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Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM
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Autores
Maiti, Amit K.
Kim-Howard, Xana
Motghare, Prasenjeet
Pradhan, Vandana
Chua, Kek Heng
Sun, Celi
Arango-Guerrero, María Teresa
Ghosh, Kanjaksha
Niewold, Timothy B.
Harley, John B.
Fecha
2014
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Oxford University Press
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Abstract
Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' and lt; 'AG' and lt; 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.
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Keywords
Alpha integrin , human , messenger , human , human , genetic , genetic , cd11b , nuclear , systemic , Cd11b antigen , Early b cell factor 1 , Fibrinogen , Integrin alpha m , Ku antigen , Ku70/80 , Nfkb1 protein , Nucleic acid , Protein , Rna , Transcription factor , Unclassified drug , Vitronectin , Cd11b antigen , Cell nucleus antigen , Chromatin , Dna binding protein , Ebf1 protein , Fibrinogen , Immunoglobulin enhancer binding protein , Itgam protein , Ku antigen , Messenger rna , Nfkb1 protein , Protein binding , Transactivator protein , Vitronectin , Allele , Ancestry group , Article , Chromatin , Gene function , Gene locus , Genetic analysis , Genetic association , Genetic predisposition , Genetic risk , Genetic variability , Genotype , Heterozygote , Human , In vitro study , In vivo study , Ligand binding , Meta analysis , Missense mutation , Monocyte , Priority journal , Protein binding , Protein expression , Rna degradation , Single nucleotide polymorphism , Systemic lupus erythematosus , Ethnology , Female , Gene expression regulation , Gene frequency , Genetic polymorphism , Genetic transcription , Genetics , Male , Metabolism , Pathology , Risk , Systemic lupus erythematosus , Alleles , Antigens , Antigens , Chromatin , Continental population groups , Dna-binding proteins , Female , Fibrinogen , Gene expression regulation , Gene frequency , Genetic predisposition to disease , Humans , Lupus erythematosus , Male , Monocytes , Nf-kappa b p50 subunit , Odds ratio , Polymorphism , Protein binding , Risk , Rna , Trans-activators , Transcription , Vitronectin
