Dataset Information

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

ABSTRACT: BACKGROUND:Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown. QUESTIONS/PURPOSES:We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis. METHODS:The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken. RESULTS:Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ? 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ? 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ? 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ? 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10). CONCLUSIONS:We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease. CLINICAL RELEVANCE:The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.

SUBMITTER: MacInnes SJ

PROVIDER: S-EPMC6370091 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

MacInnes Scott J SJ Hatzikotoulas Konstantinos K Fenstad Anne Marie AM Shah Karan K Southam Lorraine L Tachmazidou Ioanna I Hallan Geir G Dale Hårvard H Panoutsopoulou Kalliope K Furnes Ove O Zeggini Eleftheria E Wilkinson J Mark JM

Clinical orthopaedics and related research 20190201 2

<h4>Background</h4>Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown.<h4>Questions/purposes</h4>We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk l ...[more]

PMID: 30794219

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Project description:BACKGROUND:Many patients undergo both THA and spinal arthrodesis, and those patients may not fare as well as those who undergo one procedure but not the other. The mechanisms of how spinal arthrodesis affects patient function after THA remain unclear. QUESTIONS/PURPOSES:The aims of our study were to (1) determine how patient-reported outcome measures (PROMs), including the Oxford hip score as well as dislocations and complications compare after THA between patients with and without spinal arthrodesis; (2) characterize sagittal pelvic changes in these patients that occur when moving between different functional positions and test for differences between patients with and without spinal arthrodesis; and (3) assess whether differences in sagittal pelvic dynamics are associated with PROMs, complications, and dislocations after THA. METHODS:In this case-control study, we identified 42 patients (60 hips) who had undergone both THA and spinal arthrodesis between 2002 and 2016 and who were available for followup at a minimum of 12 months (mean, 6 ± 5 years) after the later of the two procedures. These cases were case-control-matched for age, gender, and body mass index with 42 patients (60 hips) who underwent only THA and had no known spinal pathology. All patients completed PROMs, including the Oxford hip score, and underwent four radiographs of the pelvis and spinopelvic complex in three positions (supine, standing, and deep-seated). Cup orientation and various spinopelvic parameters, including pelvic tilt and pelvic-femoral angle, were measured. The difference in pelvic tilt between standing and seated allowed for patient classification based on spinopelvic mobility into normal (± 10°-30°), stiff (< ± 10°) or hypermobile (> ± 30°) groups. RESULTS:Compared with the THA-only group, the THA-spinal arthrodesis group had inferior PROMs (Oxford hip score, 33 ± 10 versus 43 ± 6; p < 0.001) and more surgery-related complications (such as dislocation, loosening, periprosthetic fracture or infection, psoas irritation) (12 versus 3; p = 0.013), especially dislocation (5 versus 0; p = 0.023). We detected no difference in change of pelvic tilt between supine and standing positions between the groups. When standing, patients undergoing THA-spinal arthrodesis had greater pelvic tilt (25° ± 11° versus 17° ± 8°; p < 0.001) and the hip was more extended (193° ± 22° versus 185° ± 30°; p = 0.012). We found that patients undergoing THA-spinal arthrodesis were more likely to have spinopelvic hypermobility (12 of 42 versus three of 42; odds ratio, 5.2; p = 0.02) with anterior tilting of the pelvis. Of all biomechanical parameters, only spinopelvic hypermobility was associated with inferior PROMs (Oxford hip score, 35 ± 9 versus 40 ± 7 in normal mobility; p = 0.049) and was also present in dislocating hips that underwent revision despite acceptable cup orientation. CONCLUSIONS:In patients with spinal arthrodesis who have undergone THA, spinopelvic hypermobility is associated with inferior outcomes, including hip instability. Spinopelvic hypermobility should be routinely assessed because these patients may have a narrow zone of optimum cup orientation that would require new technology to define and assist the surgeon in obtaining it.Level of Evidence Level III, therapeutic study.

Project description:Length of stay after total hip arthroplasty (THA) has decreased over the last two decades. However, published studies that have examined same-day and early discharge protocols after THA have been done in highly selected patient groups operated on by senior surgeons in a nonrandomized fashion without control subjects.The purpose of this study was to evaluate and compare patients undergoing THA who are discharged on the same day as the surgery ("outpatient," less than 12-hour stay) with those who are discharged after an overnight hospital stay ("inpatient") with regard to the following outcomes: (1) postoperative pain; (2) perioperative complications and healthcare provider visits (readmission, emergency department or physician office); and (3) relative work effort for the surgeon's office staff.A prospective, randomized study was conducted at two high-volume adult reconstruction centers between July 2014 and September 2015. Patients who were younger than 75 years of age at surgery, who could ambulate without a walker, who were not on chronic opioids, and whose body mass index was less than 40 kg/m2 were invited to participate. All patients had a primary THA performed by the direct anterior approach with spinal anesthesia at a hospital facility. Study data were evaluated using an intention-to-treat analysis. A total of 220 patients participated, of whom 112 were randomized to the outpatient group and 108 were randomized to the inpatient group. Of the 112 patients randomized to outpatient surgery, 85 (76%) were discharged as planned. Of the remaining 27 patients, 26 were discharged after one night in the hospital and one was discharged after two nights. Of the 108 patients randomized to inpatient surgery with an overnight hospital stay, 81 (75%) were discharged as planned. Of the remaining 27 patients, 18 met the discharge criteria on the day of their surgery and elected to leave the same day, whereas nine patients stayed two or more nights.On the day of surgery, there was no difference in visual analog scale (VAS) pain among patients who were randomized to discharge on the same day and those who were randomized to remain in the hospital overnight (outpatient 2.8 ± 2.5, inpatient 3.3 ± 2.3, mean difference -0.5, 95% confidence interval [CI], -1.1 to 0.1, p = 0.12). On the first day after surgery, outpatients had higher VAS pain (at home) than inpatients (3.7 ± 2.3 versus 2.8 ± 2.1, mean difference 0.9, 95% CI, 0.3-1.5, p = 0.005). With the numbers available, there was no difference in the number of reoperations, hospital readmissions without reoperation, emergency department visits without hospital readmission, or acute office visits. At 4-week followup, there was no difference in the number of phone calls and emails with the surgeon's office (outpatient: 2.4 ± 1.9, inpatient: 2.4 ± 2.2, mean difference 0, 95% CI, -0.5 to 0.6, p = 0.94).Outpatient THA can be implemented in a defined patient population without requiring additional work for the surgeon's office. Because 24% (27 of 112) of patients planning to have outpatient surgery were not able to be discharged the same day, facilities to accommodate an overnight stay should be available.Level I, therapeutic study.

Project description:BACKGROUND:The choice of surgical approach for THA remains controversial. Some studies suggest that the direct anterior approach (DAA) leads to less muscle damage than the miniposterior approach (MPA), but there is little high-quality evidence indicating whether this accelerates recovery, or whether this approach-which may be technically more demanding-is associated with component malposition or more complications. QUESTIONS/PURPOSES:(1) Does the DAA result in faster return to activities of daily living than the MPA? (2) Does the DAA have superior patient-reported outcome measures than the MPA? (3) Does the DAA result in improved radiographic outcomes than the MPA? (4) Does the DAA have a higher risk of complications than the MPA? METHODS:Between March 1, 2013, and May 31, 2016, 116 patients undergoing primary unilateral THA were randomized to either the DAA or MPA; 15 patients withdrew after randomization, and one died 6 months after surgery from a stroke unrelated to the procedure. Recruitment stopped when 52 patients had been randomized into the DAA group and 49 in the MPA group (n = 101). After patient randomization, one high-volume surgeon performed all of the DAAs and three high-volume surgeons performed the MPA THAs. The groups did not differ in age (65 years; SD 11; range, 38-86 years), sex (52% women), or body mass index (mean 29 kg/m; SD 6 kg/m; range, 21-40 kg/m; all p > 0.40). Functional results included time to discontinue gait aids, discontinue all narcotics, and independence with various activities of daily living; accelerometer data evaluated activity level. Clinical and radiographic outcomes, Hip disability and Osteoarthritis Outcome Score, SF-12, and Harris hip scores to 1 year were also tabulated. The minimum followup was 365 days (mean ± SD, 627 ± 369 days). RESULTS:There were slight differences in early functional recovery that favored the DAA versus the MPA: time to discontinue walker use (10 versus 15 days, p = 0.01) and time to discontinue all gait aids (17 versus 24 days, p = 0.04). There were no other differences in early functional milestones, although at 2 weeks after surgery, mean steps per day were 3897 (SD 2258; range, 737-11,010) for the DAA versus 2235 for the MPA (SD 1688; range, 27-7450; p < 0.01). There was no difference in activity monitoring at 1 year. There were no differences in patient-reported outcome scores between the groups. There was no difference in the radiographic parameters measured in the two groups, including leg length discrepancy, component position, or offset, and there was no subsidence observed in any hip. There was no difference in complications between the DAA and the MPA groups (8% [four of 52] versus 10% [five of 49]; p = 0.33). CONCLUSIONS:Both the DAA and MPA approaches provided excellent early recovery with a low risk of complications. Patients undergoing the DAA had a slightly faster recovery, as measured by milestones of function and quantified by activity monitor data, but no substantive differences were evident at 2 months. Because the DAA is the less studied approach, longer term (> 1 year) complications may yet accrue, will be important to quantify, and may offset early benefits. LEVEL OF EVIDENCE:Level I, therapeutic study.

Project description:Potyviruses (family Potyviridae, genus Potyvirus) are the result of an initial radiation event that occurred 6,600 years ago. The genus currently consists of 167 species that infect monocots or dicots, including domesticated and wild plants. Potyviruses are transmitted in a non-persistent way by more than 200 species of aphids. As indicated by their wide host range, worldwide distribution, and diversity of their vectors, potyviruses have an outstanding capacity to adapt to new hosts and environments. However, factors that confer adaptability are poorly understood. Viral RNA-dependent RNA polymerases introduce nucleotide substitutions that generate genetic diversity. We hypothesized that selection imposed by hosts and vectors creates a footprint in areas of the genome involved in host adaptation. Here, we profiled genomic and polyprotein variation in all species in the genus Potyvirus. Results showed that the potyviral genome is under strong negative selection. Accordingly, the genome and polyprotein sequence are remarkably stable. However, nucleotide and amino acid substitutions across the potyviral genome are not randomly distributed and are not determined by codon usage. Instead, substitutions preferentially accumulate in hypervariable areas at homologous locations across potyviruses. At a frequency that is higher than that of the rest of the genome, hypervariable areas accumulate non-synonymous nucleotide substitutions and sites under positive selection. Our results show, for the first time, that there is correlation between host range and the frequency of sites under positive selection. Hypervariable areas map to the N terminal part of protein P1, N and C terminal parts of helper component proteinase (HC-Pro), the C terminal part of protein P3, VPg, the C terminal part of NIb (RNA-dependent RNA polymerase), and the N terminal part of the coat protein (CP). Additionally, a hypervariable area at the NIb-CP junction showed that there is variability in the sequence of the NIa protease cleavage sites. Structural alignment showed that the hypervariable area in the CP maps to the N terminal flexible loop and includes the motif required for aphid transmission. Collectively, results described here show that potyviruses contain fixed hypervariable areas in key parts of the genome which provide mutational robustness and are potentially involved in host adaptation.

Project description:The Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 originated in bats and adapted to infect humans. Several SARS-CoV-2 strains have been identified. Genetic variation is fundamental to virus evolution and, in response to selection pressure, is manifested as the emergence of new strains and species adapted to different hosts or with novel pathogenicity. The combination of variation and selection forms a genetic footprint on the genome, consisting of the preferential accumulation of mutations in particular areas. Properties of betacoronaviruses contributing to variation and the emergence of new strains and species are beginning to be elucidated. To better understand their variation, we profiled the accumulation of mutations in all species in the genus Betacoronavirus, including SARS-CoV-2 and two other species that infect humans: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Variation profiles identified both genetically stable and variable areas at homologous locations across species within the genus Betacoronavirus. The S glycoprotein is the most variable part of the genome and is structurally disordered. Other variable parts include proteins 3 and 7 and ORF8, which participate in replication and suppression of antiviral defense. In contrast, replication proteins in ORF1b are the least variable. Collectively, our results show that variation and structural disorder in the S glycoprotein is a general feature of all members of the genus Betacoronavirus, including SARS-CoV-2. These findings highlight the potential for the continual emergence of new species and strains with novel biological properties and indicate that the S glycoprotein has a critical role in host adaptation. IMPORTANCE Natural infection with SARS-CoV-2 and vaccines triggers the formation of antibodies against the S glycoprotein, which are detected by antibody-based diagnostic tests. Our analysis showed that variation in the S glycoprotein is a general feature of all species in the genus Betacoronavirus, including three species that infect humans: SARS-CoV, SARS-CoV-2, and MERS-CoV. The variable nature of the S glycoprotein provides an explanation for the emergence of SARS-CoV-2, the differentiation of SARS-CoV-2 into strains, and the probability of SARS-CoV-2 repeated infections in people. Variation of the S glycoprotein also has important implications for the reliability of SARS-CoV-2 antibody-based diagnostic tests and the design and deployment of vaccines and antiviral drugs. These findings indicate that adjustments to vaccine design and deployment and to antibody-based diagnostic tests are necessary to account for S glycoprotein variation.

Project description:Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n?=?15,748; controls, n?=?18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n?=?14,160; controls, n?=?12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n?=?12,160; controls, n?=?16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value?=?1.9?×?10-6; top gene RORA, gene P value?=?0.0003), prostate (pathway P value?=?4.1?×?10-6; top gene ARNTL, gene P value?=?0.0002) and lung cancer (pathway P value?=?6.9?×?10-7; top gene RORA, gene P value?=?2.0?×?10-6), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC).Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Dataset Information

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

Publications

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

Similar Datasets

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