Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
Background and aims Several cytokines such as IL-10, IL-17, IL-23, and vitamin D have been suspected in the pathogenesis of SLE. However, the association between these cytokines, vitamin D and disease activity is unknown. We aimed to determine the association between IL-10, IL-17, IL-23, vitamin D and SLEDAI score. Methods We included 40 patients with SLE and 20 healthy controls in the study. Clinical and laboratory parameters and, SLEDAI score were evaluated. Serum IL-10, IL-17 and IL-23 were measured by nephelometry and vitamin D by HPLC. Mann-Whitney U and Kolmogorov-Smirnov test were used for statistical analysis. Results The level of vitamin D was significantly lower (p=0003), and IL-23 was significantly higher (p=0001) in SLE patients compared to healthy controls. There was no significant difference for IL-10 and IL-17 between both group (p>0,05). However, a significant correlation between vitamin D and disease duration (p=0,02), and between IL-23 and vitamin D (p=0019) were found among SLE patients. Vitamin D levels were correlated with SLEDAI score and IL-23 in patients group. Conclusions Although there are studies suppporting the role of IL-10 and IL-17 in the pathogenesis of SLE in the literature, there was no significant difference between patients and healthy controls in our study. IL-23 levels were significantly higher, whereas vitamin D levels were significantly lower in SLE patients than in the control group. Also vitamin D levels were negative correlated with duration of disease and IL-23. Levels of IL-23 may be used to evaluated the disease activity, or may be a promising therapeutic approach for SLE patients. Background and aims Lupus nephritis (LN) is one of the most serious clinical manifestations of systemic lupus erythematosus (SLE). Recently, we have reported that the expression levels of CD64 on monocyte (mCD64), a high-affinity receptor for IgG (FcgRI), correlate with the disease activity of SLE (Lupus 2015;24:1076-80). However, the relation between lupus nephritis (LN) and mCD64 expression is yet to be elucidated. The aim of this study is to investigate whether or not mCD64 expression level correlates with the activity of LN. Methods We quantitatively measured the mCD64 expression levels by flow cytometry in eight SLE patients with biopsy proven LN before and after treatment. All patients fulfilled the 1997 American College of Rheumatology classification criteria for SLE. The mCD64 expression levels of the individual patients were measured both at active (presence of proteinuria >0.5 g/day and/or active urinary sediment) and inactive phase (absence of proteinuria and active urinary sediment). The changes were analysed statistically (Wilcoxon signed-rank test). Results The mean±SD of mCD64 expression levels before and after treatment were 42 463±15 466 and 19 190±1696 moleecules/cell, respectively (p<0.01, Wilcoxon signed-rank test). The mCD64 expression levels in active LN was significantly higher than in inactive LN. Conclusions The mCD64 expression level correlates with the activity...
<50%, MAML2 (P=8x10 -19 ) and EBF1 (P=1x10 -12 ). Interestingly, the expression of IL23R remained unaltered. Other genes that were significantly upregulated (1.5 -2.0 fold) were IL12RB2, TTC1 and PSMD6. Genes that were also significantly repressed (0.5 -0.8 fold) were SERBP1, ATXN7, PSIP1, ZNF385D, SIPA1L1. Conclusion: This combined genetic and functional meta-analysis elucidated novel genes, functional networks and pathways for psoriasis. These results will lead to important insights into the immunopathogenesis and treatment of psoriasis.
BackgroundAltered expression of microRNAs have been implicated in the pathogenesis of SLE due to their role in both the adaptive and innate immunity. Recent studies are trying to identify aberrant microRNA level as a diagnostic signature of SLE as well as to understand a role of specific microRNAs as biomarkers for disease activity (DA) and progression. The aim of our study was to evaluate the peripheral blood (PB) expression of microRNA-146a (miR-146a) in SLE patients and to determine its correlation with the DA in the clinical practice.Materials and methods40 SLE patients were included in the study. miR-146a expression levels in whole PB samples were determined by PCR (SYBR Green technology). 2-ΔΔCt method was used for analysis. 32 healthy donors were used as controls. The DA was determined by DA index (SLEDAI) with 24 descriptors. SPSS v20 was used for ROC curve and Spearman correlation analysis.ResultsmiR-146a was overexpressed in 62.5% of the patients and none of the patients showed underexpression of miR-146a. ROC curve analysis showed that the expression levels of miR-146a (AUC-0.711, p=0.002) in PB could discriminate SLE patients from HCs with 82.5% sensitivity and 56.2% specificity. miR-146a showed statistically significant correlation with the diagnosis (rs 0.363) and age (rs 0.239) but there was no correlations with SLEDAI nor with the immunological activity according to ANA titer, a-dsDNA, a-Sm, a-b2GPI, a-CL antibodies, C3 and C4 complement levels.ConclusionsmiR-146a is a known negative regulator of the type I interferon pathway by targeting the key signalling proteins and its underexpression may contribute to the disease activity of SLE as well as to the disease development. We didn’t find a correlation between the levels of miR-146a and DA as a whole as well as with the immunological activity which might reflect the variants of SLE DA in the patients who participated in the study, the difference in their genetic background or in the used medications but larger study is needed to confirm these results in the clinical practice.AcknowledgementThe study was supported by Grant 53/2014 funded by Medical University – Sofia, Bulgaria.
Background Rheumatoid arthritis (RA) is associated with altered miRNA expression profile in peripheral blood, synovial fluid and synovial membrane. There are several reports on the role of miR-223 in the disease pathogenesis but data on its use as biomarkers in the clinical practice are lacking. Objectives To analyze the expression of miR-223 in peripheral blood (PB) and synovial fluid (SF) from RA patients in regard to its use as biomarker for disease activity and severity. Methods Total RNA including miRNAs was isolated from the PB of 57 RA patients and 20 healthy controls (HCs) using PAX gene tubes and from paired SF samples from 44 patients and 11 controls by RNeasy Protect Cell Mini kit (according to manufacturer's protocol). Reverse transcription was performed in order to synthesize cDNA by using miScript II RT kit. Expression of miR-223 was analyzed by relative quantitation method (2^-(ΔΔCq)) using quantitative real-time polymerase chain reaction (qPCR). RNU6B gene was used as reference control for normalization. Data were analyzed by SPSS. The results were related to the clinical presentation and laboratory data for disease activity. The latter was assessed using disease activity score 28 (DAS28). Results MiR-223 was underexpressed in 65.91% of RA SF samples compared to PB samples. We found statistically significant (p<0.05) overexpression of miR-223 in 81.82% of the SF samples and 35.1% of the PB samples from RA patients compared to HCs. Receiver operating characteristic (ROC) curve analysis was constructed in order to evaluate the diagnostic accuracy of miR-223 in SF by using relative expression (RQ) values. Area under the curve (AUC) was 0.841 (95 CI: 0.727-0.956) with 81.4% sensitivity and 72.7% specificity when RQ value is greater than or equal to 2. The result was statistically significant (p=0.001). Levels of miR-223 in SF correlate with laboratory markers for disease activity such as ESR (p<0.01 two tailed) and CRP (p=0.051 two tailed), with the swollen joint count (p=0.029 two tailed), VAS (0.027 two tailed) and DAS28 score (p=0.003 two tailed). The Spearman's correlation coefficients were 0.463, 0.338, 0.300, 0.303 and 0.402 respectively. No correlations between miR-223 levels in blood and clinical pathological characteristics were observed. Independent T test analysis showed that miR-223 expression in blood is associated with the RA diagnosis. Conclusions MiR-223 is a potential biomarker for diagnosis with high sensitivity and specificity and for evaluating the activity of RA as its expression is altered significantly in synovial fluid and correlates with diseases activity measured by DAS28 score. We did not observed correlation between the expression of miR-223 in blood and the disease activity but we found week correlation with the RA diagnosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5687
blood samples for genetic analysis will be stored in the DANBIOdatabase/Danish Reuma Biobank, in which, since 2000/2015 respectively, collection of information regarding e.g. demographics and disease activity-/tissue samples from patients with inflammatory-and connective tissue disease has taken place. Patients will be matched (gender/age) against participants in the Danish Blood Donor Study in a 1:10 ratio. Sample size to detect degree of synergy between environmental risk behaviour and minor allele frequency of susceptible genes was calculated. Lifestyle and environmental exposures will be collected by self-report and by pulling data from Danish registries. Genetic analysis will be conducted with Illumina sequencing instruments. Results We identified 966 patients registered in DANBIO with SLE. 20 000 control patients from the Danish Blood Donor Study have completed a self-report questionnaire and genetic sequencing on collected blood samples has been performed. To exemplify the power of this study, we found from the literature risk ratios for developing SLE of about 1.5 for both current smokers and persons with polymorphisms in the signal transducer and activator of transcription 4-gene. By computer modelling we calculated the ability to detect a degree of synergy of 45% with a power of 80%. Conclusion From this study we expect to provide new information on how certain lifestyle and environmental factors may push the development of SLE in genetically predisposed individuals. Hereby point at new candidate sites of intervention in both treatment and prophylaxis. This project will have the potential to collaborate with similar upcoming projects in Europe allowing analysis of less prevalent genetic aberrations and/or environmental exposures.
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