| 1. |
- Zillikens, M. C., et al.
(författare)
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
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| 2. |
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| 3. |
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| 4. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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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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| 5. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 6. |
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| 7. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 8. |
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| 9. |
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| 10. |
- 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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| 11. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 12. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 13. |
- Artigas, MS, et al.
(författare)
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Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 8658-
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Tidskriftsartikel (refereegranskat)abstract
- Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
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| 14. |
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| 15. |
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| 16. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 17. |
- Gemoll, T, et al.
(författare)
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Chromosomal aneuploidy affects the global proteome equilibrium of colorectal cancer cells
- 2013
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Ingår i: Analytical cellular pathology (Amsterdam). - : Hindawi Limited. - 2210-7185 .- 2210-7177. ; 36:5-6, s. 149-161
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chromosomal aneuploidy has been identified as a prognostic factor in the majority of sporadic carcinomas. However, it is not known how chromosomal aneuploidy affects chromosome-specific protein expression in particular, and the cellular proteome equilibrium in general.Objective: The aim was to detect chromosomal aneuploidy-associated expression changes in cell clones carrying trisomies found in colorectal cancer.Methods: We used microcell-mediated chromosomal transfer to generate three artificial trisomic cell clones of the karyotypically stable, diploid, yet mismatch-deficient, colorectal cancer cell line DLD1 - each of them harboring one extra copy of either chromosome 3, 7 or 13. Protein expression differences were assessed by two-dimensional gel electrophoresis and mass spectrometry, compared to whole-genome gene expression data, and evaluated by PANTHER classification system and Ingenuity Pathway Analysis (IPA).Results: In total, 79 differentially expressed proteins were identified between the trisomic clones and the parental cell line. Up-regulation of PCNA and HMGB1 as well as down-regulation of IDH3A and PSMB3 were revealed as trisomy-associated alterations involved in regulating genome stability.Conclusions: These results show that trisomies affect the expression of genes and proteins that are not necessarily located on the trisomic chromosome, but reflect a pathway-related alteration of the cellular equilibrium.
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| 18. |
- Gemoll, T, et al.
(författare)
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Genetic Instability and Disease Prognostication
- 2015
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Ingår i: Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. - Cham : Springer International Publishing. - 0080-0015. ; 200, s. 81-94
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Tidskriftsartikel (refereegranskat)
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Liegmann, AS, et al.
(författare)
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Single Cell Genetic Profiling of Tumors of Breast Cancer Patients Aged 50 Years and Older Reveals Enormous Intratumor Heterogeneity Independent of Individual Prognosis
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:13
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor heterogeneity; this poses a tremendous clinical challenge, for example with respect to treatment stratification. To further elucidate genomic instability and tumor heterogeneity in older patients, we analyzed the genetic aberration profiles of 39 breast cancer patients aged 50 years and older (median 67 years) with either short (median 2.4 years) or long survival (median 19 years). The analysis was based on copy number enumeration of eight breast cancer-associated genes using multiplex interphase fluorescence in situ hybridization (miFISH) of single cells, and by targeted next-generation sequencing of 563 cancer-related genes. Results: We detected enormous inter- and intratumor heterogeneity, yet maintenance of common cancer gene mutations and breast cancer specific chromosomal gains and losses. The gain of COX2 was most common (72%), followed by MYC (69%); losses were most prevalent for CDH1 (74%) and TP53 (69%). The degree of intratumor heterogeneity did not correlate with disease outcome. Comparing the miFISH results of diploid with aneuploid tumor samples significant differences were found: aneuploid tumors showed significantly higher average signal numbers, copy number alterations (CNAs) and instability indices. Mutations in PIKC3A were mostly restricted to luminal A tumors. Furthermore, a significant co-occurrence of CNAs of DBC2/MYC, HER2/DBC2 and HER2/TP53 and mutual exclusivity of CNAs of HER2 and PIK3CA mutations and CNAs of CCND1 and PIK3CA mutations were revealed. Conclusion: Our results provide a comprehensive picture of genome instability profiles with a large variety of inter- and intratumor heterogeneity in breast cancer patients aged 50 years and older. In most cases, the distribution of chromosomal aneuploidies was consistent with previous results; however, striking exceptions, such as tumors driven by exclusive loss of chromosomes, were identified.
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| 28. |
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| 29. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 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
- 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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| 30. |
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| 31. |
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| 32. |
- Roblick, U J, et al.
(författare)
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Sequential proteome alterations during genesis and progression of colon cancer.
- 2004
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 61:10
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the proteome of colon mucosal cells accompany the transition from normal mucosa via adenoma and invasive cancer to metastatic disease. Samples from 15 patients with sporadic sigmoid cancers were analyzed. Proteins were separated by two-dimensional gel electrophoresis. Relative differences in expression levels between normal tissue, adenoma, carcinoma and metastasis were evaluated in both intra- and inter-patient comparisons. Up- and down-regulated proteins (> twofold) during development to cancer or metastasis were excised and submitted to peptide mass fingerprinting and MS/MS sequence analysis, facilitated by the use of a compact disc workstation. In total, 112 protein spots were found to be differentially regulated, of which 72 were determined as to protein identity, 46 being up-regulated toward the progression of cancer, and 26 down-regulated. Several of the identifications correlate with proteins of the cell cycle, cytoskeleton or metabolic pathways. The pattern changes now identified have the potential for design of marker panels for assistance in diagnostics and therapeutic strategies in colorectal cancer.
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| 33. |
- Sprenger, HG, et al.
(författare)
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Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity
- 2021
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 3:5, s. 636-
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Tidskriftsartikel (refereegranskat)abstract
- Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
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| 34. |
- Swanton, C, et al.
(författare)
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Chromosomal instability determines taxane response
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 106:21, s. 8671-8676
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Tidskriftsartikel (refereegranskat)abstract
- Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these “CIN-survival” genes is associated with poor outcome in estrogen receptor–positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.
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| 35. |
- Wahl, Simone, et al.
(författare)
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
- 2017
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7635, s. 81-
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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| 36. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Blegen, H, et al.
(författare)
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DNA amplifications and aneuploidy, high proliferative activity and impaired cell cycle control characterize breast carcinomas with poor prognosis
- 2003
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Ingår i: Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology. - : Hindawi Limited. - 0921-8912. ; 25:3, s. 103-114
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Tidskriftsartikel (refereegranskat)abstract
- In order to explore whether specific cytogenetic abnormalities can be used to stratify tumors with a distinctly different clinical course, we performed comparative genomic hybridization (CGH) of tumors from patients who were diagnosed with metastatic disease after an interval of less than 2 years or who remained free from distant metastases for more than 10 years. All patients presented with distant metastases after mastectomy indicating that none of the patients in this study was cured and free of remaining tumor cells. Tumors in the group of short‐term survivors showed a higher average number of chromosomal copy alterations compared to the long‐term survivors. Of note, the number of sub‐chromosomal high‐level copy number increases (amplifications) was significantly increased in the group of short‐term survivors. In both short‐ and long‐term survivors recurrent chromosomal gains were mapped to chromosomes 1q, 4q, 8q, and 5p. Copy number changes that were more frequent in the group of short‐term survivors included gains of chromosome 3q, 9p, 11p and 11q and loss of 17p. Our results indicate that low‐ and high grade malignant breast adenocarcinomas are characterized by a specific pattern of chromosomal copy number changes. Furthermore, immunohistochemical evaluation of the expression levels of Ki‐67, p27KIP1, p21WAF1, p53, cyclin A and cyclin E revealed a correlation between increased proliferative activity and poor outcome.
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| 42. |
- Blegen, H, et al.
(författare)
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Genetic instability promotes the acquisition of chromosomal imbalances in T1b and T1c breast adenocarcinomas
- 2001
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Ingår i: Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology. - : Hindawi Limited. - 0921-8912. ; 22:3, s. 123-131
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Tidskriftsartikel (refereegranskat)abstract
- In order to evaluate biological and genetic properties of early breast carcinomas we analyzed microdissected tissue from 33 primary breast carcinomas stage T1b and T1c with respect to the nuclear DNA content, the expression pattern of Ki‐67, cyclin A, p27KIP1, p53 and p21WAF1, and chromosomal gains and losses. The results show that T1b carcinomas (6–10 mm,n=17) were frequently near‐diploid (53%) with low proliferative activity and staining patterns of p53 and p21WAF1that suggest the presence of wild type protein. The majority (12/16) of the T1c tumors (11–20 mm), however, was aneuploid, and proliferative activity and p53 expression were increased. Larger tumor size correlated with an increasing number of chromosomal copy number changes and in particular with regional amplifications. High level copy number increases (amplifications), however, were found exclusively in the aneuploid tumors. Amplification events correlated with elevated cyclin A and reduced p27 expression, respectively. Our results suggest that the sequential acquisition of genomic imbalances during tumor progression is accelerated in aneuploid tumors, and may contribute to the increased malignancy potential.
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| 43. |
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| 44. |
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| 45. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 46. |
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| 48. |
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