Abstract
Introduction
Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis.
Patients/Materials & Methods
The Norway cohort comprised 2,624 subjects after THA recruited from the Norwegian Arthroplasty Registry, 779 with revision surgery for osteolysis. The UK cohort comprised 890 subjects recruited from hospitals in the north of England, 317 with radiographic evidence or revision surgery for osteolysis. All subjects had received a fully cemented or hybrid THA using small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis failure were undertaken after genome-wide genotyping. Finally, a meta-analysis of the discovery datasets was undertaken.
Results
Genome-wide association analysis identified 4 and 11 independent suggestive genetic signals for osteolysis susceptibility at P≤5×10−6 in the Norwegian and UK cohorts, respectively. Following meta-analysis, 5 independent genetic signals showed suggestive association with osteolysis at P≤5×10−6, with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, Figure 1, p=1.13×10−6). Genome-wide quantitative trait analysis in cases only showed a total of 5 and 9 independent genetic signals for time to prosthesis failure at P≤5×10−6, respectively. Following meta-analysis, 11 independent genetic signals showed suggestive evidence of association with time to failure at P≤5×10−6, with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, Figure 2, p=1.40×10−7).
Discussion
These studies provide the first genome-wide insights into the heritable biology of osteolysis, a major complication of joint replacement surgery. Although there were no dominant signals of genome-wide significance, we find replicating evidence for several independent genetic loci both for osteolysis susceptibility and time to prosthesis failure at P≤5×10−6, consistent with the complex aetiology of the disease.
Conclusion
The heritable contribution to osteolysis is modest. The identified genetic loci may however provide novel avenues for therapy development in this condition
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