| 1. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 2. |
- Yang, Jian, et al.
(författare)
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FTO genotype is associated with phenotypic variability of body mass index
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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| 3. |
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| 4. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 5. |
- Carlströmer Berthén, Nellie, et al.
(författare)
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The AxBioTick Study: Borrelia Species and Tick-Borne Encephalitis Virus in Ticks, and Clinical Responses in Tick-Bitten Individuals on the Aland Islands, Finland
- 2023
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- The AxBioTick Study: Borrelia Species and Tick-Borne Encephalitis Virus in Ticks, and Clinical Responses in Tick-Bitten Individuals on the Aland Islands, Finlandby Nellie Carlströmer Berthén 1,2,*,† , Eszter Tompa 3,† , Susanne Olausson 1,2, Clara Nyberg 1, Dag Nyman 1,2, Malin Ringbom 1,4, Linda Perander 1,4, Joel Svärd 3, Per-Eric Lindgren 3,5, Pia Forsberg 3, Peter Wilhelmsson 3,5,‡, Johanna Sjöwall 3,6,‡ and Marika Nordberg 1,4,‡ 1Borrelia Research Group of the Aland Islands, 22100 Mariehamn, The Aland Islands, Finland2Bimelix AB, 22100 Mariehamn, The Aland Islands, Finland3Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linkoping University, 581 83 Linkoping, Sweden4The Aland Islands Healthcare Services, 22100 Mariehamn, The Aland Islands, Finland5Clinical Microbiology, Laboratory Medicine, County Hospital Ryhov, 551 85 Jonkoping, Sweden6Department of Infectious Diseases, Vrinnevi Hospital, 603 79 Norrkoping, Sweden*Author to whom correspondence should be addressed.†These authors contributed equally to the study.‡These authors contributed equally to the study.Microorganisms 2023, 11(5), 1100; https://doi.org/10.3390/microorganisms11051100Received: 30 March 2023 / Revised: 17 April 2023 / Accepted: 19 April 2023 / Published: 22 April 2023(This article belongs to the Special Issue Research on Ticks and Tick-Borne Pathogens)Download Browse Figures Versions NotesArticle Views585 AbstractThe AxBioTick study was initiated to investigate the prevalence of ticks and tick-borne pathogens and their impact on antibody and clinical responses in tick-bitten individuals on the Aland Islands. This geographical area is hyperendemic for both Lyme borreliosis (LB) and Tick-borne encephalitis (TBE). Blood samples and ticks were collected from 100 tick-bitten volunteers. A total of 425 ticks was collected, all determined to Ixodes ricinus using molecular tools. Of them 20% contained Borrelia species, of which B. garinii and B. afzelii were most common. None contained the TBE virus (TBEV). Blood samples were drawn in conjunction with the tick bite, and eight weeks later. Sera were analyzed for Borrelia- and TBEV-specific antibodies using an ELISA and a semiquantitative antibody assay. In total 14% seroconverted in Borrelia C6IgG1, 3% in TBEV IgG, and 2% in TBEV IgM. Five participants developed clinical manifestations of LB. The high seroprevalence of both Borrelia (57%) and TBEV (52%) antibodies are likely attributed to the endemic status of the corresponding infections as well as the TBE vaccination program. Despite the similar prevalence of Borrelia spp. detected in ticks in other parts of Europe, the infection rate in this population is high. The AxBioTick study is continuing to investigate more participants and ticks for co-infections, and to characterize the dermal immune response following a tick bite.
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| 6. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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| 7. |
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| 8. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 9. |
- Draxler, Joar, et al.
(författare)
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A numerical model for simulating the effect of strain rate on eutectic band thickness
- 2020
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Ingår i: Welding in the World. - : Springer. - 0043-2288 .- 1878-6669. ; 64:10, s. 1635-1658
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Tidskriftsartikel (refereegranskat)abstract
- Large tensile strains acting on the solidifying weld metal can cause the formation of eutectic bands along grain boundaries. These eutectic bands can lead to severe liquation in the partially melted zone of a subsequent overlapping weld. This can increase the risk of heat-affected zone liquation cracking. In this paper, we present a solidification model for modeling eutectic bands. The model is based on solute convection in grain boundary liquid films induced by tensile strains. The proposed model was used to study the influence of strain rate on the thickness of eutectic bands in Alloy 718. It was found that when the magnitude of the strain rate is 10 times larger than that of the solidification rate, the calculated eutectic band thickness is about 200 to 500% larger (depending on the solidification rate) as compared to when the strain rate is zero. In the paper, we also discuss how eutectic bands may form from hot cracks.
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| 10. |
- Draxler, Joar, et al.
(författare)
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Modeling and simulation of weld solidification cracking part I : A pore-based crack criterion
- 2019
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Ingår i: Welding in the World. - : Springer. - 0043-2288 .- 1878-6669. ; 63:5, s. 1489-1502
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Tidskriftsartikel (refereegranskat)abstract
- Several advanced alloy systems are susceptible to weld solidification cracking. One example is nickel-based superalloys, which are commonly used in critical applications such as aerospace engines and nuclear power plants. Weld solidification cracking is often expensive to repair and, if not repaired, can lead to catastrophic failure. This study, presented in three papers, presents an approach for simulating weld solidification cracking applicable to large-scale components. The results from finite element simulation of welding are post-processed and combined with models of metallurgy, as well as the behavior of the liquid film between the grain boundaries, in order to estimate the risk of crack initiation. The first paper in this study describes the crack criterion for crack initiation in a grain boundary liquid film. The second paper describes the model for computing the pressure and the thickness of the grain boundary liquid film, which are required to evaluate the crack criterion in paper 1. The third and final paper describes the application of the model to Varestraint tests of alloy 718. The derived model can fairly well predict crack locations, crack orientations, and crack widths for the Varestraint tests. The importance of liquid permeability and strain localization for the predicted crack susceptibility in Varestraint tests is shown.
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| 11. |
- Draxler, Joar, et al.
(författare)
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Modeling and simulation of weld solidification cracking part II : A model for estimation of grain boundary liquid pressure in a columnar dendritic microstructure
- 2019
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Ingår i: Welding in the World. - : Springer Science and Business Media LLC. - 0043-2288 .- 1878-6669. ; 63:5, s. 1503-1519
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Tidskriftsartikel (refereegranskat)abstract
- Several advanced alloy systems are susceptible to weld solidification cracking. One example is nickel-based superalloys, which are commonly used in critical applications such as aerospace engines and nuclear power plants. Weld solidification cracking is often expensive to repair, and if not repaired, can lead to catastrophic failure. This study, presented in three papers, presents an approach for simulating weld solidification cracking applicable to large-scale components. The results from finite element simulation of welding are post-processed and combined with models of metallurgy, as well as the behavior of the liquid film between the grain boundaries, in order to estimate the risk of crack initiation. The first paper in this study describes the crack criterion for crack initiation in a grain boundary liquid film. The second paper describes the model for computing the pressure and the thickness of the grain boundary liquid film, which are required to evaluate the crack criterion in paper 1. The third and final paper describes the application of the model to Varestraint tests of Alloy 718. The derived model can fairly well predict crack locations, crack orientations, and crack widths for the Varestraint tests. The importance of liquid permeability and strain localization for the predicted crack susceptibility in Varestraint tests is shown. © 2019, The Author(s).
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| 12. |
- Draxler, Joar, et al.
(författare)
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Modeling and simulation of weld solidification cracking part III : Simulation of solidification cracking in Varestraint tests of alloy 718
- 2019
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Ingår i: Welding in the World. - : Springer. - 0043-2288 .- 1878-6669. ; 63:6, s. 1883-1901
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Tidskriftsartikel (refereegranskat)abstract
- Several advanced alloy systems are susceptible to weld solidification cracking. One example is nickel-based superalloys, which are commonly used in critical applications such as aerospace engines and nuclear power plants. Weld solidification cracking is often expensive to repair, and if not repaired, can lead to catastrophic failure. This study, presented in three papers, presents an approach for simulating weld solidification cracking applicable to large-scale components. The results from finite element simulation of welding are post-processed and combined with models of metallurgy, as well as the behavior of the liquid film between the grain boundaries, in order to estimate the risk of crack initiation. The first paper in this study describes the crack criterion for crack initiation in a grain boundary liquid film. The second paper describes the model required to compute the pressure and thickness of the liquid film required in the crack criterion. The third and final paper describes the application of the model to Varestraint tests of alloy 718. The derived model can fairly well predict crack locations, crack orientations, and crack widths for the Varestraint tests. The importance of liquid permeability and strain localization for the predicted crack susceptibility in Varestraint tests is shown.
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| 13. |
- Emrich, Christina, et al.
(författare)
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Low Power Cryogenic Rad-hard LNAs for Space
- 2019
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Konferensbidrag (refereegranskat)abstract
- We present the design and implementation of a packaged cryogenic InP HEMT MMIC LNA for space borne applications. The particular module is part of the submillimetre wave instrument (SWI) band1 and band2 receiver channel development for the ESA Jupiter ICy moons Explorer mission (JUICE) programme. The main objective of the activity has been to develop a general connectorized rad-hard LNA package for space applications, and to qualify the cryogenic InP HEMT MMIC process at Chalmers University of Tehnology which today covers a frequency range up to the W-band with state-of-the-art performance in terms of noise, gain and power dissipation. The activity has currently moved from a pre-qualification phase to a lot acceptance test (LAT) phase and has up till now included various environmental tests e.g. vibration, total dose radiation tests up to 300kRad on die level, and thermal cycling both to hot and cold temperatures. The InP HEMT MMIC process can be operated at ultra low power with ultra low noise which makes it an excellent candidate for deep space missions and satellite communication links, but also for the next generation of radioastronomy telescopes based on cryogenic receivers e.g. HEB and SIS multipixel cameras.
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| 14. |
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| 15. |
- Geier, Joel E., et al.
(författare)
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Simplified representative models for long-term flow and advective transport in fractured crystalline bedrock
- 2019
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Ingår i: Hydrogeology Journal. - : Springer Science and Business Media LLC. - 1431-2174 .- 1435-0157. ; 27:2, s. 595-614
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Tidskriftsartikel (refereegranskat)abstract
- Simplified representative models (SRMs) of the hydrogeological system at radioactive-waste repository sites are presented and demonstrated to give useful predictions of the key hydrogeological factors affecting long-term safety. The SRM is constructed from complex site-descriptive models, which have been developed to be consistent with detailed site information and data from short-term (with duration of days, weeks, up to months) field experiments, by keeping elements that are important for long-term predictions into thousands of years and simplifying features of less importance. The simplified approach relies only on fundamental hydrogeological principles and the mathematics can be kept relatively simple. The purpose of SRM is to provide a means of verifying predictions from complex numerical models, with an approach that is easy to evaluate and allows transparent evaluation of factors influencing long-term results. The approach is applied to evaluations of sites for two repositories in fractured crystalline bedrock in Sweden: one for spent nuclear fuel rod assemblies and one for waste with lower levels of radioactivity. The results indicate that the SRMs are able to yield results similar to those of calculations based on much more complex models. Further, the approach allows an evaluation of additional sources of uncertainty that are difficult or expensive to conduct with the complex models. These capabilities make SRMs a very useful and transparent tool for regulatory review.
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| 16. |
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| 17. |
- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 18. |
- Gummesson, Anders, 1973, et al.
(författare)
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Non-alcoholic fatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects: A cross-sectional, population-based study in middle-aged subjects
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study aims to estimate the relationship between non-alcoholic fatty liver disease (NAFLD) and measures of atherosclerotic cardiovascular disease (ASCVD), and to determine to what extent such relationships are modified by metabolic risk factors. The study was conducted in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort (n = 1015, age 50-64 years, 51.2% women). NAFLD was defined as computed tomography liver attenuation <= 40 Hounsfield Units, excluding other causes of liver fat. Coronary artery calcification score (CACS) was assessed using the Agatston method. Carotid plaques and intima media thickness (IMT) were measured by ultrasound. Metabolic status was based on assessments of glucose homeostasis, serum lipids, blood pressure and inflammation. A propensity score model was used to balance NAFLD and non NAFLD groups with regards to potential confounders and associations between NAFLD status and ASCVD variables in relation to metabolic status were examined by logistic and generalized linear regression models. NAFLD was present in 106 (10.4%) of the subjects and strongly associated with obesity-related traits. NAFLD was significantly associated with CACS after adjustment for confounders and metabolic risk factors (OR 1.77, 95% CI 1.07-2.94), but not with carotid plaques and IMT. The strongest association between NAFLD and CACS was observed in subjects with few metabolic risk factors (n = 612 [60% of all] subjects with 0-1 out of 7 predefined metabolic risk factors; OR 5.94, 95% CI 2.13-16.6). NAFLD was independently associated with coronary artery calcification but not with measures of carotid atherosclerosis in this cohort. The association between NAFLD and CACS was most prominent in the metabolically healthy subjects.
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| 19. |
- Hedayati, Ali, 1984-, et al.
(författare)
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Ash Transformation during Fixed-Bed Combustion of Agricultural Biomass with a Focus on Potassium and Phosphorus
- 2022
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Ingår i: Energy & Fuels. - : American Chemical Society (ACS). - 0887-0624 .- 1520-5029. ; 36:7, s. 3640-3653
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Tidskriftsartikel (refereegranskat)abstract
- In this study, ash transformation during fixed-bed combustion of different agricultural opportunity fuels was investigated with a special focus on potassium (K) and phosphorus (P). The fuel pellets were combusted in an underfed fixed-bed pellet burner. Residual ashes (bottom ash and slag) and particulate matter were collected and characterized by scanning electron microscopy-energy-dispersive X-ray spectroscopy, X-ray diffraction, inductively coupled plasma, and ion chromatography. The interpretation of the results was supported by thermodynamic equilibrium calculations. For all fuels, almost all P (>97%) was found in residual-/coarse ash fractions, while K showed different degrees of volatilization, depending on fuel composition. During combustion of poplar, which represents Ca-K-rich fuels, a carbonate melt rich in K and Ca decomposed into CaO, CO2, and gaseous K species at sufficiently high temperatures. Ca5(PO4)3OH was the main P-containing crystalline phase in the bottom ash. For wheat straw and grass, representing Si-K-rich fuels, a lower degree of K volatilization was observed than for poplar. P was found here in amorphous phosphosilicates and CaKPO4. For wheat grain residues, representing P-K-rich fuels, a high degree of both K and P retention was observed due to the interaction of K and P with the fuel-bed constituents, i.e., char, ash, and slag. The residual ash was almost completely melted and rich in P, K, and Mg. P was found in amorphous phosphates and different crystalline phases such as KMgPO4, K2CaP2O7, K2MgP2O7, and K4Mg4(P2O7)3. In general, the results therefore imply that an interaction between ash-forming elements in a single burning fuel particle and the surrounding bed ash or slag is important for the overall retention of P and K during fuel conversion in fixed-bed combustion of agricultural biomass fuels.
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| 20. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 21. |
- Ikram, M. Arfan, et al.
(författare)
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Common variants at 6q22 and 17q21 are associated with intracranial volume
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 539-544
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Tidskriftsartikel (refereegranskat)abstract
- During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
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| 22. |
- Johansson, Jonny, et al.
(författare)
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Project: EISCAT 3D
- 2007
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Annan publikation (populärvet., debatt m.m.)
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| 23. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 24. |
- Justice, A. E., et al.
(författare)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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| 25. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 26. |
- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
-
Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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| 27. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 28. |
- Langner, Taro, et al.
(författare)
-
Kidney segmentation in neck-to-knee body MRI of 40,000 UK Biobank participants
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- The UK Biobank is collecting extensive data on health-related characteristics of over half a million volunteers. The biological samples of blood and urine can provide valuable insight on kidney function, with important links to cardiovascular and metabolic health. Further information on kidney anatomy could be obtained by medical imaging. In contrast to the brain, heart, liver, and pancreas, no dedicated Magnetic Resonance Imaging (MRI) is planned for the kidneys. An image-based assessment is nonetheless feasible in the neck-to-knee body MRI intended for abdominal body composition analysis, which also covers the kidneys. In this work, a pipeline for automated segmentation of parenchymal kidney volume in UK Biobank neck-to-knee body MRI is proposed. The underlying neural network reaches a relative error of 3.8%, with Dice score 0.956 in validation on 64 subjects, close to the 2.6% and Dice score 0.962 for repeated segmentation by one human operator. The released MRI of about 40,000 subjects can be processed within one day, yielding volume measurements of left and right kidney. Algorithmic quality ratings enabled the exclusion of outliers and potential failure cases. The resulting measurements can be studied and shared for large-scale investigation of associations and longitudinal changes in parenchymal kidney volume.
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| 29. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
-
Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 30. |
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| 31. |
- Lim, Elaine T, et al.
(författare)
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Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.
- 2014
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10-8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10-117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10-4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
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| 32. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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| 33. |
- Lindgren, Cecilia M, et al.
(författare)
-
Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
-
Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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| 34. |
- Lindgren, Joel, 1982-, et al.
(författare)
-
A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life
- 2014
-
Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 102:3, s. 252-259
-
Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2<2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.
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| 35. |
- Lindgren, Joel, et al.
(författare)
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A Native Chemical Ligation Approach for Combinatorial Assembly of Affibody Molecules
- 2012
-
Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 13:7, s. 1024-1031
-
Tidskriftsartikel (refereegranskat)abstract
- Affinity molecules labeled with different reporter groups, such as fluorophores or radionuclides, are valuable research tools used in a variety of applications. One class of engineered affinity proteins is Affibody molecules, which are small (6.5 kDa) proteins that can be produced by solid phase peptide synthesis (SPPS), thereby allowing site-specific incorporation of reporter groups during synthesis. The Affibody molecules are triple-helix proteins composed of a variable part, which gives the protein its binding specificity, and a constant part, which is identical for all Affibody molecules. In the present study, native chemical ligation (NCL) has been applied for combinatorial assembly of Affibody molecules from peptide fragments produced by Fmoc SPPS. The concept is demonstrated for the synthesis of three different Affibody molecules. The cysteine residue introduced at the site of ligation can be used for directed immobilization and does not interfere with the function of the investigated proteins. This strategy combines a high-yield production method with facilitated preparation of proteins with different C-terminal modifications.
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| 36. |
- Lindgren, Joel, 1982-
(författare)
-
Chemical Engineering of Small Affinity Proteins
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small robust affinity proteins have shown great potential for use in therapy, in vivo diagnostics, and various biotechnological applications. However, the affinity proteins often need to be modified or functionalized to be successful in many of these applications. The use of chemical synthesis for the production of the proteins can allow for site-directed functionalization not achievable by recombinant routes, including incorporation of unnatural building blocks. This thesis focuses on chemical engineering of Affibody molecules and an albumin binding domain (ABD), which both are three-helix bundle proteins of 58 and 46 amino acids, respectively, possible to synthesize using solid phase peptide synthesis (SPPS).In the first project, an alternative synthetic route for Affibody molecules using a fragment condensation approach was investigated. This was achieved by using native chemical ligation (NCL) for the condensation reaction, yielding a native peptide bond at the site of ligation. The constant third helix of Affibody molecules enables a combinatorial approach for the preparation of a panel of different Affibody molecules, demonstrated by the synthesis of three different Affibody molecules using the same helix 3 (paper I).In the next two projects, an Affibody molecule targeting the amyloid-beta peptide, involved in Alzheimer’s disease, was engineered. Initially the N-terminus of the Affibody molecule was shortened resulting in a considerably higher synthetic yield and higher binding affinity to the target peptide (paper II). This improved variant of the Affibody molecule was then further engineered in the next project, where a fluorescently silent variant was developed and successfully used as a tool to lock the amyloid-beta peptide in a β-hairpin conformation during studies of copper binding using fluorescence spectroscopy (paper III).In the last two projects, synthetic variants of ABD, interesting for use as in vivo half-life extending partners to therapeutic proteins, were engineered. In the first project the possibility to covalently link a bioactive peptide, GLP-1, to the domain was investigated. This was achieved by site-specific thioether bridge-mediated cross-linking of the molecules via a polyethylene glycol (PEG)-based spacer. The conjugate showed retained high binding affinity to human serum albumin (HSA) and a biological activity comparable to a reference GLP-1 peptide (paper IV). In the last project, the possibility to increase the proteolytic stability of ABD through intramolecular cross-linking, to facilitate its use in e.g. oral drug delivery applications, was investigated. A tethered variant of ABD showed increased thermal stability and a considerably higher proteolytic stability towards pepsin, trypsin and chymotrypsin, three important proteases found in the gastrointestinal (GI) tract (paper V).Taken together, the work presented in this thesis illustrates the potential of using chemical synthesis approaches in protein engineering.
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| 37. |
- Lindgren, Joel, et al.
(författare)
-
Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (A beta) peptide in monomeric form : Low pH was found to reduce A beta/Cu(II) binding affinity
- 2013
-
Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 120, s. 18-23
-
Tidskriftsartikel (refereegranskat)abstract
- Aggregation of amyloid-beta (A beta) peptides into oligomers and amyloid plaques in the human brain is considered a causative factor in Alzheimer's disease (AD). As metal ions are over-represented in AD patient brains, and as distinct A beta aggregation pathways in presence of Cu(II) have been demonstrated, metal binding to A beta likely affects AD progression. A beta aggregation is moreover pH-dependent, and AD appears to involve inflammatory conditions leading to physiological acidosis. Although metal binding specificity to A beta varies at different pH's, metal binding affinity to A beta has so far not been quantitatively investigated at sub-neutral pH levels. This may be explained by the difficulties involved in studying monomeric peptide properties under aggregation-promoting conditions. We have recently devised a modified Affibody molecule, Z(A beta 3)(12-58), that binds A beta with sub-nanomolar affinity, thereby locking the peptide in monomeric form without affecting the N-terminal region where metal ions bind. Here, we introduce non-fluorescent A beta-binding Affibody variants that keep A beta monomeric while only slightly affecting the A beta peptide's metal binding properties. Using fluorescence spectroscopy, we demonstrate that Cu(II)/A beta(1-40) binding is almost two orders of magnitude weaker at pH 5.0 (apparent K-D = 51 mu M) than at pH 7.3 (apparent K-D = 0.86 mu M). This effect is arguably caused by protonation of the histidines involved in the metal ligandation. Our results indicate that engineered variants of Affibody molecules are useful for studying metal-binding and other properties of monomeric A beta under various physiological conditions, which will improve our understanding of the molecular mechanisms involved in AD.
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| 38. |
- Lindgren, Joel, 1982-, et al.
(författare)
-
Intramolecular thioether crosslinking of therapeutic proteins to increase proteolytic stability
- 2014
-
Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 15:14, s. 2132-2138
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Protein-based pharmaceuticals typically display high selectivity and low toxicity, but are also characterized by low oral availability, mainly because of enzymatic degradation in the gastrointestinal tract and poor permeability across the intestinal wall. One way to increase the proteolytic stability of peptides and proteins is by intramolecular crosslinking, such as the introduction of disulfide bridges. However, disulfide bridges are at risk of thiol-disulfide exchange or reduction during production, purification, and/or therapeutic use, whereas thioether bridges are expected to be stable under the same conditions. In this study, thioether crosslinking was investigated for a 46 aa albumin-binding domain (ABD) derived from streptococcal protein G. ABD binds with high affinity to human serum albumin (HSA) and has been proposed as a fusion partner to increase the in vivo half-lives of therapeutic proteins. In the study, five ABD variants with single or double intramolecular thioether bridges were designed and synthesized. The binding affinity, secondary structure, and thermal stability of each protein was investigated by SPR-based biosensor analysis and CD spectroscopy. The proteolytic stability in the presence of the major intestinal proteases pepsin (found in the stomach) and trypsin in combination with chymotrypsin (found in pancreatin secreted to the duodenum by the pancreas) was also investigated. The most promising crosslinked variant, ABD_CL1, showed high thermal stability, retained high affinity in binding to HSA, and showed dramatically increased stability in the presence of pepsin and trypsin/chymotrypsin, compared to the ABD reference protein. This suggests that the intramolecular thioether crosslinking strategy can be used to increase the stability towards gastrointestinal enzymes.
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| 39. |
|
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| 40. |
- Lindgren, Joel, et al.
(författare)
-
N-terminal engineering of amyloid-beta-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
- 2010
-
Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2319-2329
-
Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)
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| 41. |
- Lindgren, Joel, et al.
(författare)
-
N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
- 2010
-
Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2319-2329
-
Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)
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| 42. |
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| 43. |
- Lindgren, Lars-Erik, et al.
(författare)
-
Simulation of additive manufacturing using coupled constitutive and microstructure models
- 2016
-
Ingår i: Additive Manufacturing. - : Elsevier. - 2214-8604 .- 2214-7810. ; 12:Part B, s. 144-158
-
Tidskriftsartikel (refereegranskat)abstract
- The paper describes the application of modeling approaches used in Computational Welding Mechanics (CWM) applicable for simulating Additive Manufacturing (AM). It focuses on the approximation of the behavior in the process zone and the behavior of the solid material, particularly in the context of changing microstructure. Two examples are shown, one for the precipitation hardening Alloy 718 and one for Ti-6Al-4V. The latter alloy is subject to phase changes due to the thermal cycling
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| 44. |
- Locke, Adam E, et al.
(författare)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 45. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 46. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 47. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 48. |
- Nilsson, Anders, et al.
(författare)
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Intramolecular Thioether Crosslinking to Increase the Proteolytic Stability of Affibody Molecules
- 2017
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Ingår i: ChemBioChem. - : WILEY-V C H VERLAG GMBH. - 1439-4227 .- 1439-7633. ; 18:20, s. 2056-2062
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Tidskriftsartikel (refereegranskat)abstract
- Protein therapeutics suffer from low oral bioavailability, mainly due to poor membrane permeability and digestion by gastrointestinal proteases. To improve proteolytic stability, intramolecular thioether crosslinks were introduced into a three-helix affibody molecule binding the human epidermal growth factor receptor (EGFR). Solid-phase peptide synthesis was used to produce an unmodified control protein domain and three different crosslinked protein domain variants: one with a thioether crosslink between the N-terminal lysine residue and a cysteine residue in the second loop region (denoted K4), a second with a crosslink between the C-terminal lysine residue and a cysteine residue in the first loop region (denoted K58), and a third with crosslinks in both positions (denoted K4K58). Circular dichroism (CD) and surface-plasmon-resonance-based (SPR-based) biosensor studies of the protein domains showed that the three-helix structure and high-affinity binding to EGFR were preserved in the crosslinked protein domains. In vitro digestion by gastrointestinal proteases demonstrated that the crosslinked protein domains showed increased stability towards pepsin and towards a combination of trypsin and chymotrypsin.
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| 49. |
- Rubins, Daniel J., et al.
(författare)
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In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1
- 2021
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Ingår i: Molecular Imaging and Biology. - : Springer. - 1536-1632 .- 1860-2002. ; 23, s. 241-249
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In vivo imaging of programmed death ligand 1 (PD-L1) during immunotherapy could potentially monitor changing PD-L1 expression and PD-L1 expression heterogeneity within and across tumors. Some protein constructs can be used for same-day positron emission tomography (PET) imaging. Previously, we evaluated the PD-L1-targeting Affibody molecule [F-18]AlF-NOTA-Z(PD-L1_1) as a PET tracer in a mouse tumor model of human PD-L1 expression. In this study, we evaluated the affinity-matured Affibody molecule Z(PD-L1_4), to determine if improved affinity for PD-L1 resulted in increased in vivo targeting of PD-L1.Procedures: Z(PD-L1_4) was conjugated with NOTA and radiolabeled with either [F-18]AlF or Ga-68. [F-18]AlF-NOTA-Z(PD-L1_4) and [Ga-68]NOTA-Z(PD-L1_4) were evaluated in immunocompromised mice with LOX (PD-L1+) and SUDHL6 (PD-L1-) tumors with PET and ex vivo biodistribution measurements. In addition, whole-body PET studies were performed in rhesus monkeys to predict human biodistribution in a model with tracer binding to endogenous PD-L1, and to calculate absorbed radiation doses.Results: Ex vivo biodistribution measurements showed that both tracers had > 25 fold higher accumulation in LOX tumors than SUDHL6 ([F-18]AlF-NOTA-Z(PD-L1_4): LOX: 8.7 +/- 0.7 %ID/g (N = 4) SUDHL6: 0.2 +/- 0.01 %ID/g (N = 6), [Ga-68]NOTA-Z(PD-L1_4): LOX: 15.8 +/- 1.0 %ID/g (N = 6) SUDHL6: 0.6 +/- 0.1 %ID/g (N = 6)), considerably higher than Z(PD-L1_1). In rhesus monkeys, both PET tracers showed fast clearance through kidneys and low background signal in the liver ([F-18]AlF-NOTA-Z(PD-L1_4): 1.26 +/- 0.13 SUV, [Ga-68]NOTA-Z(PD-L1_4): 1.11 +/- 0.06 SUV). PD-L1-expressing lymph nodes were visible in PET images, indicating in vivo PD-L1 targeting. Dosimetry estimates suggest that both PET tracers can be used for repeated clinical studies, although high kidney accumulation may limit allowable radioactive doses.Conclusions: [F-18]AlF-NOTA-Z(PD-L1_4) and [Ga-68]NOTA-Z(PD-L1_4) are promising candidates for same-day clinical PD-L1 PET imaging, warranting clinical evaluation. The ability to use either [F-18] or [Ga-68] may expand access to clinical sites.
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| 50. |
- Schreiber, Olof, 1980-, et al.
(författare)
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Influence of Lactobacillus reuteri on the colonic microbiota in health and DSS-induced colitis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To investigate the impact of Lactobacillus reuteri and Dextran Sulphate Sodium (DSS) on the colonic microbiota by investigating bacterial content and composition in the individual colonic mucus layers and mesenteric lymph nodes. Methods: Rats were divided into 4 groups: control, L. reuteri, DSS and L. reuteri+DSS. L. reuteri was given as a cocktail containing 109 cfu of four different strains of L. reuteri by gavage daily for 16 days. Colitis was induced by 5% DSS in the drinking water for 9 days. The firmly and loosely mucus layers and mesenteric lymph nodes were collected, homogenized and its bacterial content was monitored using both culturing as well as the molecular method terminal restriction fragment length polymorphism (TRFLP). Results: In controls, the number of bacteria was significantly lower in the inner firmly adherent mucus layer than the outer loosely adherent layer, indicating a barrier function of the inner mucus layer. The composition of the microbiota was also different between layers. L. reuteri prevented colitis but did not alter the microbiota. DSS obliterated the differences between mucus layers both in terms of number of bacteria, and bacterial composition, indicating that DSS destroys the mucus regardless of the addition of L. reuteri. L. reuteri did however significantly decrease bacterial translocation in the DSS-model. Conclusion: The firmly adherent mucus layer serves as a barrier towards luminal bacteria. DSS alters the colonic microbiota and destroys the mucus barrier. L. reuteri ameliorates DSS-colitis by decreasing bacterial translocation.
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