Format

Send to

Choose Destination
Sci Rep. 2019 Oct 28;9(1):15433. doi: 10.1038/s41598-019-51864-9.

Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus.

Author information

1
Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia. sarah.a.jones@monash.edu.
2
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia.
3
Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia.
4
Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
5
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052, Australia.
6
Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.
7
Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center