Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.
Elife
; 52016 Feb 15.
Article
in En
| MEDLINE
| ID: mdl-26880555
ABSTRACT
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polymorphism, Genetic
/
HLA-D Antigens
/
Autoimmunity
/
Gene Expression Regulation
Type of study:
Prognostic_studies
Limits:
Humans
Country/Region as subject:
America do norte
/
Europa
Language:
En
Journal:
Elife
Year:
2016
Type:
Article
Affiliation country:
United States