Genetic Variation in the CRP Promoter: Association with Systemic Lupus Erythematosus (SLE)

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
Human Molecular Genetics (Impact Factor: 6.39). 05/2008; 17(8):1147-55. DOI: 10.1093/hmg/ddn004
Source: PubMed


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.

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Available from: Rosalind Ramsey-Goldman, Oct 05, 2015
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    • "1 196.79 CRP [35] "
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    ABSTRACT: The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.
    01/2014; 2014(6710):203435. DOI:10.1155/2014/203435
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    • "Examples of genetic manipulations in mice that involve alterations in the clearance or response to apoptotic debris include C1q, Mer receptor tyrosine kinase, and serum amyloid P. In humans, homozygous C1q deficiency is the most highly penetrant complement deficiency leading to SLE. In another parallel with the mouse, genetic variants in human C-reactive protein - a protein that functions in the clearance of apoptotic debris in an analogous way to serum amyloid P - are also associated with an increased risk of lupus [13]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset and progression of clinical manifestations are also complex and multi-step, including breach of tolerance in the adaptive immune system, amplification of autoimmunity through innate and adaptive immune system dysregulation, and end-organ damage. Studies of murine genetic manipulations and human risk variants have provided important clues to the cellular and molecular pathogenesis of SLE, operating at multiple of these steps. The breakdown of B-cell tolerance is probably a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Examples of amplification of autoimmunity on the adaptive immune system side include disturbances in B-cell/T-cell collaboration. B cells can also amplify innate immune cell activation via antibody-dependent and antibody-independent mechanisms. Indeed, one of the key amplification loops in SLE is the activation of plasmacytoid dendritic cells via autoantibodies and RNA-containing and DNA-containing immune complexes, which act as Toll-like receptor ligands, stimulating the secretion of large quantities of IFNα. A more recent link between the innate and adaptive immune system in SLE includes the neutrophil, which can be primed by interferon and autoantibodies to release neutrophil extracellular traps as an additional source of immunogenic DNA, histones, and neutrophil proteins. The innate immune system activation then feeds back, driving autoreactive B-cell and T-cell survival and maturation. This self-perpetuating disease cycle creates the opportunity for targeted treatment inventions at multiple steps.
    Arthritis Research & Therapy 11/2012; 14(4). DOI:10.1186/ar3917 · 3.75 Impact Factor
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    • "Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease and is considered to be caused by complex interactions between genetic risk, environmental, and hormonal factors that result in an immune dysregulation, and autoantibody production ensued [1–3]. Epidemiological studies reported that SLE is more common in Asians (46.7/100 000) than in Caucasians (20.7/100 000), and ethnicity also influences the age of onset and severity of its manifestations [4, 5]. "
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    ABSTRACT: Several variants of CTLA-4 have been reported to be associated with susceptibility systemic lupus erythematosus (SLE); however, findings have been inconsistent across different populations. Using a case-control study design, we have investigated the role of CTLA-4 polymorphism at positions -1661 and -1722 on SLE susceptibility in our Chinese SLE population in central China's Hubei province. Samples were collected from 148 SLE patients and 170 healthy controls. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotypes of the two sites. Statistically significant difference was observed in genotypes for -1722, but not for -1661. The frequency of the T allele on the -1722 SNP was significantly increased in SLE patients: 57.8% versus 40.6% in controls (P < 0.001, OR = 2.002). While the detected C allele frequency in the controls was significantly elevated in comparison to that in the SLE patients (59.4% versus 42.2%). On the contrary, no association was found between SLE and CTLA-4 polymorphism at position -1661.
    BioMed Research International 09/2011; 2011:167395. DOI:10.1155/2011/167395 · 2.71 Impact Factor
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