casein-kinase-ii and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.. We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.. We identified three novel loci that surpassed genome-wide significance, including. This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

Topics: Antigens, Differentiation, T-Lymphocyte; Case-Control Studies; Casein Kinase II; Cell Cycle Proteins; Databases, Factual; DNA-Binding Proteins; Drug Repositioning; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Molecular Targeted Therapy; Oncogene Proteins; Reproducibility of Results; Treatment Outcome

Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci.. In stage 1, we conducted a new GWAS of SLE in a North American case-control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3.. As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10(-8)). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10(-7)) and at 8p23/BLK (P = 8.1 × 10(-6)). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10(-8)), which was replicated in stage 3.. Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.

Topics: Adult; Case-Control Studies; Casein Kinase II; Cell Cycle Proteins; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 8; Computer Simulation; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; HLA-DQ alpha-Chains; HLA-DQ beta-Chains; Humans; Lupus Erythematosus, Systemic; Major Histocompatibility Complex; Male; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; src-Family Kinases; STAT4 Transcription Factor; Tenascin; Transcriptome; White People

The three casein kinase II (CK-II) phosphate acceptors (p35, p17 and p15) in the Superdex CK-II fraction prepared from a 1.5 M NaCl extract of porcine liver were selectively purified by glycyrrhizin (GL)-affinity column chromatography (HPLC) as a heterocomplex associated with CK-II. Determination of the N-terminal amino acid sequences and immunological tests confirmed that these three CK-II phosphate acceptors belong to the family of 60S acidic ribosomal proteins (P0, P1 and P2). Three polyphenol-containing anti-oxidant compounds [catechin, epigallocatechin gallate (EGCG) and quercetin] inhibited CK-II activity (phosphorylation of these ribosomal P proteins) in a dose-dependent manner in vitro. Quercetin (ID50 = approx. 50 nM) was found to be an effective CK-II inhibitor. In contrast, CK-II activity was significantly stimulated by lower doses (0.3-3 microl) of GL, but was inhibited at high doses above 30 microM. As expected, GL at high doses above 200 microM inhibited the immunocomplex formation of 60S acidic ribosomal P proteins with their specific antibodies in the sera from patients with systemic lupus erythematosus (SLE). These results suggest that (i) a GL-affinity column is useful for effective purification of 60S acidic ribosomal P proteins from various mammalian cells as a heterocomplex associated with CK-II; and (ii) a relative high dose of GL may prevent the immunocomplex formation of 60S acidic ribosomal P proteins with their specific antibodies in the sera of SLE patients.

Topics: Amino Acid Sequence; Animals; Antibody Specificity; Antigen-Antibody Complex; Antioxidants; Autoantibodies; Casein Kinase II; Chromatography, Affinity; Glycyrrhizic Acid; Humans; Liver; Lupus Erythematosus, Systemic; Molecular Sequence Data; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Ribosomal Proteins; Swine