LRP5 gene polymorphisms and radiographic joint damage in rheumatoid arthritis patients
Rheumatoid arthritis (RA) is characterized by increased bone resorption and impaired bone formation. Osteoblast function is regulated by the canonical LRP5/Wnt/β-catenin pathway. Bone mineral density and RA joint destruction are partially inherited. In line with this, we found significant associations between LRP5 SNPs (p.A1330V, p.N740N, p.V667M) and RA radiographic damage severity.
Increased bone resorption and impaired bone formation characterize rheumatoid arthritis (RA). Canonical Wnt/β-catenin pathway, signalled by lipoprotein receptor-related protein-5 (LRP5), regulates osteoblast function. Since bone mineral density (BMD) and RA joint destruction are partially inherited, we studied their association with LRP5 single nucleotide polymorphisms (SNPs).
Clinical data and peripheral blood for biomarkers assessment and LRP5 genotyping were collected from 208 RA patients. Hands and feet X-rays were scored [modified Sharp/van der Heijde Score (SHS), joint space narrowing (JSN), and erosion scores]. Lumbar spine, total left proximal femur, and left hand BMD were assessed by dual-energy X-ray absorptiometry (DXA).
TT genotypes for p.A1330V and p.N740N LRP5 SNPs associated with total SHS, erosion score, and hands erosion score; the same for p.A1330V with feet JSN score and p.N740N with hands total score. AG genotype for p.V667M associated with sclerostin and hands JSN score. Femoral BMD associated with TC genotype for p.N740N. Multiple test correction precluded a few of these associations. Among V667M-N740N-A1330V haplotypes: GTT associated with higher feet JSN score (OR = 3.80; p = 0.016) and ATT with higher JSN score (OR = 4.60; p = 0.032), hands total score (OR = 5.65; p = 0.022), and total SHS (OR = 6.74; p = 0.024).
Significant associations between LRP5 SNPs (p.A1330V, p.N740N, and p.V667M) and the severity of radiographic damage reinforce the evidence of bone destruction heritability in RA.
KeywordsBone mineral density DXA LRP5 Modified Sharp/van der Heijde score Rheumatoid arthritis Sclerostin
The authors wish to acknowledge Associação Nacional de Reumatologia for the funding, Conceição Gonçalves (MSc) from the Laboratório Nobre in the Faculty of Medicine of the University of Porto, the nursing Service of Rheumatology Day Hospital of São João Hospital Centre, Alexandra Bernardo (M.D.) and Sofia Pimenta (M.D.) from the Rheumatology Department of São João Hospital Center.
Compliance with ethical standards
Conflicts of interest
The study protocol was approved by the São João Hospital Centre (Porto, Portugal) Ethical Committee.
All procedures performed in the study involving human participants were in accordance with the ethical standards of São João Hospital Centre (Porto, Portugal) Ethical Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from each patient.
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