Genetic variation in the CRP promoter: association with systemic lupus erythematosus.

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
Human Molecular Genetics (Impact Factor: 6.68). 05/2008; 17(8):1147-55. DOI: 10.1093/hmg/ddn004
Source: PubMed

ABSTRACT The pentraxin C-reactive protein (CRP), an innate immune system opsonin which binds nuclear debris and apoptotic bodies, may protect against autoimmunity. A relative deficiency of CRP levels in patients with systemic lupus erythematosus (SLE) might contribute to altered handling of self-antigens. We report that the proximal 5' promoter region of CRP contains several polymorphisms that exhibit association with SLE in multiple populations. Strongest association was observed at the proximal promoter single nucleotide polymorphism (SNP) rs3093061 (CRP-707) (P = 6.41 x 10(-7) and P = 2.13 x 10(-6) in African-American and Caucasian case-control samples respectively). This association remains after adjustment for admixture. Linkage disequilibrium exists between SNPs in the proximal promoter and association of functional haplotypes containing rs3091244/rs3093062 (CRP-409/-390) appear to be driven by the rs3093061 (CRP-707) association. These data demonstrate that rs3093061 at the -707 site within the CRP gene is an SLE susceptibility locus.


Available from: Rosalind Ramsey-Goldman, Jun 03, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin-6 (IL-6)–induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. This study was undertaken to investigate disease activity, IL-6 levels, and CRP levels in relation to a CRP gene polymorphism and IFNα.Methods Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single-nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 levels were quantified by immunoassays. Clinical disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K).ResultsCRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (P = 0.005). We found a strong association between disease activity and CRP levels (P < 0.0005) when patients with measurable IFNα levels as well as the minor allele of rs1205 were excluded from the analysis. Similarly, when patients with elevated IFNα levels and/or the rs1205 polymorphism were excluded, IL-6 levels were associated with CRP levels.Conclusion The present study demonstrates that the serum IFNα level as well as the CRP genotype affect the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene.
    Arthritis & Rheumatology 06/2014; 66(6). DOI:10.1002/art.38408 · 7.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, genome-wide association studies have led to an expansion in the identification of regions containing confirmed genetic risk variants within complex human diseases, such as systemic lupus erythematosus (SLE). Many of the strongest SLE genetic associations can be divided into groups based on their potential roles in different processes implicated in lupus pathogenesis, including ubiquitination, DNA degradation, innate immunity, cellular immunity, lymphocyte development, and antigen presentation. Recent advances have also shown several genetic associations with SLE subphenotypes and subcriteria. Many areas for further exploration remain to move lupus genetic studies toward clinically informative end points.
    Rheumatic Disease Clinics of North America 08/2014; 40(3). DOI:10.1016/j.rdc.2014.04.002 · 1.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Takayasu arteritis (TA) patients with active disease often have elevated serum C-reactive protein (CRP) levels, which usually decline with the disease remission. The serum CRP concentration has been showed to be related to CRP gene polymorphisms in previous studies. The present study aims to investigate the associations of serum level of CRP and CRP polymorphisms with TA. A total of 178 unrelated Chinese Han TA patients and 229 unrelated Chinese Han individuals without documented disease were enrolled in our studies. After a systemic search in the HapMap database, four single-nucleotide polymorphisms (SNPs) were selected, namely, rs1800947, rs3093077, rs1205, and rs2808630. The ligase detection reaction (LDR) was used in genotyping. CRP concentrations were determined using turbidimetric immunoassay. Genotype frequencies and allele frequencies of CRP variations were similar between TA patients and controls. CRP haplotype frequencies in patients were not significantly different from those of controls. No significant association between serum CRP concentrations and genotypes was found. Moreover, no association was found in CRP concentration between patients with types I, II, and III TA or between patients with or without pulmonary involvement. By contrast, serum CRP concentration was directly correlated with disease severity. In conclusion, CRP polymorphisms were not associated with TA susceptibility or serum CRP levels in the Chinese Han population. However, higher CRP level was correlated with a more serious disease status, which implies that CRP possibly contributes to the progression of TA.
    Clinical Rheumatology 06/2014; DOI:10.1007/s10067-014-2674-3 · 1.77 Impact Factor