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Sökning: WFRF:(Chubb Daniel)

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1.
  • Freitag, Daniel F., et al. (författare)
  • Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
  • 2015
  • Ingår i: The Lancet Diabetes & Endocrinology. - : Elsevier. - 2213-8595. ; 3:4, s. 243-253
  • Tidskriftsartikel (refereegranskat)abstract
    • Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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2.
  • Wang, Yufei, et al. (författare)
  • Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer
  • 2014
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 46:7, s. 736-741
  • Tidskriftsartikel (refereegranskat)abstract
    • We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
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3.
  • Broderick, Peter, et al. (författare)
  • Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk
  • 2012
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 44:1, s. 58-83
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 x 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 x 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 x 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.
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4.
  • Chubb, Daniel, et al. (författare)
  • Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk
  • 2013
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 45:10, s. 366-1221
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 x 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 x 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 x 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 x 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.
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5.
  • Chubb, Daniel, et al. (författare)
  • The Efficacy of Clinical Assessment in the Postoperative Monitoring of Free Flaps : A Review of 1140 Consecutive Cases
  • 2010
  • Ingår i: Plastic and reconstructive surgery (1963). - 0032-1052 .- 1529-4242. ; 125:4, s. 1157-1166
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Effective postoperative monitoring of the vascular pedicle to a free flap can potentiate rapid return to the operating room in the setting of compromise, allowing for the potential to salvage the flap. The only ubiquitous method for postoperative monitoring of free flaps is clinical bedside monitoring, but although the use of clinical monitoring may be inferred in large reported series of free flaps, there has been little discussed in the literature of specific clinical outcome measures. Methods: The authors present their experience with 1140 consecutive cases of free tissue transfer and the use of clinical monitoring as a sole method of monitoring, and subgroup analysis of different recipient sites. Results: There were 94 take-backs, four of which had no pedicle compromise (false-positives) and there were four false-negatives. The overall flap salvage rate was 62.8 percent and the false-positive rate was 0.4 percent. Subgroup analyses demonstrated statistically significant differences between recipient sites for the false-positive rates: fewer false-positives with breast reconstruction cases (p < 0.05) and significantly more false-positives in the extremity group (p < 0.05). There was an improved flap salvage rate in cases of venous compromise compared with arterial compromise (69 percent versus 51 percent, p = 0.015). Conclusions: This largest reported series to date provides an outcome-based analysis of postoperative monitoring for free flaps, providing a benchmark standard against which adjunctive monitoring techniques can be compared. Future studies need to be assessed in the context of individual recipient sites, with significant differences in monitoring outcomes between sites.
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6.
  • Meyer, Esther, et al. (författare)
  • Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
  • 2017
  • Ingår i: Nature genetics. - 1546-1718. ; 49
  • Tidskriftsartikel (refereegranskat)abstract
    • Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
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7.
  • Rozen, Warren M, et al. (författare)
  • The efficacy of postoperative monitoring : A single surgeon comparison of clinical monitoring and the implantable Doppler probe in 547 consecutive free flaps
  • 2010
  • Ingår i: Microsurgery. - 0738-1085 .- 1098-2752. ; 30:2, s. 105-110
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: An important element in achieving high success rates with free flap surgery has been the use of different techniques for monitoring flaps postoperatively as a means to detecting vascular compromise. Successful monitoring of the vascular pedicle to a flap can potentiate rapid return to theater in the setting of compromise, with the potential to salvage the flap. There is little evidence that any technique offers any advantage over clinical monitoring alone. Methods: A consecutive series of 547 patients from a single plastic surgical unit who underwent a fasciocutaneous free flap operation for breast reconstruction [deep inferior epigastric artery perforator (DIEP) flap, superficial interior epigastric artery l flap, or superior gluteal artery perforator (SGAP) flap] were included. A comparison was made between the first 426 consecutive patients in whom flap monitoring was performed using clinical monitoring alone and the subsequent 121 patients in whom monitoring was achieved with the Cook-Swartz implantable Doppler probe. Outcome measures included flap salvage rate and false-positive rate. Results: There was a strong trend toward improved salvage rates with the implantable Doppler probe compared with clinical monitoring (80% vs. 66%, P = 0.48). When combined with the literature (meta-analysis), the data prove statistically significant (P < 0.01). There was no statistical difference between the groups for false-positive rates. Conclusion: Flap monitoring with the implantable Doppler probe can improve flap salvage rates without increasing the rate of false-positive takebacks.
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9.
  • Weinhold, Niels, et al. (författare)
  • The CCND1 c.870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma
  • 2013
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 45:5, s. 522-525
  • Tidskriftsartikel (refereegranskat)abstract
    • A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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10.
  • Whitaker, Iain S., et al. (författare)
  • Postoperative Monitoring of Free Flaps in Autologous Breast Reconstruction : A Multicenter Comparison of 398 Flaps Using Clinical Monitoring, Microdialysis, and the Implantable Doppler Probe
  • 2010
  • Ingår i: Journal of reconstructive microsurgery. - 0743-684X .- 1098-8947. ; 26:6, s. 409-416
  • Tidskriftsartikel (refereegranskat)abstract
    • Many techniques for flap monitoring following free tissue transfer have been described; however, there is little evidence that any of these techniques allow for greater rates of flap salvage over clinical monitoring alone. We sought to compare three established monitoring techniques across three experienced microsurgical centers in a comparable cohort of patients. A retrospective, matched cohort study of 398 consecutive free flaps in 347 patients undergoing autologous breast reconstruction was undertaken across three institutions during the same 3-year period, with a single form of postoperative monitoring used at each institution: clinical monitoring alone, the Cook-Swartz implantable Doppler probe, or microdialysis. Both objective and subjective measures of efficacy were assessed. Clinical monitoring alone, the implantable Doppler probe, and microdialysis showed statistically similar rates of flap salvage. False-negative rates were also statistically similar (only seen in the clinically monitored group). However, there was a statistically significant increase in false-positive alarms causing needless take-backs to theater in the microdialysis and implantable Doppler arms, p < 0.001. This study did not find any technique superior to clinical monitoring alone. New monitoring technologies should be compared objectively with clinical monitoring as the current standard in postoperative flap monitoring.
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