| 31. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 32. |
- Schofield, James P. R., et al.
(författare)
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Topological data analysis (TDA) of U-BIOPRED paediatric peripheral blood gene expression identified asthma phenotypes characterised by alternative splicing of glucocorticoid receptor (GR) mRNA
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Molecular stratification of childhood asthma could enable targeted therapy.Aims: Unbiased analysis of gene expression in paediatric severe (SA) and moderate/mild asthma (MA) blood samples to identify sub-phenotypes.Methods: Transcriptomic profiling by microarray analysis of blood from the U-BIOPRED paediatric cohort (Fleming ERJ 2015), pre- and school-age children, (SApre, n=62; MApre, n=42; SAsc, n=75 and MAsc, n=37). Topological data analysis (TDA) was used for unbiased clustering.Results: Sub-phenotypes, P1, P2, P3 and P4 were identified and are highlighted in the TDA network in the figure and a heatmap of selected variables. P1 (38% of the cohort, median 11 yrs) was characterised by low expression of glucocorticoid receptor (GR) mRNA splice variant with a long 3’ UTR (q = 2.43E-17), but no significant difference in the expression of glucocorticoid receptor (GR) mRNA splice variant with a short 3’ UTR. In P1, COX2 expression was up (q = 1.89E-06) and IFN-γ was down (q = 5.61E-06), characteristics of a decreased steroid response.Conclusion: Unbiased analysis of U-BIOPRED paediatric peripheral blood gene expression identified a sub-phenotype, P1, with an inhibited steroid response. P1 is associated with low expression of a splice variant of GR with a long 3’ UTR.
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| 33. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 34. |
- Brem, Jürgen, et al.
(författare)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
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Ingår i: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
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Tidskriftsartikel (refereegranskat)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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| 35. |
- Jiang, Jiyang, et al.
(författare)
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A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood
- 2018
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of similar to 5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 x 10(-35)), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the "COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.
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| 36. |
- Pershad, K., et al.
(författare)
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Generating a panel of highly specific antibodies to 20 human SH2 domains by phage display
- 2010
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 23:4, s. 279-288
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Tidskriftsartikel (refereegranskat)abstract
- To demonstrate the utility of phage display in generating highly specific antibodies, affinity selections were conducted on 20 related Src Homology 2 (SH2) domains (ABL1, ABL2, BTK, BCAR3, CRK, FYN, GRB2, GRAP2, LYN, LCK, NCK1, PTPN11 C, PIK3R1 C, PLC gamma 1 C, RASA1 C, SHC1, SH2D1A, SYK N, VAV1 and the tandem domains of ZAP70). The domains were expressed in Escherichia coli, purified and used in affinity selection experiments. In total, 1292/3800 of the resultant antibodies were shown to bind the target antigen. Of the 695 further evaluated in specificity ELISAs against all 20 SH2 domains, 379 antibodies were identified with unique specificity (i.e. monospecific). Sequence analysis revealed that there were at least 150 different clones with 1-19 different antibodies/antigen. This includes antibodies that distinguish between ABL1 and ABL2, despite their 89% sequence identity. Specificity was confirmed for many on protein arrays fabricated with 432 different proteins. Thus, even though the SH2 domains share a common three-dimensional structure and 20-89% identity at the primary structure level, we were able to isolate antibodies with exquisite specificity within this family of structurally related domains.
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| 37. |
- Schofield, Peter R, et al.
(författare)
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Ethnic density, urbanicity and psychosis risk for migrant groups - A population cohort study
- 2017
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964. ; 190, s. 82-87
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rates of psychotic disorder are raised for many migrant groups. Understanding the role played by the social context in which they live may help explain why. This study investigates the effect of both neighbourhood ethnic density and urbanicity on the incidence of non-affective psychosis for migrant groups. Method: Population based cohort of all those born 1965 or later followed from their 15th birthday (2,224,464 people) to 1st July 2013 (37,335,812 person years). Neighbourhood exposures were measured at age 15. Results: For all groups incidence of non-affective psychosis was greater in lower ethnic density neighbourhoods. For migrants of African origin there was a 1.94-fold increase (95% CI, 1.17-3.23) comparing lowest and highest density quintiles; with similar effects for migrants from Europe (excluding Scandinavia): incidence rate ratio (IRR) 1.99 (95% CI, 1.56-2.54); Asia: IRR 1.63 (95% CI, 1.02-2.59); and the Middle East: IRR 1.68 (95% CI, 1.19-2.38). This initial analysis found no evidence for an urbanicity effect for migrant groups. Adjusting for ethnic density revealed a positive association between level of urbanicity and psychosis for two groups, with a statistically significant linear trend (average effect of a one quintile increase) for migrants from Europe: IRR 1.09 (95% CI, 1.02-1.16) and the Middle East: IRR 1.12 (95% CI, 1.01-1.23). Conclusions: In this first nationwide population-based study of ethnic density, urbanicity and psychosis we show that lower ethnic density is associated with increased incidence of non-affective psychosis for different migrant groups; masking urban/rural differences in psychosis for some groups.
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| 38. |
- Schofield, Peter R, et al.
(författare)
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Neighbourhood ethnic density and psychosis - Is there a difference according to generation?
- 2018
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964. ; 195, s. 501-505
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Tidskriftsartikel (refereegranskat)abstract
- Background: For different migrant groups living in an area with few people from the same ethnic background is associated with increased psychosis incidence (the ethnic density effect). We set out to answer the question: are there generational differences in this effect? Methods: Analysis of a population based cohort (2.2 million) comprising all those born 1st January 1965, or later, living in Denmark on their 15th birthday. This included 90,476 migrants from Africa, Europe (excluding Scandinavia) and the Middle East, with 55% first generation and the rest second-generation migrants. Neighbourhood co-ethnic density was determined at age 15 and we adjusted for age, gender, calendar period, parental psychiatric history and parental income. Results: For first-generation migrants from Africa, there was no statistically significant difference (p = 0.30) in psychosis rates when comparing lowest with highest ethnic density quintiles, whereas the second generation showed a 3.87-fold (95% CI 1.77-8.48) increase. Similarly, for migrants from the Middle East, the first generation showed no evidence of an ethnic density effect (p = 0.94) while the second showed a clear increase in psychosis when comparing lowest with highest quintiles, incidence rate ratio (IRR) 2.43 (95% CI, 1.18-5.00). For European migrants, there was some limited evidence of an effect in the first generation, (IRR) 1.69 (95% CI, 1.19-2.40), with this slightly raised in the second: IRR 1.80 (95% CI, 1.27-2.56). Conclusions: We found strong evidence for an ethnic density effect on psychosis incidence for second-generation migrants but this was either weak or absent for the first generation.
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| 39. |
- Semb, Gunvor, et al.
(författare)
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A Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 1. Planning and management.
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - : Taylor & Francis. - 2000-656X .- 2000-6764. ; 51:1, s. 2-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Longstanding uncertainty surrounds the selection of surgical protocols for the closure of unilateral cleft lip and palate, and randomised trials have only rarely been performed. This paper is an introduction to three randomised trials of primary surgery for children born with complete unilateral cleft lip and palate (UCLP). It presents the protocol developed for the trials in CONSORT format, and describes the management structure that was developed to achieve the long-term engagement and commitment required to complete the project.METHOD: Ten established national or regional cleft centres participated. Lip and soft palate closure at 3-4 months, and hard palate closure at 12 months served as a common method in each trial. Trial 1 compared this with hard palate closure at 36 months. Trial 2 compared it with lip closure at 3-4 months and hard and soft palate closure at 12 months. Trial 3 compared it with lip and hard palate closure at 3-4 months and soft palate closure at 12 months. The primary outcomes were speech and dentofacial development, with a series of perioperative and longer-term secondary outcomes.RESULTS: Recruitment of 448 infants took place over a 9-year period, with 99.8% subsequent retention at 5 years.CONCLUSION: The series of reports that follow this introductory paper include comparisons at age 5 of surgical outcomes, speech outcomes, measures of dentofacial development and appearance, and parental satisfaction. The outcomes recorded and the numbers analysed for each outcome and time point are described in the series.TRIAL REGISTRATION: ISRCTN29932826.
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