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Sökning: WFRF:(Syvänen Ann Christine 1950 )

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1.
  • Flannick, Jason, et al. (författare)
  • Data Descriptor Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
  • 2017
  • Ingår i: Scientific Data. - 2052-4463. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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 (&gt; 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.</p>
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2.
  • Leonard, Dag, et al. (författare)
  • Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants
  • 2013
  • Ingår i: Circulation : Cardiovascular Genetics. - 1942-325X .- 1942-3268. ; 6:3, s. 255-263
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P&lt;0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P&lt;0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.</p>
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3.
  • Manning, Alisa, et al. (författare)
  • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
  • 2017
  • Ingår i: Diabetes. - AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.</p>
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4.
  • Nolte, Ilja M., et al. (författare)
  • Genetic loci associated with heart rate variability and their effects on cardiac disease risk
  • 2017
  • Ingår i: Nature Communications. - NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 &lt; r(g) &lt; -0.55) and blood pressure (-0.35 &lt; r(g) &lt; -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.</p>
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5.
  • Reid, Sarah, et al. (författare)
  • High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
  • 2020
  • Ingår i: Annals of the Rheumatic Diseases. - BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:3, s. 363-369
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>OBJECTIVES:</strong> To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).</p><p><strong>METHODS:</strong> Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.</p><p><strong>RESULTS:</strong> SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10<sup>-86</sup> and OR 7.48 (6.73 to 8.32), p=2.2×10<sup>-304</sup> for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10<sup>-5</sup>), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10<sup>-2</sup>), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10<sup>-5</sup>), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10<sup>-3</sup>), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10<sup>-2</sup>), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10<sup>-3</sup>), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10<sup>-2</sup>), anti-β<sub>2</sub>-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10<sup>-3</sup>) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10<sup>-2</sup>) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10<sup>-2</sup>), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10<sup>-2</sup>), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10<sup>-7</sup>), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10<sup>-3</sup>) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10<sup>-2</sup>) in high to low quartile comparison.</p><p><strong>CONCLUSIONS:</strong> A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.</p>
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6.
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7.
  • Björk, Albin, et al. (författare)
  • Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren's syndrome
  • 2020
  • Ingår i: RMD Open. - BMJ PUBLISHING GROUP. - 2056-5933. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Objective: Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjogren's syndrome (pSS).</p><p>Methods: Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).</p><p>Results: mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p&lt;0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p&lt;0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p&lt;0.0001) and correlated well with mRNA-based IFN scores (r=0.62-0.79, p&lt;0.0001), as well as with each other (r=0.94, p&lt;0.0001). Concordance of classification as 'high' or 'low' IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89-0.93, p&lt;0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p&lt;0.0001) and performed well in classifying patients and controls (AUC=0.96, p&lt;0.0001).</p><p>Conclusions: We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.</p>
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8.
  • Dahlberg, Johan, 1988- (författare)
  • Genetic Cartography at Massively Parallel Scale
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Massively parallel sequencing (MPS) is revolutionizing genomics. In this work we use, refine, and develop new tools for the discipline.</p><p>MPS has led to the discovery of multiple novel subtypes in Acute Lymphoblastic Leukemia (ALL). In <strong>Study I</strong> we screen for fusion genes in 134 pediatric ALL patients, including patients without an assigned subtype. In approximately 80% of these patients we detect novel or known fusion gene families, most of which display distinct methylation and expression patterns. This shows the potential for improvements in the clinical stratification of ALL. Large sample sizes are important to detect recurrent somatic variation. In <strong>Study II</strong> we investigate if a non-index overlapping pooling schema can be used to increase sample size and detect somatic variation. We designed a schema for 172 ALL samples and show that it is possible to use this method to call somatic variants.</p><p>Around the globe there are many ongoing and completed genome projects. In <strong>Study III</strong> we sequenced the genome of 1000 Swedes to create a reference data set for the Swedish population. We identified more than 10 million variants that were not present in publicly available databases, highlighting the need for population-specific resources. Data, and the tools developed during this study, have been made publicly available as a resource for genomics in Sweden and abroad.</p><p>The increased amount of sequencing data has created a greater need for automation. In <strong>Study IV</strong> we present Arteria, a computational automation system for sequencing core facilities. This system has been adopted by multiple facilities and has been used to analyze thousands of samples. In <strong>Study V</strong> we developed CheckQC, a program that provides automated quality control of Illumina sequencing runs. These tools make scaling up MPS less labour intensive, a key to unlocking the full future potential of genomics.</p><p>The tools, and data presented here are a valuable contribution to the scientific community. Collectively they showcase the power of MPS and genomics to bring about new knowledge of human health and disease.</p>
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9.
  • Edvardsen, Hege, et al. (författare)
  • SNP in TXNRD2 Associated With Radiation-Induced Fibrosis : A Study of Genetic Variation in Reactive Oxygen Species Metabolism and Signaling.
  • 2013
  • Ingår i: International journal of radiation oncology, biology, physics. - 1879-355x. ; 86:4, s. 791-9
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>PURPOSE:</strong> The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs).</p><p><strong>METHODS AND MATERIALS:</strong> 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients.</p><p><strong>RESULTS:</strong> Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005).</p><p><strong>CONCLUSION:</strong> Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance.</p>
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10.
  • Farias, Fabiana H. G., et al. (författare)
  • A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
  • 2019
  • Ingår i: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 27, s. 432-441
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G &gt; T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G &gt; T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.</p>
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