Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.
Highlights
Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the axial bones, leading to spinal ankylosis
Within the AS cohort, 1021 patients (91.2%) were positive for human leukocyte antigen (HLA)-B27 and 485 patients (43.3%) were positive for syndesmophyte formation based on spinal X-ray analysis (146 patients with modified Stoke’s Ankylosing Spondylitis Spinal Score (mSASSS) being less than 24 and 339 patients with mSASSS of being 24 or more)
We carried out genetic analyses to investigate whether receptor activator of the nuclear factor-kappa (RANK), receptor activator of nuclear factor-kappa ligand (RANKL), and OPG genes are involved in AS susceptibility
Summary
Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the axial bones, leading to spinal ankylosis. Multiple factors including genetic compositions, infectious agents, and immune response dysfunctions contribute to the development of AS in individuals. Overwhelming majority of individuals who are positive for HLA-B27 do not have AS, and HLA-B27 positivity only accounts for a small fraction of the AS heritability [1]. A proper balance between bone resorption and synthesis is essential to maintain bone mechanical strength and structure [8]. In AS patients, chronic inflammation and osteogenesis break the balance between bone resorption and synthesis, resulting in structural bone damage, spinal immobility, and significant functional impairment [9,10,11]. The osteogenesis in AS patients is accompanied by bone
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