GENETIC RELATIONSHIPS IN A GROUP OF METAL-ON-METAL TOTAL HIP BEARING FAILURES

INTRODUCTION

Since the recall of some metal on metal (MoM) THR bearings, surgeons have seen patients with pain, elevated Co and Cr levels and adverse local tissue reactions (ALTR). While many variables may contribute to THR MoM failures, many times these variables are not present in patients who present with symptoms. We investigate the possible genetic predilection of a group of patients who were revised after MoM THR surgery for pain, high Co/Cr levels and ALTR.

METHODS

IRB approval was obtained prior to our study. We have analyzed 19 control (asymptomatic MoM THR patients > 6 years after surgery) and 19 disease (revised MoM THR for high metal ions and ALTR). The 38 sample intensity files were subject to sample Quality Control (QC) using Contrast QC (< 0.4) with an Affymetrix Genotyping Console. The resulting 38 sample files with genotype calls were loaded and further analyzed using the Association Workflow in Partek Genomics Suite 6.6 (Partek, Missouri). Hardy-Weinberg equilibrium test was performed on the single nucleotide polymorphism (SNP) level. The difference between the observed and expected frequencies of each allele at each locus were tested by Fisher's exact test and χ2 test. To get the working SNP list, two filters were used: (1) a SNP no-call rate should be less than 5%, and (2) minor allele frequency of a SNP should be greater than 5%.

After filtering, association analysis of the SNPS with disease was done using Chi² Test. In this study, χ² statistic was used to assess the difference in allele frequencies between the control and disease samples. The value of χ2 statistic, degrees of freedom, and the associated p-value for each SNP were calculated. Dot Plot was used to visualize the genotypes of all samples.

To measure the non-random association of alleles at different loci, Linkage Disequilibrium analysis was performed using the neighborhood size of 20 and statistic r². The resulting correlations show the value of r² for SNPs. The r² = 1 means that two SNPs are tightly associated.

RESULTS

We found that several SNPs are linked to the revision disease group that showed evidence of metal sensitivity. Among them, a strong association in the disease group was found in a SNP called MS1. In the disease group 17/19 patients were either heterozygous or recessive homozygous for MS1, with 17/19 asymptomatic patients were of the homozygous dominant MS1 isoform. Based on the Linkage Disequilibrum analysis results, several other SNPs were also fund to be strongly correlated with the disease group (Fig 1). The controls had an average Co level of 2.4 and Cr level of 1.3 while the disease group 18 and 10.4 respectively.

CONCLUSIONS

This study found a strong genetic relationship in a gene we designate as MS1 where the homozygous recessive and heterozygous isoform genotypes were found in the disease group of revised MoM THRs. A strong correlation of several SNPs was also found. This may be a good predictor of failures and an avenue for personalized choice of implants in the future.

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