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Institution

Karolinska Institutet

EducationStockholm, Sweden
About: Karolinska Institutet is a education organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Population & Poison control. The organization has 46212 authors who have published 121142 publications receiving 6008130 citations.


Papers
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Journal ArticleDOI
TL;DR: Next-generation sequencing is used to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls to identify new, rare and probably functional variants that could aid functional experiments and predictive models.
Abstract: More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

752 citations

Journal ArticleDOI
TL;DR: The CHO cells with stably transfected adenosine receptors provide an identical cellular background for such a pharmacological characterization and are valuable systems for further characterization of specific receptor subtypes and for the development of new ligands.
Abstract: Four adenosine receptor subtypes of the family of G protein-coupled receptors, designated A1, A2A, A2B and A3 are currently known. In this study all human subtypes were stably transfected into Chinese hamster ovary (CHO) cells in order to be able to study their pharmacological profile in an identical cellular background utilizing radioligand binding studies (A1, A2A, A3) or adenylyl cyclase activity assays (A2B). The A1 subtype showed the typical pharmacological profile with 2-chloro-N6-cyclopentyladenosine (CCPA) as the agonist with the highest affinity and a marked stereoselectivity for the N6-phenylisopropyladenosine (PIA) diastereomers. In competition with antagonist radioligand biphasic curves were observed for agonists. In the presence of GTP all receptors were converted to a single low affinity state indicating functional coupling to endogenous G proteins. For A2A adenosine receptors CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadeno sine) and N-ethylcarboxamidoadenosine (NECA) were found to be the most potent agonists followed by R- and S-PIA with minor stereoselectivity. The relative potencies of agonists for the A2B adenosine receptor could only be tested by measurement of receptor-stimulated adenylyl cyclase activity. NECA was the most potent agonist with an EC50-value of 2.3 microM whereas all other compounds tested were active at concentrations in the high micromolar range. Inhibition of NECA-stimulated adenylyl cyclase identified xanthine amino congener (XAC; 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3-dipropylxa nthine) as the most potent antagonist at this receptor subtype. The A3 receptor was characterized utilizing the nonselective agonist [3H]NECA. The N6-benzyl substituted derivatives of adenosine-5'-N-methyluronamide (MECA) turned out to be the most potent agonists. The notion of xanthine-insensitivity of the A3 receptor should be dropped at least for the human receptor as xanthines with submicromolar affinity were found. Overall, the pharmacological characteristics of the human receptors are similar to other species with some species-specific characteristics. In this study we present for the first time the comparative pharmacology of all known human adenosine receptor subtypes. The CHO cells with stably transfected adenosine receptors provide an identical cellular background for such a pharmacological characterization. These cells are valuable systems for further characterization of specific receptor subtypes and for the development of new ligands.

751 citations

Journal ArticleDOI
TL;DR: There was some correlation between observed dramatic fluctuations in the gut microbiome and intensified medication due to a flare of the disease, and these results will help guide therapies that will redirect the Gut microbiome towards a healthy state and maintain remission in IBD.
Abstract: Inflammatory bowel disease (IBD) is characterized by flares of inflammation with a periodic need for increased medication and sometimes even surgery. The aetiology of IBD is partly attributed to a deregulated immune response to gut microbiome dysbiosis. Cross-sectional studies have revealed microbial signatures for different IBD subtypes, including ulcerative colitis, colonic Crohn's disease and ileal Crohn's disease. Although IBD is dynamic, microbiome studies have primarily focused on single time points or a few individuals. Here, we dissect the long-term dynamic behaviour of the gut microbiome in IBD and differentiate this from normal variation. Microbiomes of IBD subjects fluctuate more than those of healthy individuals, based on deviation from a newly defined healthy plane (HP). Ileal Crohn's disease subjects deviated most from the HP, especially subjects with surgical resection. Intriguingly, the microbiomes of some IBD subjects periodically visited the HP then deviated away from it. Inflammation was not directly correlated with distance to the healthy plane, but there was some correlation between observed dramatic fluctuations in the gut microbiome and intensified medication due to a flare of the disease. These results will help guide therapies that will redirect the gut microbiome towards a healthy state and maintain remission in IBD.

750 citations

Journal ArticleDOI
TL;DR: Infections as a major preventable cause of human cancer (Internal Medicine in the 21st Century) and how to prevent it.
Abstract: Infections may be responsible for over 15% of all malignancies worldwide. Important mechanisms by which infectious agents may induce carcinogenesis include the production of chronic inflammation, the transformation of cells by insertion of oncogenes and inhibition of tumour suppressors, and the induction of immunosuppression. Common characteristics shared by infectious agents linked to malignancies are that they are persistent in the host, often highly prevalent in the host population and induce cancer after a long latency. The associations between a selection of infectious agents and malignancies are covered in detail.

749 citations

Journal ArticleDOI
TL;DR: It is demonstrated using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation, and evidence that height- and BMI-associated variants have been under natural selection is found.
Abstract: We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

748 citations


Authors

Showing all 46522 results

NameH-indexPapersCitations
Meir J. Stampfer2771414283776
Albert Hofman2672530321405
Guido Kroemer2361404246571
Eric B. Rimm196988147119
Scott M. Grundy187841231821
Jing Wang1844046202769
Tadamitsu Kishimoto1811067130860
John Hardy1771178171694
Marc G. Caron17367499802
Ramachandran S. Vasan1721100138108
Adrian L. Harris1701084120365
Douglas F. Easton165844113809
Zulfiqar A Bhutta1651231169329
Judah Folkman165499148611
Ralph A. DeFronzo160759132993
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
2023101
2022500
20217,763
20206,922
20196,057
20185,548