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- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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- Lill, Christina M., et al.
(författare)
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Closing the case of APOE in multiple sclerosis : no association with disease risk in over 29 000 subjects
- 2012
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:9, s. 558-562
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Tidskriftsartikel (refereegranskat)abstract
- Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments.Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively).Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
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- Schroeder, Julia, et al.
(författare)
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MicroRNA-138 is a potential regulator of memory performance in humans
- 2014
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 8, s. 501-
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate memory genes, these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P-value = 7.8 x 10(-9)). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5 x 10(-4)). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3' untranslated region (3' UTR) of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3' UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.
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- Sharma, Manu, et al.
(författare)
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Large-scale replication and heterogeneity in Parkinson disease genetic loci
- 2012
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Ingår i: Neurology. - 1526-632X. ; 79:7, s. 67-659
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
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- Alm, A., et al.
(författare)
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Caries in adolescence - influence from early childhood
- 2012
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Ingår i: Community Dentistry and Oral Epidemiology. - : Wiley. - 0301-5661 .- 1600-0528. ; 40:2, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To analyse the relationship between caries determinants in early childhood and caries prevalence in proximal surfaces in adolescents at the age of 15 years. Methods: The present longitudinal study is part of a series of surveys of oral health in 671 children followed from 1 to 15 years of age. Data were selected from examinations, interviews and questionnaires at 1, 3 and 6 years and bitewing radiographs at 15 years of age. Uni- and multivariable logistic regression analyses were performed to identify caries-related determinants. The outcome variable was carious lesions and fillings (DFa) in approximal tooth surfaces at 15 years of age. Statistical comparisons were made between caries-free teenagers, DFa = 0 and teenagers with DFa > 0, DFa 4 and DFa 8, respectively. Results: In the final logistic regression analyses, caries experience at 6 years and mother's self-estimation of her oral health care as being less good to poor remained statistically significant and were related to caries in all three caries groups (i.e. DF > 0, 4 and 8) at 15 years of age. The consumption of sweets at 1 year remained statistically significant, with a caries experience of DF 4 and 8. The variables 'parents born abroad' and female gender were statistically significantly associated with DFa 4 and DFa 8, respectively. Furthermore, infrequent toothbrushing habits at 3 years of age and failure to attend the examination at 1 year were statistically significantly associated with caries at 15 years in the univariable analyses. Conclusion: Early caries experience, consumption of sweets at an early age and mother's self-estimation of her oral health care as being less good to poor are associated with approximal caries in adolescents. The study indicates that caries determinants identified during early childhood have a strong impact on approximal caries in adolescence.
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- Gustafsson, Erika, et al.
(författare)
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Directed evolution of chemotaxis inhibitory protein of Staphylococcus aureus generates biologically functional variants with reduced interaction with human antibodies
- 2010
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 23:2, s. 91-101
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Tidskriftsartikel (refereegranskat)abstract
- Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is a protein that binds and blocks the C5a receptor (C5aR) and formylated peptide receptor, thereby inhibiting the immune cell recruitment associated with inflammation. If CHIPS was less reactive with existing human antibodies, it would be a promising anti-inflammatory drug candidate. Therefore, we applied directed evolution and computational/rational design to the CHIPS gene in order to generate new CHIPS variants displaying lower interaction with human IgG, yet retaining biological function. The optimization was performed in four rounds: one round of random mutagenesis to add diversity into the CHIPS gene and three rounds of DNA recombination by Fragment INduced Diversity (FIND((R))). Every round was screened by phage selection and/or ELISA for decreased interaction with human IgG and retained C5aR binding. The mean binding of human anti-CHIPS IgG decreased with every round of evolution. For further optimization, new amino acid substitutions were introduced by rational design, based on the mutations identified during directed evolution. Finally, seven CHIPS variants with low interaction with human IgG and retained C5aR blocking capacity could be identified.
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- Gøgsig, Thomas M, et al.
(författare)
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Mild and efficient nickel-catalyzed Heck reactions with electron-rich olefins.
- 2012
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134:1, s. 443-52
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Tidskriftsartikel (refereegranskat)abstract
- A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive β-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.
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| 15. |
- Isaksson, Helén, et al.
(författare)
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Prevalence of dental erosion and association with lifestyle factors in Swedish 20-year olds
- 2014
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Ingår i: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 72:6, s. 448-457
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate the prevalence, distribution and severity of dental erosion and its association with lifestyle, oral and general health in young adults. Materials and methods. Four hundred and ninety-four individuals, 20-years of age, participated. Dental erosion in molars and maxillary incisors was evaluated. Caries, plaque and gingivitis were registered. Saliva samples were taken and the subjects were interviewed about behavioural and dietary habits and oral and general health. Body mass index (BMI) was calculated. The individuals were sub-divided into two groups according to the presence and absence of dental erosion: within the group with erosion was a sub-group of individuals with extensive erosion. Results. Of the individuals 25% had no erosion, 75% had erosion and 18% had extensive erosion. Erosion was found in molars in 74% of the individuals and on buccal and palatal surfaces in maxillary incisors in 4% and 7%, respectively. Cupping was seen in 65% of individuals and severe erosion in molars in 1.6%. Compared to subjects with no erosion, those with extensive erosion had a higher consumption of soft drinks (p = 0.05), caries prevalence (p < 0.01), prevalence of mutans Streptococci (p < 0.01) and BMI (p < 0.05). Furthermore, subjects with erosion had higher caries prevalence (p < 0.01) and BMI (p < 0.01) than those with no erosion. Conclusions. Swedish young adults have a high prevalence of dental erosion, but the level of severe erosion is low. The study disclosed a relationship between dental erosion and behavioural factors, oral health and BMI.
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- Lunde, Mai Lill Suhr, et al.
(författare)
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Gene expression analysis by cDNA microarray in oral cancers from two Western populations
- 2010
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 30:4, s. 1083-1091
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In this work, gene expression profile was examined in 19 cases of oral cancer (OC) obtained from patients from Sweden (n=8) and UK (n=11) and the findings were tested for correlation to patient's clinicopathological data. MATERIALS AND METHODS: Following total RNA extraction, cDNA synthesis, labeling with fluorescent dyes and hybridization to the 21 k human oligonucleotide microarrays, slides were scanned and images were subjected to Genepix and J-Express analysis. Results for selected genes were validated by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR). RESULTS: 42 genes were identified as being differentially expressed. These included 39 genes of known functions (such as fatty acid synthase (FASN), 5' nucleotidase, ecto (NT5E), high mobility group AT-hook (HMGA1), and v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS)) and 3 novel genes; 26 (67%) of the 39 genes with known functions were previously reported in oral/head and neck tumors examined from other populations. Hierarchical clustering of the samples using the 42 genes demonstrated that samples mainly clustered in the same population. CONCLUSION: These results illustrate that microarrays can be used to identify distinct patterns of gene expression in different populations, but with no direct association to clinicopathological parameters. The fact that 67% of the 39 genes with known functions found in this work were previously reported in oral/head and neck tumors from other populations provides clear evidence that development of these tumors follows the same biological pathways irrespective of the source of the samples used.
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- Salomone, A., et al.
(författare)
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Direct observation of a lithiated oxirane: A synergistic study using spectroscopic, crystallographic, and theoretical methods on the structure and stereodynamics of lithiated ortho-trifluoromethyl styrene oxide
- 2014
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Ingår i: CHEMICAL SCIENCE. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 5:2, s. 528-538
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Tidskriftsartikel (refereegranskat)abstract
- α-Lithiated epoxides, long considered "fleeting" intermediates in the reactions of epoxides with strong bases, have nowadays proven to be key synthons for asymmetric synthesis. In this study, the solution and the solid state structure of an α-lithiated aryloxirane, namely α-lithiated ortho-trifluoromethyl styrene oxide (1-Li), were determined. Single crystal X-ray diffraction analysis of 1-Li performed at 100 K applying the X-TEMP-2 device revealed a self-assembled heterochiral dimeric structure with a rare central six-membered (O-Li-C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance ( 1H, 13C, 19F, 7Li) studies suggested that 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single σ-contact between lithium and a carbon atom. Line shape analysis provided activation parameters for both the dynamic interconversion of the two dimers and the enantiomerisation of 1-Li, which proved to be mostly entropy controlled. The structural assignment in solution was supported by density functional theory computations through the investigation of conformers of monomeric and dimeric complexes of 1-Li featuring different degrees of specific solvation. A mechanism based on the equilibration of six-membered homo- and heterochiral dimers was proposed to explain the configurational instability exhibited by 1-Li in THF. © 2014 The Royal Society of Chemistry.
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