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Risk of Revision After Arthroplasty Associated withSpecific Gene Loci: A Genomewide Association Study of Single-Nucleotide Polymorphisms in 1,130 TwinsTreated with Arthroplasty
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-2152-4343
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.ORCID iD: 0000-0002-3233-2638
2022 (English)In: Journal of Bone and Joint Surgery, ISSN 0301-620X, E-ISSN 2044-5377, Vol. 104, no 7, p. 610-620Article in journal (Refereed) Published
Abstract [en]

Background:

The risk of revision surgery following total joint arthroplasty (TJA) may be influenced by genetic factors. Therefore, we sought to identify genetic variants associated with the risk of revision surgery in a genomewide association study

Methods

We investigated a cohort of 1,130 twins from the Swedish Twin Registry treated with TJA. During a mean of 9.4 years of follow-up, 75 individuals underwent revision surgery for aseptic loosening (the primary outcome) and 94, for any reason (the secondary outcome). Genetic information was collected using the Illumina OmniExpress and PsychArray panels, and the Haplotype Reference Consortium served as the reference for gene imputation. Adjusted Cox regression models were fitted to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

Nine single-nucleotide polymorphisms (SNPs) reached genomewide significance for aseptic loosening. The first SNP, rs77149046, located in the endosome-lysosome associated apoptosis and autophagy regulator family member 2 (ELAPOR2) gene, conferred an HR of 5.40 (CI, 3.23-9.02; p = 1.32×10−10), followed by 4 SNPs within the region coding for sodium-dependent taurine and beta-alanine transporter (SLC6A6), with HRs ranging from 3.35 to 3.43. The sixth SNP, rs7853989 (HR, 3.46; CI, 2.33-5.13; p = 6.91×10−10), was located in a region coding for the ABO blood group system. This SNP has been described as predictive for blood type B. Seven significant SNPs were found for the risk of revision for any reason, with the first 4 again being located in the SLC6A6 region. The leading SNP, rs62233562, conferred an HR of 3.11 (CI, 2.19-4.40; p = 1.74×10−10) for revision surgery. Similar HRs were found for SNPs 3:14506680 (p = 1.78×10−10), rs2289129 (p = 1.78×10−10), and rs17309567 (p = 3.16×10−10). The fifth SNP, rs11120968, was located in the calmodulin-binding transcription activator 1 (CAMTA1) gene (HR, 2.34; CI, 1.74-3.13, p = 1.45×10−8).

Conclusions

We identified 12 unique SNPs associated with an increased risk of revision surgery. Among these, 2 were in ELAPOR2, which is closely linked to bone formation. Another SNP is located in a gene region encoding for the ABO system, which merits further studies of causal relationships.

Place, publisher, year, edition, pages
2022. Vol. 104, no 7, p. 610-620
National Category
Orthopaedics Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-401795DOI: 10.2106/JBJS.21.00750ISI: 000778606600009OAI: oai:DiVA.org:uu-401795DiVA, id: diva2:1383902
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2022-12-01Bibliographically approved
In thesis
1. Hip Revision Surgery: Identification of Genetic Markers and Evaluation of Novel Treatment Strategies
Open this publication in new window or tab >>Hip Revision Surgery: Identification of Genetic Markers and Evaluation of Novel Treatment Strategies
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Total hip arthroplasty (THA) is, despite its overall good outcome, for some patients followed by hip revision surgery. This seems in parts to be because of genetic susceptibility to revision surgery. The most common reason for revision surgery is aseptic loosening followed by periprosthetic joint infection and dislocation. Cups made of porous tantalum (TM cups) were thought to be favorable in revision surgery to address aseptic loosening, but they seem to confer an increased risk of dislocation. The effectiveness and biocompatibility in vivo of TM cups have not been researched. Dual mobility cups (DMCs) with two articulating surfaces are proposed to prevent dislocation to a higher degree than standard polyethylene liners.

Our hypotheses were that TM cups are superior to their historical treatment alternative in terms of re-revision rates; that the combination of DMC cemented into TM cups would decrease the risk for dislocation after revision surgery; that tantalum ion liberation is marginal after the use of TM cups; and that certain risk genes are associated with an increased risk for revision surgery after total joint arthroplasty.

Studies I&II were register-based cohort studies comparing the implant survival of TM cups and conventional acetabular reinforcement rings (study I), and the combination of TM cups/DMC with TM cups/standard polyethylene liners (study II). We found that TM cups perform equally well as reinforcement rings, but that the two implants differ in their failure mechanisms. Cementing a DMC into TM cups adequately addressed the issue of recurrent dislocation. In study III we investigated whether tantalum ion liberation does occur after implantation of a TM cups and how this affects patients’ immunological response by comparison of three groups: primary non-tantalum THA, primary tantalum THA and revision tantalum THA. We found the highest concentration of tantalum ions in the revision cases, yet tantalum ions were not associated with an immunological response, and we found no signs of alteration in the investigated lymphocyte subsets. Study IV aimed to identify possible risk genes for revision surgery after total hip or knee replacement by a genome wide association study. We found six significant risk genes for the endpoint revision surgery for any reason, and three for the endpoint revision due to aseptic loosening. We found a variety of suggestive risk genes within the region coding for the ABO-system.

In conclusion, the novel treatment options TM cups and DMC show good results in hip revision surgery, but longer follow-up is warranted. The use of porous tantalum seems not to be associated with the immunological activation that can be observed in metallosis. The risk for revision surgery is associated with certain risk genes.

Abstract [sv]

Höftproteskirurgi är ett väldigt framgångsrikt kirurgiskt ingrepp och förbättrar livskvalité samtidigt som den minskar smärta hos den drabbade patienten. Tyvärr behöver ca 10 % av alla patienter genomgå en omoperation av höftleden, oftast eftersom protesen lossnar, men den konstgjorda leden kan även hoppa ur led (luxation).

Vid omoperation av höften har under de senaste två decennierna två relativt nya implantat använts: cupar gjorda av poröst tantalum som ska minska risken för lossning och cupar med två artikulationsytor, så kallade dubbelcupar, som ska minska risken för luxation. Dessa två implantat är dock ej undersökta i jämförande studier. Likaså är det inte känt huruvida tantalum genom frisättning av joner kan påverka patienternas immunsystem. Vidare finns det antaganden att risken för att behöva genomgå omoperation ska vara ärftligt betingad.

Denna avhandling undersökte i sina fyra delarbeten om cupar gjorda av tantalum visar en bättre överlevnad än de historiska behandlingsalternativen; om dubbelcupar visar det bättre utfallet avseende risken för luxation i jämförelse med standardcupar; om frisättning av tantaljoner förekommer efter användning av tantalumcupar och hur detta påverkar patienternas immunologi; om risken för reoperation är associerad med vissa riskgener.

Implantatöverlevnad analyserades med hjälp av överlevnadskurvor. Tantalumjoner uppmättes och deras medianvärden jämfördes mellan olika grupper av patienter som opererades med proteser som innehöll tantalum och de som opererades med konventionella proteser. Därutöver relaterades tantalumjoner till särskilda markörer inom immunsystemet. För att hitta riskgener för omoperationer jämfördes genomet hos individer som genomgick reoperation efter protesinsättning med de som inte gjorde det.

De mest intressanta fynden var att tantalumcupar visade ett lika gott resultat efter omoperation som deras historiska behandlingsalternativ. Dock luxerade höften hos en stor andel av patienterna. Höfter som opererades med dubbelcupar visade en lägre risk för luxation i jämförelse med standardcupar. Tantaljoner frisattes till viss mån, och vi fann enbart svaga korrelationer med vissa lymfocyter. Vi fann sex riskgener som ökade risken för reoperation oavsett orsak. Tre gener associerades med en ökad risk för reoperation på grund av lossning av implantaten. Många riskgener som var nära statistisk signifikans befann sig inom genen som kodar för ABO-grupperingen.

Vår konklusion är att tantalumcupar är ett säkert och pålitligt alternativ vid reoperation men att man bör beakta risken för att protesen kan hoppa ur led. Detta kan hanteras genom användning av dubbelcupar i kombination med tantalumcupar. Tantalum påverkar ej patienters immunsystem. De identifierade riskgenerna behöver bekräftas i nya studier, men även en eventuell riskökning för omoperation för vissa blodgrupper bör studeras.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1627
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-401796 (URN)978-91-513-0845-6 (ISBN)
Public defence
2020-02-28, Gunnesalen, Psykiatrins hus, Akademiska sjukhuset, Sjukhusvägen, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2020-02-07 Created: 2020-01-09 Last updated: 2020-03-05

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Brüggemann, AndersEriksson, NiclasMichaëlsson, KarlHailer, Nils

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