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A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis
- Source :
- Arthritis & Rheumatism. 62:2864-2875
- Publication Year :
- 2010
- Publisher :
- Wiley, 2010.
-
Abstract
- Objective We previously observed the association of the co-occurrence of the HLA–DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)–positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs. Methods SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription–PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay. Results A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti–cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5. Conclusion The RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.
- Subjects :
- musculoskeletal diseases
Adult
Male
Genotype
Immunology
Single-nucleotide polymorphism
Polymorphism, Single Nucleotide
Article
White People
Arthritis, Rheumatoid
Rheumatology
Gene expression
Humans
Immunology and Allergy
Rheumatoid factor
Genetic Predisposition to Disease
Pharmacology (medical)
RNA, Messenger
Age of Onset
Promoter Regions, Genetic
biology
RANK Ligand
Promoter
Middle Aged
Black or African American
Reverse transcription polymerase chain reaction
RANKL
biology.protein
Female
Antibody
Age of onset
SOXD Transcription Factors
Subjects
Details
- ISSN :
- 00043591
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Arthritis & Rheumatism
- Accession number :
- edsair.doi.dedup.....894ea94530d958b1ca3d7cf8c683ed66
- Full Text :
- https://doi.org/10.1002/art.27589