| 1. |
- Brüggemann, Anders
(author)
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Hip Revision Surgery : Identification of Genetic Markers and Evaluation of Novel Treatment Strategies
- 2020
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 2. |
- Bögl, Hans Peter, 1969-, et al.
(author)
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Increased rate of reoperation in atypical femoral fractures is related to patient characteristics and not fracture type : A nationwide cohort study
- 2020
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In: Osteoporosis International. - : SPRINGER LONDON LTD. - 0937-941X .- 1433-2965. ; 31:5, s. 951-959
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Journal article (peer-reviewed)abstract
- Atypical femoral fractures are burdened with a high rate of reoperation. In our nationwide analysis, the increased rate of reoperation was related to patient background characteristics, such as age and health status, rather than fracture type. Introduction Patients with atypical fractures are complex to treat and burdened with a high risk of reoperation. We hypothesized that patients with surgically treated, complete atypical fractures have a higher risk of any reoperation and reoperation related to healing complications than patients with common femoral shaft fractures but that this increase would become insignificant when adjusted for predefined characteristics. Methods A cohort of 163 patients with atypical fractures and 862 patients with common femoral shaft or subtrochanteric fractures treated from 2008 to 2010 and who had follow-up radiographs and register data available until 31 December 2014 was included. Reoperations were identified by a complementary review of radiographs and register data and were used to calculate risks for any reoperation and reoperations related to healing complications. Results Patients with atypical fractures were more likely to be reoperated for any reason, age-adjusted OR 1.76 (95% CI, 1.08 to 2.86). However, patients with common fractures had a shorter follow-up due to a threefold higher death rate. Accordingly, in a multivariable-adjusted time-to-event model, the increased risk lost statistical significance for any reoperations, cause-specific HR 1.34 (95% CI, 0.85 to 2.13), and for reoperations related to healing complications, HR 1.32 (95% CI, 0.58 to 3.0). Continued use of bisphosphonate in the first year after the fracture did not affect the reoperation rate. Conclusions Our findings suggest that the increased risk of reoperation after an atypical femur fracture is largely explained by patient characteristics and not fracture type.
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| 3. |
- Bögl, Hans Peter, et al.
(author)
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Reduced Risk of Reoperation Using Intramedullary Nailing with Femoral Neck Protection in Low-Energy Femoral Shaft Fractures
- 2020
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In: Journal of Bone and Joint Surgery. American volume. - : LIPPINCOTT WILLIAMS & WILKINS. - 0021-9355 .- 1535-1386. ; 102:17, s. 1486-1494
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Journal article (peer-reviewed)abstract
- Background: In Sweden, approximately 1 in 4 women who are >= 50 years of age will sustain a hip fracture. Patients treated for a femoral shaft fracture are likely to have an even higher risk. We hypothesized that intramedullary nails protecting the femoral neck reduce the risk of subsequent hip fracture and allow the patient to avoid a challenging reoperation.Methods: Between 2008 and 2010, 5,475 fractures of the femoral shaft, in patients who were >= 55 years of age, were registered in a national registry in Sweden. Of these patients, 897 fulfilled the inclusion criteria. We used radiographs and register data to identify the reasons for and the types of reoperation that occurred between the index surgical procedure and December 31, 2014. The categories of implants were determined through a review of radiographs as intramedullary nails with and without femoral neck protection. Reoperations related to peri-implant fractures (including hip fractures) were analyzed as a subgroup of all major reoperations. Multivariable-adjusted, cause-specific hazard ratios (HRs) were calculated to compare the risk of reoperation between cases with nails with and without femoral neck protection.Results: Among the 897 patients, a total of 82 reoperations were performed. In 640 patients who were treated with intramedullary nails with femoral neck protection, there were 7 peri-implant fractures (no hip fractures) and 27 major reoperations. Among the 257 patients who were treated with intramedullary nails without femoral neck protection, 14 peri-implant hip fractures and 24 major reoperations were identified. Patients who received nails with femoral neck protection had a lower hazard for any peri-implant fracture (multivariable-adjusted cause-specific HR, 0.19 [95% confidence interval (CI), 0.07 to 0.5]) and major reoperation (multivariable-adjusted cause-specific HR, 0.51 [95% CI, 0.28 to 0.92]).Conclusions: Intramedullary nails with femoral neck protection in the treatment of low-energy femoral shaft fractures prevent secondary hip fractures and decrease the overall risk of reoperation for 4 to 6 years postoperatively.
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| 4. |
- Folkersen, Lasse, et al.
(author)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Journal article (peer-reviewed)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 5. |
- Kaluza, Joanna, et al.
(author)
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Anti-inflammatory diet and risk of heart failure : two prospective cohort studies
- 2020
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:4, s. 676-682
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Journal article (peer-reviewed)abstract
- AimThe impact of the anti‐inflammatory potential of diet on risk of heart failure (HF) and the potential modification of this association by smoking, a trigger of systemic inflammation, has not been previously investigated. We examined the association between anti‐inflammatory potential of diet and risk of HF taking into account smoking status.Methods and resultsThe study population included the Cohort of Swedish Men (40 514 men) and the Swedish Mammography Cohort (34 809 women), age 45–83 years, without HF, ischaemic heart disease, or cancer at baseline. Anti‐inflammatory potential of diet was estimated using an anti‐inflammatory diet index (AIDI; 0–16 scores). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for HF risk factors. Over a mean follow‐up of 14.9 years (1 119 110 person‐years, 1998–2014), 8161 new HF diagnoses (4443 in men, 3718 in women) were identified. Compared to the lowest quintile of the AIDI (scores ≤4), the HRs for men and women in the highest quintile (scores ≥8) were 0.92 (95% CI 0.84–1.02; P‐trend = 0.02) and 0.86 (95% CI 0.78–0.96; P‐trend = 0.001), respectively. An inverse association between the AIDI and HF incidence was observed in current and ex‐smokers but not in never‐smokers (P‐interaction = 0.046). Comparing extreme quintiles, the HRs were 0.86 (95% CI 0.74–1.00; P‐trend = 0.007) in current smokers, 0.81 (95% CI 0.71–0.92; P‐trend = 0.001) in ex‐smokers, and 0.95 (95% CI 0.86–1.06; P‐trend = 0.10) in never‐smokers.ConclusionThese results suggest that adherence to a diet with high anti‐inflammatory potential may be associated with lower HF incidence in current and ex‐smokers.
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| 6. |
- Karlsson, Mikael, et al.
(author)
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Associations between dietary patterns at age 71 and the prevalence of sarcopenia 16 years later
- 2020
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In: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 39:4, s. 1077-1084
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: The growing recognition of the significance of sarcopenia has highlighted the need to understand etiologic factors, where food intake likely plays a role. The aim was to investigate the association between dietary patterns at mean age 71 and the prevalence of sarcopenia at mean age 87 in a Swedish cohort of community dwelling men.METHODS: Dietary habits were assessed using a 7-day food record. Adherences to official dietary guidelines, defined by the World Health Organization (WHO) by using the Healthy Diet Indicator, and Mediterranean-like dietary habits by using the Mediterranean Diet Score, were calculated. Sarcopenia was determined using the definition from the European Working Group on Sarcopenia in Older People (EWGSOP) and associations to each dietary pattern were analyzed using logistic regression, adjusted for potential confounders.RESULTS: Our study population included 254 men, mean age 71 at baseline, and 53 (21%) were defined as sarcopenic 16 years later. There was no linear relationship between increased adherence to WHO dietary guidelines and future prevalence of sarcopenia, although those with medium adherence seemed to be protected (crude OR = 0.41, 95% CI 0.19-0.92). On the other hand, an inverse relationship to sarcopenia was found for each SD increment in the Mediterranean diet score (crude OR = 0.68, 95% CI 0.46-0.99), which remained after adjusting for potential confounders. Sensitivity analysis indicated relationships to be independent of changes in physical activity and dietary misreporting.CONCLUSIONS: In this prospective study of elderly men, using a single measure of diet at age 71 as a reflection of habitual dietary habits, healthy dietary patterns tended to protect against the development of sarcopenia over 16 years. In particular, we found indications that increased adherence to a Mediterranean dietary pattern might be advantageous.
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| 7. |
- Larsson, Susanna C., et al.
(author)
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Alcohol Consumption and Cardiovascular Disease A Mendelian Randomization Study
- 2020
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 13:3, s. 121-127
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Journal article (peer-reviewed)abstract
- Background: The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases. Methods: Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale consortia and UK Biobank. Analyses were conducted using the inverse variance-weighted, weighted median, MR-PRESSO, MR-Egger, and multivariable MR methods. Results: Genetically predicted alcohol consumption was consistently associated with stroke and peripheral artery disease across the different analyses. The odds ratios (ORs) per 1-SD increase of log-transformed alcoholic drinks per week were 1.27 ([95% CI, 1.12-1.45]P=2.87x10(-4)) for stroke and 3.05 ([95% CI, 1.92-4.85]P=2.30x10(-6)) for peripheral artery disease in the inverse variance-weighted analysis. There was some evidence for positive associations of genetically predicted alcohol consumption with coronary artery disease (OR, 1.16 [95% CI, 1.00-1.36];P=0.052), atrial fibrillation (OR, 1.17 [95% CI, 1.00-1.37];P=0.050), and abdominal aortic aneurysm (OR, 2.60 [95% CI, 1.15-5.89];P=0.022) in the inverse variance-weighted analysis. These associations were somewhat attenuated in multivariable MR analysis adjusted for smoking initiation. There was no evidence of associations of genetically predicted alcohol consumption with heart failure (OR, 1.00 [95% CI, 0.68-1.47];P=0.996), venous thromboembolism (OR, 1.04 [95% CI, 0.77-1.39];P=0.810), and aortic valve stenosis (OR, 1.03 [95% CI, 0.56-1.90];P=0.926). Conclusions: This study provides evidence of a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral artery disease. The causal role of alcohol consumption for other cardiovascular diseases requires further research.
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| 8. |
- Larsson, Susanna C., et al.
(author)
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Genetic predisposition to smoking in relation to 14 cardiovascular diseases
- 2020
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 41:35, s. 3304-3310
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Journal article (peer-reviewed)abstract
- AIMS: The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).METHODS AND RESULTS: Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.CONCLUSION: This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.
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| 9. |
- Larsson, Susanna C., et al.
(author)
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Genetically proxied milk consumption and risk of colorectal, bladder, breast, and prostate cancer : a two-sample Mendelian randomization study
- 2020
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Observational studies have shown that milk consumption is inversely associated with colorectal, bladder, and breast cancer risk, but positively associated with prostate cancer. However, whether the associations reflect causality remains debatable. We investigated the potential causal associations of milk consumption with the risk of colorectal, bladder, breast, and prostate cancer using a genetic variant near the LCT gene as proxy for milk consumption.METHODS: We obtained genetic association estimates for cancer from the UK Biobank (n = 367,643 women and men), FinnGen consortium (n = 135,638 women and men), Breast Cancer Association Consortium (n = 228,951 women), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254 men). Milk consumption was proxied by a genetic variant (rs4988235 or rs182549) upstream of the gene encoding lactase, which catalyzes the breakdown of lactose.RESULTS: Genetically proxied milk consumption was associated with a reduced risk of colorectal cancer. The odds ratio (OR) for each additional milk intake increasing allele was 0.95 (95% confidence interval [CI] 0.91-0.99; P = 0.009). There was no overall association of genetically predicted milk consumption with bladder (OR 0.99; 95% CI 0.94-1.05; P = 0.836), breast (OR 1.01; 95% CI 1.00-1.02; P = 0.113), and prostate cancer (OR 1.01; 95% CI 0.99-1.02; P = 0.389), but a positive association with prostate cancer was observed in the FinnGen consortium (OR 1.07; 95% CI 1.01-1.13; P = 0.026).CONCLUSIONS: Our findings strengthen the evidence for a protective role of milk consumption on colorectal cancer risk. There was no or limited evidence that milk consumption affects the risk of bladder, breast, and prostate cancer.
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| 10. |
- Larsson, Susanna C., et al.
(author)
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IGF-1 and cardiometabolic diseases : a Mendelian randomisation study
- 2020
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In: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:9, s. 1775-1782
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Abnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases. Methods Serum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 individuals in UK Biobank. Genetic association estimates for the outcomes were obtained from consortia of type 2 diabetes (74,124 cases, 824,006 controls), coronary artery disease (60,801 cases, 123,504 controls), heart failure (47,309 cases, 930,014 controls), atrial fibrillation (65,446 cases, 522,744 controls), and ischaemic stroke (60,341 cases, 454,450 controls). Results Genetic predisposition to elevated serum IGF-1 levels was associated with higher risk of type 2 diabetes and coronary artery disease. The OR (95% CI) per SD increment in IGF-1 level was 1.14 (1.05, 1.24) for type 2 diabetes and 1.09 (1.02, 1.16) for coronary artery disease. The association between IGF-1 and coronary artery disease was attenuated after adjustment for type 2 diabetes (OR 1.06 [95% CI 1.00, 1.13]), suggesting that the association may be partly mediated via type 2 diabetes. There was limited evidence of associations between IGF-1 levels and heart failure, atrial fibrillation and ischaemic stroke. Conclusions/interpretation This study found evidence that increased IGF-1 levels may be causally associated with higher risk of type 2 diabetes.
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