Jacqueline Frost

University of the Witwatersrand, Johannesburg, Gauteng, South Africa

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Publications (5)16.58 Total impact

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    ABSTRACT: The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n=263) were compared to healthy controls (n=374). Genotyping was performed using the Immunochip and four digit high resolution HLA typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA DRB1 and HLA DQA1 loci. After conditioning on HLA DRB1 alleles the effect in the rest of the extended MHC diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ; LOC100131131|IL1R1; KIAA1919|REV3L; LOC643749|TRAF3IP2; and SNPs in the intron and UTR of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5×10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The sero-positive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
    Molecular medicine (Cambridge, Mass.). 07/2014; 20:341-349.
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    ABSTRACT: To investigate the differential expression of MMP-1, tissue inhibitor of metalloproteinase-1 (TIMP-1) and hepatocyte growth factor (HGF) in clinically involved (affected) and uninvolved (unaffected) skin in patients with SSc. Punch biopsies from affected forearm and unaffected upper back skin of 16 black South Africans with dcSSc and skin samples of 15 ethnically matched healthy controls were studied. Quantitative mRNA expression of MMP-1, TIMP-1 and HGF was performed by relative reverse transcription quantitative PCR. Compared with controls, TIMP-1 expression was significantly upregulated in patients, a 796- and 397-fold difference for affected and unaffected skin (P < 0.00001 for both), respectively. Conversely, MMP-1 expression was significantly decreased in patients, a 10- and 12.5-fold difference for affected and unaffected skin (P = 0.0004 for both), respectively. HGF expression was up-regulated in both affected and unaffected skin, a 14- and 18-fold difference (P = 0.004 and P = 0.002), respectively. Within the patient group, HGF expression in affected skin of patients correlated significantly with the European scleroderma disease activity score (r = 0.60, P = 0.013). Perturbations in gene expression of TIMP-1, MMP-1 and HGF were evident in both affected and unaffected skin of the dcSSc patients. Targeting TIMP-1, which showed the greatest dysregulation, needs to be explored as a way of reducing collagen deposition and fibrosis in dcSSc.
    Rheumatology (Oxford, England) 01/2012; 51(6):1049-52. · 4.24 Impact Factor
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    ABSTRACT: High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African-American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10(-14) for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African-American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African-American subjects and absent in African patients with SLE. The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population. These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness and are likely pathogenic in SLE.
    Annals of the rheumatic diseases 11/2011; 71(3):463-8. · 8.11 Impact Factor
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    Rheumatology (Oxford, England) 12/2009; 49(4):820-1. · 4.24 Impact Factor
  • Clinical Immunology - CLIN IMMUNOL. 01/2009; 131.