Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus
| Autor: | Ina Rudloff, Stefan J. White, Stuart Cantsilieris, Wendy Dankers, Melissa Northcott, Elena J. Tucker, James Harris, Qiang Cheng, Eric F Morand, Brendan E. Russ, Marcel F. Nold, Andrew E. J. Toh, Huapeng Fan, Sarah A. Jones |
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| Přispěvatelé: | Clinical Immunology and Rheumatology |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Linkage disequilibrium lcsh:Medicine Locus (genetics) Single-nucleotide polymorphism Genome-wide association study Regulatory Sequences Nucleic Acid Biology Polymorphism Single Nucleotide Genome Linkage Disequilibrium Article 03 medical and health sciences Systemic lupus erythematosus 0302 clinical medicine Genetics research medicine Humans Lupus Erythematosus Systemic SNP Genetic Predisposition to Disease Polymorphism lcsh:Science skin and connective tissue diseases 030203 arthritis & rheumatology Genetics Multidisciplinary Lupus erythematosus Lupus Erythematosus Nucleic Acid business.industry lcsh:R Single Nucleotide Lupus Erythematosus Systemic/genetics medicine.disease Systemic/genetics 030104 developmental biology lcsh:Q Female Personalized medicine business Regulatory Sequences Genome-Wide Association Study |
| Zdroj: | Scientific Reports Scientific reports, 9(1). Nature Publishing Group Scientific Reports, Vol 9, Iss 1, Pp 1-9 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Personalized medicine approaches are increasingly sought for diseases with a heritable component. Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease resulting from loss of immunologic tolerance, but the genetic basis of SLE remains incompletely understood. Genome wide association studies (GWAS) identify regions associated with disease, based on common single nucleotide polymorphisms (SNPs) within them, but these SNPs may simply be markers in linkage disequilibrium with other, causative mutations. Here we use an hierarchical screening approach for prediction and testing of true functional variants within regions identified in GWAS; this involved bioinformatic identification of putative regulatory elements within close proximity to SLE SNPs, screening those regions for potentially causative mutations by high resolution melt analysis, and functional validation using reporter assays. Using this approach, we screened 15 SLE associated loci in 143 SLE patients, identifying 7 new variants including 5 SNPs and 2 insertions. Reporter assays revealed that the 5 SNPs were functional, altering enhancer activity. One novel variant was linked to the relatively well characterized rs9888739 SNP at the ITGAM locus, and may explain some of the SLE heritability at this site. Our study demonstrates that non-coding regulatory elements can contain private sequence variants affecting gene expression, which may explain part of the heritability of SLE. |
| Databáze: | OpenAIRE |
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