Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM
| Autor: | Vandana Pradhan, Kek Heng Chua, María Teresa Arango-Guerrero, Prasenjeet Motghare, Xana Kim-Howard, Timothy B. Niewold, Loren L. Looger, Amit K. Maiti, John B. Harley, Swapan K. Nath, Kanjaksha Ghosh, Juan Manual Anaya, Celi Sun |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Transcription Genetic Messenger rna Monocyte Monocytes Ancestry group Transcription (biology) Pathology Odds Ratio Gene expression regulation Genetic transcription Rna degradation Antigens Nuclear General Medicine Itgam protein Chromatin Human Ethnology Genotype Single-nucleotide polymorphism Article Genetics Protein binding Humans RNA Messenger Polymorphism Molecular Biology Alleles Lupus erythematosus Polymorphism Genetic Genetic predisposition Nfkb1 protein Racial Groups RNA systemic Gene frequency messenger Immunoglobulin enhancer binding protein Alpha integrin Protein expression Transcription factor genetic Unclassified drug Trans-activators Continental population groups Gene locus Nf-kappa b p50 subunit In vivo study Gene Frequency cd11b Lupus Erythematosus Systemic Missense mutation Integrin alpha m Ligand binding Genetics (clinical) Priority journal Allele Ku70 CD11b Antigen Ebf1 protein biology Cd11b antigen Genetic analysis Association Studies Articles Odds ratio DNA-Binding Proteins Ku70/80 Integrin alpha M Female Transcription Protein Binding Risk Heterozygote Early b cell factor 1 Genetic predisposition to disease Transactivator protein Ku antigen Systemic lupus erythematosus Genetic Predisposition to Disease Cell nucleus antigen Vitronectin Antigens Ku Autoantigen Allele frequency Genetic risk Messenger RNA Genetic polymorphism Protein Dna binding protein In vitro study Fibrinogen NF-kappa B p50 Subunit Molecular biology Dna-binding proteins Single nucleotide polymorphism nuclear Metabolism Gene Expression Regulation Nucleic acid Genetic association Trans-Activators biology.protein Rna Genetic variability Gene function Meta analysis |
| Zdroj: | Repositorio EdocUR-U. Rosario Universidad del Rosario instacron:Universidad del Rosario |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddu106 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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