Genes May Contribute to Hip Graft Failure

March 15, 2007

MANCHESTER, England -- Failures of total hip replacements are significantly more likely to occur when patients carry variants in genes encoding for collagen breakdown and the vitamin D receptor, according to investigators here.

MANCHESTER, England, March 15 -- Failures of total hip replacements are significantly more likely to occur when patients carry variants in genes encoding for collagen breakdown and the vitamin D receptor, according to investigators here.

Genetic testing could identify candidates for a total hip who are likely to develop osteolysis or have failure of the implant, suggested Hammy Malik, M.D., of the University of Manchester, and colleagues, online in the Annals of the Rheumatic Diseases.

The investigators found that patients with specific mutations in genes encoding for the protease matrix metalloproteinase 1 (MMP1) were at risk for aseptic loosening of their implants or early joint failure.

On the other hand, mutations in the gene encoding for interleukin-6 (IL-6), a regulator of bone metabolism, were not associated with an increased risk of complications, the investigators found.

"Aseptic loosening and possibly deep infection of total hip replacement may be due to the genetic influence of candidate susceptibility genes," they wrote. They added that detection of these single nucleotide polymorphisms could serve a predictive marker for implant survival.

Previous studies have suggested that periprosthetic bone loss around artificial hips may be caused by a cascade of events triggered by particulate debris, and exacerbated by the release of inflammatory cytokines, leading to bone resorption mediated by osteoclasts.

In particular, MMP1, IL-6, and the vitamin D receptor have been singled out as key players in the process. The authors hypothesized that individual variations in biologic response to stimuli leading to joint failure might be linked to differences in genetic susceptibility.

To test this theory, they conducted a case-control study of 312 Caucasian patients with osteoarthritis who underwent a cemented Charnley total hip arthroplasty with polyethylene acetabular cup.

The cases included 91 patients who had early aseptic loosening of the implants (defined as loosening that occurred within six years of implantation in line with the yearly incidence of loosening in relation to the evolution of the Charnley low-friction arthroplasty), and 71 patients who had microbiological evidence of deep infection at the time of surgical revision.

The 150 controls were patients who had undergone the same procedure but were clinically asymptomatic for more than 10 years, and had no radiographic features of aseptic loosening or at-risk signs.

The investigators genotyped DNA samples from all patients, looking for single nucleotide polymorphisms (SNPs) in the genes encoding for MMP1, IL-6, and the vitamin D receptor.

They found that of four common polymorphisms in genes encoding for MMP1, an allele in which there is a cytosine base in place of thymine (the C allele) and the C/C genotype were both strongly associated with aseptic failure compared with controls. Possession of the C allele conferred a more than three-fold higher risk for aseptic failure (odds ratio 3.27; 95% confidence interval, 2.21 to 4.83, P=0.001).

In addition, a mutation in the vitamin D receptor gene in which guanine is replaced by thymine (the T allele) and the T/T genotype were both significantly associated with osteolysis caused by deep infection, compared with controls. The odds ratio for those carrying the T allele was 1.76 (95% CI 1.16 to 2.66, P=0.007).

There were no significant associations between septic or aseptic failure and any of the other SNPs the authors examined.

"Association studies such as the one described in this report can be very useful in elucidating the relationship between complex disease phenotype and a specific genotype," they authors wrote. "However, they have a number of caveats such as small sample size, population stratification and linkage disequilibrium. We have managed to collect a large number of study and control cases, with approximately twice as many controls as study subjects in the aseptic group. Slightly fewer septic cases were recruited, which probably represents the lower prevalence of this complication."