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Publications (10 of 227) Show all publications
Liu, C., Marioni, R. E., Hedman, Å. K., Pfeiffer, L., Tsai, P.-C., Reynolds, L. M., . . . Levy, D. (2018). A DNA methylation biomarker of alcohol consumption.. Molecular Psychiatry, 23, 422-433
Open this publication in new window or tab >>A DNA methylation biomarker of alcohol consumption.
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2018 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, p. 422-433Article in journal (Refereed) Published
Abstract [en]

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-319698 (URN)10.1038/mp.2016.192 (DOI)000423441700028 ()27843151 (PubMedID)
Note

De tio första författarna delar på förstaförfattarskapet. De sex sista författarna delar på sistaförfattarskapet.

Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-03-19Bibliographically approved
Stenemo, M., Nowak, C., Byberg, L., Sundström, J., Giedraitis, V., Lind, L., . . . Ärnlöv, J. (2018). Circulating proteins as predictors of incident heart failure in the elderly. European Journal of Heart Failure, 20(1), 55-62
Open this publication in new window or tab >>Circulating proteins as predictors of incident heart failure in the elderly
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2018 (English)In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 20, no 1, p. 55-62Article in journal (Refereed) Published
Abstract [en]

Aims

To identify novel risk markers for incident heart failure using proteomic profiling of 80 proteins previously associated with cardiovascular pathology.

Methods and results

Proteomic profiling (proximity extension assay) was performed in two community‐based prospective cohorts of elderly individuals without heart failure at baseline: the Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS, n = 901, median age 70.2 (interquartile range 70.0–70.3) years, 80 events]; and the Uppsala Longitudinal Study of Adult Men [ULSAM, n = 685, median age 77.8 (interquartile range 76.9–78.1) years, 90 events]. Twenty‐nine proteins were associated with incident heart failure in the discovery cohort PIVUS after adjustment for age and sex, and correction for multiple testing. Eighteen associations replicated in ULSAM. In pooled analysis of both cohorts, higher levels of nine proteins were associated with incident heart failure after adjustment for established risk factors: growth differentiation factor 15 (GDF‐15), T‐cell immunoglobulin and mucin domain 1 (TIM‐1), tumour necrosis factor‐related apoptosis‐inducing ligand receptor 2 (TRAIL‐R2), spondin‐1 (SPON1), matrix metalloproteinase‐12 (MMP‐12), follistatin (FS), urokinase‐type plasminogen activator surface receptor (U‐PAR), osteoprotegerin (OPG), and suppression of tumorigenicity 2 (ST2). Of these, GDF‐15, U‐PAR, MMP‐12, TRAIL‐R2, SPON1 and FS were associated with worsened echocardiographic left ventricular systolic function at baseline, while only TIM‐1 was positively associated with worsened diastolic function (P < 0.02 for all).

Conclusion

Proteomic profiling identified several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident heart failure in elderly individuals. Our results encourage additional studies investigating the underlying mechanisms and the clinical utility of our findings.

Keywords
Biomarkers, Epidemiology, Heart failure, Left ventricular dysfunction, Proteomics, Risk prediction
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-334416 (URN)10.1002/ejhf.980 (DOI)000423809700007 ()28967680 (PubMedID)
Funder
EU, Horizon 2020, 634869Swedish Research Council, 2012-2215; 2015-03477; 221-2013-1673Marianne and Marcus Wallenberg Foundation, 2012.0082Swedish Heart Lung Foundation, 20140422; 20150429; 20120169Knut and Alice Wallenberg Foundation, 2013.0126Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, 1637
Note

Tove Fall och Johan Ärnlöv delar på sistaförfattarskapet.

Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-03-23Bibliographically approved
Jiang, X., O'Reilly, P. F., Aschard, H., Hsu, Y.-H., Richards, J. B., Dupuis, J., . . . Kiel, D. P. (2018). Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, 9, Article ID 260.
Open this publication in new window or tab >>Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 260Article in journal (Refereed) Published
Abstract [en]

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-343676 (URN)10.1038/s41467-017-02662-2 (DOI)000422650500011 ()29343764 (PubMedID)
Available from: 2018-03-05 Created: 2018-03-05 Last updated: 2018-03-05Bibliographically approved
Nielsen, J. B., Fritsche, L. G., Zhou, W., Teslovich, T. M., Holmen, O. L., Gustafsson, S., . . . Willer, C. J. (2018). Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development. American Journal of Human Genetics, 102(1), 103-115
Open this publication in new window or tab >>Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development
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2018 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 1, p. 103-115Article in journal (Refereed) Published
Abstract [en]

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-341499 (URN)10.1016/j.ajhg.2017.12.003 (DOI)000419305500008 ()29290336 (PubMedID)
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-02-19Bibliographically approved
Malik, R., Chauhan, G., Traylor, M., Sargurupremraj, M., Okada, Y., Mishra, A., . . . Dichgans, M. (2018). Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nature Genetics, 50(4), 524-537
Open this publication in new window or tab >>Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 4, p. 524-537Article in journal (Refereed) Published
Abstract [en]

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-352708 (URN)10.1038/s41588-018-0058-3 (DOI)000429529300013 ()29531354 (PubMedID)
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., . . . Loos, R. J. F. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50(1), 26-+
Open this publication in new window or tab >>Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 1, p. 26-+Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-343882 (URN)10.1038/s41588-017-0011-x (DOI)000423157400007 ()29273807 (PubMedID)
Funder
NIH (National Institute of Health), R01DK089256 R01DK101855 K99HL130580 R01DK106621 HL094535 HL109946 R01DK075787 R01HD057194 U01HG007416 1R01HL09257R01HL128914; K24HL105780; R01DK110113; U01HG007417; R01DK107786; K23HL114724EU, European Research Council, SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC; 323195; 293574
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Mahajan, A., Wessel, J., Willems, S. M., Zhao, W., Robertson, N. R., Chu, A. Y., . . . McCarthy, M. I. (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nature Genetics, 50(4), 559-571
Open this publication in new window or tab >>Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 4, p. 559-571Article in journal (Refereed) Published
Abstract [en]

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 x 10(-7)); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <= 1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-352709 (URN)10.1038/s41588-018-0084-1 (DOI)000429529300016 ()29632382 (PubMedID)
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Cornelis, M. C., Gustafsson, S., Ärnlöv, J., Elmståhl, S., Söderberg, S., Sundström, J., . . . Ingelsson, E. (2018). Targeted proteomic analysis of habitual coffee consumption.. Journal of Internal Medicine, 283(2), 200-211
Open this publication in new window or tab >>Targeted proteomic analysis of habitual coffee consumption.
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2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 2, p. 200-211Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Coffee drinking has been implicated in mortality and a variety of diseases but potential mechanisms underlying these associations are unclear. Large-scale systems epidemiological approaches may offer novel insights to mechanisms underlying associations of coffee with health.

OBJECTIVE: We performed an analysis of known and novel protein markers linked to cardiovascular disease and their association with habitual coffee intake in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 816) and followed up top proteins in the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 635) and EpiHealth (n = 2418).

METHODS: In PIVUS and ULSAM, coffee intake was measured by 7-day dietary records whilst a computer-based food frequency questionnaire was used in EpiHealth. Levels of up to 80 proteins were assessed in plasma by a proximity extension assay.

RESULTS: Four protein-coffee associations adjusted for age, sex, smoking and BMI, met statistical significance in PIVUS (FDR < 5%, P < 2.31 × 10(-3) ): leptin (LEP), chitinase-3-like protein 1 (CHI3L), tumour necrosis factor (TNF) receptor 6 and TNF-related apoptosis-inducing ligand. The inverse association between coffee intake and LEP replicated in ULSAM (β, -0.042 SD per cup of coffee, P = 0.028) and EpiHealth (β, -0.025 SD per time of coffee, P = 0.004). The negative coffee-CHI3L association replicated in EpiHealth (β, -0.07, P = 1.15 × 10(-7) ), but not in ULSAM (β, -0.034, P = 0.16).

CONCLUSIONS: The current study supports an inverse association between coffee intake and plasma LEP and CHI3L1 levels. The coffee-CHI3L1 association is novel and warrants further investigation given links between CHI3L1 and health conditions that are also potentially influenced by coffee.

Keywords
biomarkers, coffee, epidemiology, population, proteomics
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-334452 (URN)10.1111/joim.12703 (DOI)000425830100008 ()29044854 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-05-07Bibliographically approved
Roos, V., Elmstahl, S., Ingelsson, E., Sundström, J., Ärnlöv, J. & Lind, L. (2017). Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity. Metabolic Syndrome and Related Disorders, 15(3), 118-123
Open this publication in new window or tab >>Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity
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2017 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 118-123Article in journal (Refereed) Published
Abstract [en]

Background: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors. Methods: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI > 30 kg/m(2)) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire. Results: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes. Conclusions: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.

Keywords
metabolic syndrome, obesity, lifestyle factors, MHO
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-321438 (URN)10.1089/met.2016.0120 (DOI)000397585500003 ()28339343 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-09Bibliographically approved
Scott, R. A., Scott, L. J., Maegi, R., Marullo, L., Gaulton, K. J., Kaakinen, M., . . . Prokopenko, I. (2017). An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes, 66(11), 2888-2902
Open this publication in new window or tab >>An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 11, p. 2888-2902Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2017
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-340702 (URN)10.2337/db16-1253 (DOI)000413559100018 ()28566273 (PubMedID)
Funder
NIH (National Institute of Health), HHSN268200625226C
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2256-6972

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