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- Padyukov, Leonid, et al.
(författare)
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A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 70:2, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies (GWAS) have only been published from ACPA-positive subsets of RA or from studies that have not separated the two subsets. The aim of the current study is to provide and compare GWAS data for both subsets. Methods and results GWAS using the Illumina 300K chip was performed for 774 ACPA-negative patients with RA, 1147 ACPA-positive patients with RA and 1079 controls from the Swedish population-based case-control study EIRA. Imputation was performed which allowed comparisons using 1 723 056 single nucleotide polymorphisms (SNPs). No SNP achieved genome-wide significance (2.9 x 10(-8)) in the comparison between ACPA-negative RA and controls. A case-case association study was then performed between ACPA-negative and ACPA-positive RA groups. The major difference in this analysis was in the HLA region where 768 HLA SNPs passed the threshold for genome-wide significance whereas additional contrasting SNPs did not reach genome-wide significance. However, one SNP close to the RPS12P4 locus in chromosome 2 reached a p value of 2 x 10(6) and this locus can thus be considered as a tentative candidate locus for ACPA-negative RA. Conclusions ACPA-positive and ACPA-negative RA display significant risk allele frequency differences which are mainly confined to the HLA region. The data provide further support for distinct genetic aetiologies of RA subsets and emphasise the need to consider them separately in genetic as well as functional studies of this disease.
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| 2. |
- Seddighzadeh, Maria
(författare)
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The prognostic significance of uPA, uPAR an d the cytokine IL-1-alpha in urinary bladder cancer
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumor invasion and metastasis are the major causes of cancer-related death. Proteases are important for the invasive and metastatic propensities of tumors. We have studied the mechanism underlying endogenous expression of the serine protease urokinase plasminogen activator (uPA) by human breast cancer cells. The expression of uPA mRNA was found to be affected by manipulation of the activity of the MEK-ERK signaling pathway. A minor portion of total ERK was phosphorylated (and hence active) in the NMA-MB-231 breast cancer cell line. Decreased ERK activity was associated with decreased uPA expression, whereas stimulation of ERK activity did not lead to an increase in uPA expression. In contrast, increased ERK activity was found to lead to increased expression of the cyclin kinase inhibitor p21Cip1. These data suggest that ERK activity in these cells is tuned to a level that allows rapid cell proliferation and high levels of uPA expression Urinary bladder carcinoma is heterogeneous in nature and can follow distinct clinical courses. More than fifty percent of all patients with muscle invasive bladder tumors that develop metastasis die from their disease. It is important to identify factors that can predict the prognosis of patients with muscle invasive tumors, both to be able to offer a more individualized treatment strategy and also to be able to develop therapeutic methods that can target these factors. In a prospective study we found that the expression of uPA and its receptor (uPAR) predict the outcome of patients with bladder cancer and that elevated levels of uPAR were associated with an increased risk for development of metastasis. Moreover, we observed that high uPA expression was associated with an increased risk of death from cancer in the group of patients with muscle invasive tumors. The risk associated with elevated uPA was lower in cystectomized patients, suggesting that treatment improved the prognosis. Elevated uPAR expression did not show this pattern. Interleukin-1-alpha (IL-1-alpha) is a multifunctional cytokine with many potential roles in cancer. One such role is that of inducing expression of uPA in the tumor stroma. IL-1-alpha has been shown to be expressed by bladder cancer cell lines and has also been shown to inhibit cell proliferation and angiogenesis in vitro. We observed that bladder tumor cells produce IL-1-alpha but did not observe any correlation to uPA expression. Interestingly, low IL-1-alpha expression was associated with a relative risk of 1.76 for death in cancer in the group of patients with muscle invasive tumors. The results indicate that uPA, uPAR and IL-1-alpha can be used as markers for refined staging of tumors. Inhibition of the uPA system and/or treatment of patients with IL-1-alpha may be considered as future therapy of urinary bladder cancer.
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| 5. |
- Vuong, Mai T, et al.
(författare)
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Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy
- 2010
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Ingår i: KIDNEY INTERNATIONAL. - : Nature Publishing Group. - 0085-2538 .- 1523-1755. ; 78:12, s. 1281-1287
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Tidskriftsartikel (refereegranskat)abstract
- The Fc-alpha receptor (Fc alpha R/CD89) is involved in IgA complex formation and may affect the development of IgA nephropathy (IgAN). In this study, we tested the genetic variations of the CD89 gene in relation to disease susceptibility in IgAN and the expression of soluble CD89 (sCD89) in sera of patients with IgAN and in controls. There was a significant difference between the levels of sCD89-IgA complexes, measured by sandwich enzyme-linked immunosorbent assay (ELISA), in 177 patients with IgAN with and without disease progression at the time of first diagnosis. No such difference was found in 42 patients with other renal diseases. The patients with IgAN without disease progression had stable but high levels of sCD89 over 5-15 years of follow-up in contrast to stable but low levels of sCD89 in the disease progression group. Moreover, levels of sCD89 complexes were correlated with one of the five CD89 genetic variants in 212 patients with IgAN and 477 healthy Caucasians; the single-nucleotide polymorphism (SNP) rs11084377 was significantly associated with a lower expression of sCD89. However, no association between CD89 gene polymorphisms and susceptibility to IgAN was detected. Thus, we found an association between the levels of sCD89-IgA complexes in serum and the severity of IgAN, and a possible genetic component in regulating the production or expression of sCD89.
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| 6. |
- Vuong, Mai Tuyet, et al.
(författare)
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Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy
- 2009
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 24:10, s. 3061-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis. METHODS: We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden. RESULTS: Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P
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| 7. |
- Wang, Chuan, et al.
(författare)
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Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies
- 2011
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Ingår i: Journal of Rheumatology. - Toronto : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 38:10, s. 2130-2132
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Tidskriftsartikel (refereegranskat)abstract
- Objective.Two interferon regulatory factor 5 (IRF5) gene variants were examined for association with rheumatoid arthritis (RA).Methods.A total of 2300 patients with RA and 1836 controls were recruited from 2 independent RA studies in Sweden. One insertion-deletion polymorphism (CGGGG indel) and one single-nucleotide polymorphism (rs10488631) in the IRF5 gene were genotyped and analyzed within RA subgroups stratified by rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).Results.The CGGGG indel was preferentially associated with the RF-negative (OR 1.29, p = 7.9 × 10−5) and ACPA-negative (OR 1.27, p = 7.3 × 10−5) RA subgroups compared to the seropositive counterparts. rs10488631 was exclusively associated within the seronegative RA subgroups (RF-negative: OR 1.24, p = 0.016; ACPA-negative: OR 1.27, p = 4.1 × 10−3).Conclusion.Both the CGGGG indel and rs10488631 are relevant for RA susceptibility, especially for seronegative RA.
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