Polymorphisms in rs2069845 are associated with IL-6 and soluble IL-6 receptor levels during total joint replacement

Abstract

As the number of patients undergoing total joint replacement (TJR) surgery increases, so does the number of revision surgeries. One driver of implant failure and subsequent revision surgery is peri-implant osteolysis, which is driven by inflammation-mediated bone loss. IL-6 is an inflammatory cytokine that is elevated during the peri-operative period. Early elevations in IL-6 levels have been linked to osteolysis development. The current study asked whether there is genetic contribution to the IL-6-related peri-operative inflammatory reaction to TJR surgery. Patients undergoing primary TJR (total hip or total knee) provided pre-operative and post-operative blood samples for measurement of the circulating levels of IL-6 and the soluble IL-6 receptor (sIL-6r), as well as evaluation of allele status of three single nucleotide polymorphisms (SNPs) linked to IL-6 or sIL-6r levels - rs2069845, rs2228145, and rs4537545. Circulating sIL-6r levels were associated with allele status in the rs2228145 SNP. More interestingly, allele status in the rs2069845 SNP was associated with the change in circulating IL-6 levels following TJR surgery. Specifically, patients with the A,A allele had increasing levels of IL-6, while those harboring the G,A allele had decreasing levels of IL-6. While implant survival was not assessed, the critical role of IL-6 in peri-implant osteolysis suggests that the rs2069845 allele may influence orthopedic implant success. rs2069845 polymorphisms may be a useful patient-specific marker of inflammatory response to TJR surgery.

Fig 1. Perioperative IL-6 and sIL-6r dynamics according to rs2069845 allele status.

(a) Pre-operative and (b) post-operative circulating IL-6 levels according to allele variant. (c) Comparison of the pre- and post-operative IL-6 levels according to allele variant for the two most prevalent alleles. (d) Pre-operative and (e) post-operative circulating sIL-6r levels according to allele variant. (f) Comparison of the pre- and post-operative sIL-6r levels according to allele variant for the two most prevalent alleles (A,A and G,A). Data are presented as individual measures with the mean and standard deviations. Significant pair-wise comparisons from non-parametric Mann-Whitney U tests are presented, when significant, as bars over the data in panels a, b, d, e. The results from non-parametric mixed effects comparisons of the effects of allele, time, and the allele by time interaction for the two most common alleles are presented as legends in panels c and f.

Fig 2. Perioperative IL-6 and sIL-6r dynamics for rs2228145.

(a) Pre-operative and (b) post-operative circulating IL-6 levels according to allele variant. (c) Comparison of the pre- and post-operative IL-6 levels according to allele variant for the two most common alleles. (d) Pre-operative and (e) post-operative circulating sIL-6r levels according to allele variant. (f) Comparison of the pre- and post-operative sIL-6r levels according to allele variant for the two most common alleles (A,A and C,A). Data are presented as individual measures with the mean and standard deviations. Significant pair-wise comparisons from non-parametric Mann-Whitney U tests are presented, when significant, as bars over the data in panels a, b, d, e. The results from non-parametric mixed effects comparisons of the effects of allele, time, and the allele by time interaction for the two most common alleles are presented as legends in panels c and f.

Fig 3. Perioperative IL-6 and sIL-6r dynamics for rs4537545.

(a) Pre-operative and (b) post-operative circulating IL-6 levels according to allele variant. (c) Comparison of the pre- and post-operative IL-6 levels according to allele variant for the two most common alleles. (d) Pre-operative and (e) post-operative circulating sIL-6r levels according to allele variant. (f) Comparison of the pre- and post-operative sIL-6r levels according to allele variant for the two most common alleles (C,C and C,T). Data are presented as individual measures with the mean and standard deviations. Significant pair-wise comparisons from non-parametric Mann-Whitney U tests are presented, when significant, as bars over the data in panels a, b, d, e. The results from non-parametric mixed effects comparisons of the effects of allele, time, and the allele by time interaction for the two most common allele are presented as legends in panels c and f.