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Elife. 2016 Feb 15;5. pii: e12089. doi: 10.7554/eLife.12089.

Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.

Author information

1
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
2
School of Biotechnology, Shri Mata Vaishno Devi University, Katra, India.
3
Department of Neurology, Yale School of Medicine, New Haven, United States.
4
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
5
Pole de pathologies rhumatismales, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, Belgium.
6
Division of Rheumatology, Department of Medicine, Penn State Medical School, Hershey, United States.
7
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
8
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
9
Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States.
10
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, United States.
11
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
12
Cincinnati VA Medical Center, Cincinnati, United States.
13
Cincinnati Children's Hospital Medical Center, Cincinnati, United States.
14
Department of Medicine, University of Southern California, Los Angeles, United States.
15
Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
16
Rheumatic Diseases Division, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, United States.

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.

KEYWORDS:

HLA; LD; SLE risk; evolutionary biology; genomics; haplotype; human; human biology; medicine; risk allele; targeted sequencing

Comment in

PMID:
26880555
PMCID:
PMC4811771
DOI:
10.7554/eLife.12089
[Indexed for MEDLINE]
Free PMC Article

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