotic, immunological, and vascular abnormalities. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates collagen production and B-cell survival. To determine if certain IL-10 genotypes are risk factors for the development of SSc and influence disease-associated autoimmune responses, 248 Caucasian and 264 Japanese SSc patients and controls were genotyped for three loci: -3575, -2849, and -2763. Sera from patients were characterized for SSc-associated autoantibodies. In Caucasians, at -3575 and -2763, the frequency of AA homozygotes was higher in patients as compared with controls (P=0.0005; P=0.002). In Japanese subjects, the frequency of AC heterozygotes at -2763 was higher, and that of CC homozygotes lower, in patients with diffuse SSc as compared to controls (P=0.04). Particular IL-10 genotypes were associated with SSc-related autoantibodies. These results suggest that IL-10 genotypes contribute to the etiology of scleroderma.     

The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis

Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.