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Träfflista för sökning "WFRF:(Sawalha Amr H) "

Sökning: WFRF:(Sawalha Amr H)

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1.
  • Sawalha, Amr H., et al. (författare)
  • Common variants within MECP2 confer risk of systemic lupus erythematosus
  • 2008
  • Ingår i: PLoS ONE. - 1932-6203. ; 3:3, s. e1727-
  • Tidskriftsartikel (refereegranskat)abstract
    • Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE.
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3.
  • Webb, Ryan, et al. (författare)
  • A polymorphism within IL21R confers risk for systemic lupus erythematosus
  • 2009
  • Ingår i: Arthritis and Rheumatism. - 0004-3591 .- 1529-0131. ; 60:8, s. 2402-2407
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Interleukin-21 (IL-21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL-21 receptor (IL-21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL-21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE. METHODS: We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a European-derived cohort and a Hispanic cohort) and in ethnically matched healthy controls. RESULTS: We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta-analysis odds ratio 1.16 [95% confidence interval 1.08-1.25], P=1.0x10(-4)). CONCLUSION: Our findings indicate that IL21R is a novel susceptibility gene for SLE.
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4.
  • Webb, Ryan, et al. (författare)
  • Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients
  • 2011
  • Ingår i: Annals of the Rheumatic Diseases. - 0003-4967 .- 1468-2060. ; 70:1, s. 151-156
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities. Objectives To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE. Methods The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset. Results Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values < 0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset >= 50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specifi c manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients. Conclusions The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
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5.
  • Webb, Ryan, et al. (författare)
  • Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus
  • 2009
  • Ingår i: Arthritis and Rheumatism. - 0004-3591 .- 1529-0131. ; 60:4, s. 1076-1084
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. METHODS: We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. RESULTS: We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. CONCLUSION: Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.
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