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1.
  • Ademuyiwa, Adesoji O., et al. (författare)
  • Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
  • 2016
  • Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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2.
  • Hollestelle, Antoinette, et al. (författare)
  • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
  • 2016
  • Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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3.
  • Huyghe, Jeroen R., et al. (författare)
  • Discovery of common and rare genetic risk variants for colorectal cancer
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
  • Tidskriftsartikel (refereegranskat)abstract
    • To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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4.
  • Jiao, Xiang, et al. (författare)
  • PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
  • 2017
  • Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
  • Tidskriftsartikel (refereegranskat)abstract
    • Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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5.
  • Ahearn, Thomas U., et al. (författare)
  • Common variants in breast cancer risk loci predispose to distinct tumor subtypes
  • 2022
  • Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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6.
  • Ahlinder, Jon, et al. (författare)
  • Life stage-specific inbreeding depression in long-lived Pinaceae species depends on population connectivity
  • 2021
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Inbreeding depression (ID) is a fundamental selective pressure that shapes mating systems and population genetic structures in plants. Although it has been shown that ID varies over the life stages of shorter-lived plants, less is known about how the fitness effects of inbreeding vary across life stages in long-lived species. We conducted a literature survey in the Pinaceae, a tree family known to harbour some of the highest mutational loads ever reported. Using a meta-regression model, we investigated distributions of inbreeding depression over life stages, adjusting for effects of inbreeding levels and the genetic differentiation of populations within species. The final dataset contained 147 estimates of ID across life stages from 41 studies. 44 Fst estimates were collected from 40 peer-reviewed studies for the 18 species to aid genetic differentiation modelling. Partitioning species into fragmented and well-connected groups using Fst resulted in the best way (i.e. trade-off between high goodness-of-fit of the model to the data and reduced model complexity) to incorporate genetic connectivity in the meta-regression analysis. Inclusion of a life stage term and its interaction with the inbreeding coefficient (F) dramatically increased model precision. We observed that the correlation between ID and F was significant at the earliest life stage. Although partitioning of species populations into fragmented and well-connected groups explained little of the between-study heterogeneity, the inclusion of an interaction between life stage and population differentiation revealed that populations with fragmented distributions suffered lower inbreeding depression at early embryonic stages than species with well-connected populations. There was no evidence for increased ID in late life stages in well-connected populations, although ID tended to increase across life stages in the fragmented group. These findings suggest that life stage data should be included in inbreeding depression studies and that inbreeding needs to be managed over life stages in commercial populations of long-lived plants.
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7.
  • Bien, Stephanie A., et al. (författare)
  • Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
  • 2019
  • Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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8.
  • Brunner, Fabian J., et al. (författare)
  • Application of non-HDL cholesterol for population-based cardiovascular risk stratification : results from the Multinational Cardiovascular Risk Consortium
  • 2019
  • Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 394:10215, s. 2173-2183
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.
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9.
  • Bull, Caroline J., et al. (författare)
  • Adiposity, metabolites, and colorectal cancer risk : Mendelian randomization study
  • 2020
  • Ingår i: BMC Medicine. - : BMC. - 1741-7015. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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10.
  • Carlsson-Graner, Ulla, et al. (författare)
  • Patterns of disease and host resistance in spatially structured systems
  • 2014
  • Ingår i: European journal of plant pathology. - Netherlands : Springer. - 0929-1873 .- 1573-8469. ; 138:3, s. 499-511
  • Tidskriftsartikel (refereegranskat)abstract
    • We use data from species of the anther-smut fungi and the host plants Lychnis alpina and Silene dioica to show that spatial structuring at different scales can influence patterns of disease and host resistance. Patterns of disease and host resistance were surveyed in an archipelago subject to land-uplift where populations of S. dioica constitute an age-structured metapopulation, and in three contrasting areas within the mainland range of L. alpina, where population distributions range from continuous, through patchy but spatially connected to highly isolated demes. In S. dioica, disease levels depend on the age, size and density of local patches and populations. Disease is most predictably found in larger dense host patches and populations of intermediate age, and more frequently goes extinct in small old populations. The rate of local disease spread is affected by the level of host resistance; S. dioica populations showing an increase in disease over time are more susceptible than populations where the disease has remained at low levels. Among-population variation in resistance is driven by founding events and populations remain differentiated due to limited gene flow between islands. As observed in the L. alpina system, when populations are more connected, a greater fraction of populations have disease present. Results from a simulation model argue that, while increased dispersal in connected systems can increase disease spread, it may also favour selection of host resistance which ultimately reduces disease levels within populations. This could explain the observed lower disease prevalence in L. alpina in regions where populations are more continuous.
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11.
  • Carlsson-Granér, Ulla, et al. (författare)
  • Plant disease and islands
  • 2009
  • Ingår i: Encyclopedia of Islands. - : University of California Press. - 9780520256491 - 0520256492 ; , s. 748-752
  • Bokkapitel (refereegranskat)
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12.
  • Catapano, Filomena, et al. (författare)
  • In Situ Evidence of Ion Acceleration between Consecutive Reconnection Jet Fronts
  • 2021
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 908:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Processes driven by unsteady reconnection can efficiently accelerate particles in many astrophysical plasmas. An example is the reconnection jet fronts in an outflow region. We present evidence of suprathermal ion acceleration between two consecutive reconnection jet fronts observed by the Magnetospheric Multiscale mission in the terrestrial magnetotail. An earthward propagating jet is approached by a second faster jet. Between the jets, the thermal ions are mostly perpendicular to magnetic field, are trapped, and are gradually accelerated in the parallel direction up to 150 keV. Observations suggest that ions are predominantly accelerated by a Fermi-like mechanism in the contracting magnetic bottle formed between the two jet fronts. The ion acceleration mechanism is presumably efficient in other environments where jet fronts produced by variable rates of reconnection are common and where the interaction of multiple jet fronts can also develop a turbulent environment, e.g., in stellar and solar eruptions.
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13.
  • Chen, Li-Jen, et al. (författare)
  • Electron energization and mixing observed by MMS in the vicinity of an electron diffusion region during magnetopause reconnection
  • 2016
  • Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:12, s. 6036-6043
  • Tidskriftsartikel (refereegranskat)abstract
    • Measurements from the Magnetospheric Multiscale (MMS) mission are reported to show distinct features of electron energization and mixing in the diffusion region of the terrestrial magnetopause reconnection. At the ion jet and magnetic field reversals, distribution functions exhibiting signatures of accelerated meandering electrons are observed at an electron out-of-plane flow peak. The meandering signatures manifested as triangular and crescent structures are established features of the electron diffusion region (EDR). Effects of meandering electrons on the electric field normal to the reconnection layer are detected. Parallel acceleration and mixing of the inflowing electrons with exhaust electrons shape the exhaust flow pattern. In the EDR vicinity, the measured distribution functions indicate that locally, the electron energization and mixing physics is captured by two-dimensional reconnection, yet to account for the simultaneous four-point measurements, translational invariant in the third dimension must be violated on the ion-skin-depth scale.
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14.
  • Chen, Zhishan, et al. (författare)
  • Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
  • 2024
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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15.
  • Conti, David, V, et al. (författare)
  • Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
  • 2021
  • Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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16.
  • Couch, Fergus J., et al. (författare)
  • Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
  • 2016
  • Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
  • Tidskriftsartikel (refereegranskat)abstract
    • Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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17.
  • Dixon-Suen, Suzanne C, et al. (författare)
  • Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
  • 2022
  • Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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18.
  • Drotz, Marcus K., et al. (författare)
  • Ecotype Differentiation in the Face of Gene Flow within the Diving Beetle Agabus bipustulatus (Linnaeus, 1767) in Northern Scandinavia
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2, s. e31381-
  • Tidskriftsartikel (refereegranskat)abstract
    • The repeated occurrence of habitat-specific polyphyletic evolved ecotypes throughout the ranges of widely distributed species implies that multiple, independent and parallel selection events have taken place. Ecological transitions across altitudinal gradients over short geographical distances are often associated with variation in habitat-related fitness, these patterns suggest the action of strong selective forces. Genetic markers will therefore contribute differently to differences between ecotypes in local hybrid zones. Here we have studied the adaptive divergence between ecotypes of the water beetle Agabus bipustulatus along several parallel altitudinal gradients in northern Scandinavia. This water beetle is well known for its remarkable morphological variation associated with mountain regions throughout the western Palaearctic. Two morphological ecotypes are recognised: a montane type with reduced flight muscles and a lowland type with fully developed muscles. Using a multilocus survey of allozyme variation and a morphological analysis with landmark-based morphometrics, across thirty-three populations and seven altitudinal gradients, we studied the local adaptive process of gene flow and selection in detail. Populations were sampled at three different elevations: below, at and above the tree line. The results indicate that the levels of divergence observed between ecotypes in morphology and allele frequencies at alpha-Glycerophosphate dehydrogenase relative to those shown by neutral molecular markers reflects local diversifying selection in situ. Four main lines of evidence are shown here: (1) A repeated morphological pattern of differentiation is observed across all altitudinal transects, with high reclassification probabilities. (2) Allele and genotype frequencies at the alpha-Gpdh locus are strongly correlated with altitude, in sharp contrast to the presumable neutral markers. (3) Genetic differentiation is two to three times higher among populations across the tree line than among populations at or below. (4) Genetic differentiation between ecotypes within independent mountain areas is reflected by different sets of allozymes.
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19.
  • Eriksson, Elin, 1989-, et al. (författare)
  • Electron Energization at a Reconnecting Magnetosheath Current Sheet
  • 2018
  • Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:16, s. 8081-8090
  • Tidskriftsartikel (refereegranskat)abstract
    • We present observations of electron energization within a sub-ion-scale magnetosheath current sheet (CS). A number of signatures indicate ongoing reconnection, including the thickness of the CS (similar to 0.7 ion inertial length), nonzero normal magnetic field, Hall magnetic fields with electrons carrying the Hall currents, and electron heating. We observe localized electron acceleration and heating parallel to the magnetic field at the edges of the CS. Electrostatic waves observed in these regions have low phase velocity and small wave potentials and thus cannot provide the observed acceleration and heating. Instead, we find that the electrons are accelerated by a parallel potential within the separatrix regions. Similar acceleration has been reported based on magnetopause and magnetotail observations. Thus, despite the different plasma conditions in magnetosheath, magnetopause, and magnetotail, the acceleration mechanism and corresponding heating of electrons is similar. Plain Language Summary Magnetic reconnection is an important physical energy conversion process in astrophysical and laboratory plasmas. The easiest place to analyze magnetic reconnection is in near-Earth space. Due to lack of sufficient electron resolution of previous spacecraft missions, there are many unanswered questions regarding electron heating and acceleration processes at small scales. In particular, the regime where thermal pressure dominates over magnetic pressure, the most common state of plasmas in the Universe, is little explored. In this letter we study such a regime using the four-spacecraft Magnetospheric Multiscale mission. We analyze a reconnecting current sheet in the magnetosheath. We show that electrons are energized by a parallel potential, similar to what has been observed in the different plasma regimes the magnetopause and magnetotail. Thus, despite different plasma conditions, a similar acceleration mechanism and corresponding heating of electrons is occurring in all these regions.
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20.
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21.
  • Escala-Garcia, Maria, et al. (författare)
  • A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
  • 2020
  • Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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22.
  • Fernandez-Rozadilla, Ceres, et al. (författare)
  • Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
  • 2023
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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23.
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24.
  • Gingell, Imogen, et al. (författare)
  • MMS Observations and Hybrid Simulations of Surface Ripples at a Marginally Quasi-Parallel Shock
  • 2017
  • Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 122:11, s. 11003-11017
  • Tidskriftsartikel (refereegranskat)abstract
    • Simulations and observations of collisionless shocks have shown that deviations of the nominal local shock normal orientation, that is, surface waves or ripples, are expected to propagate in the ramp and overshoot of quasi-perpendicular shocks. Here we identify signatures of a surface ripple propagating during a crossing of Earth's marginally quasi-parallel (theta(Bn) similar to 45 degrees) or quasi-parallel bow shock on 27 November 2015 06: 01: 44 UTC by the Magnetospheric Multiscale (MMS) mission and determine the ripple's properties using multispacecraft methods. Using two-dimensional hybrid simulations, we confirm that surface ripples are a feature of marginally quasi-parallel and quasi-parallel shocks under the observed solar wind conditions. In addition, since these marginally quasi-parallel and quasi-parallel shocks are expected to undergo a cyclic reformation of the shock front, we discuss the impact of multiple sources of nonstationarity on shock structure. Importantly, ripples are shown to be transient phenomena, developing faster than an ion gyroperiod and only during the period of the reformation cycle when a newly developed shock ramp is unaffected by turbulence in the foot. We conclude that the change in properties of the ripple observed by MMS is consistent with the reformation of the shock front over a time scale of an ion gyroperiod.
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25.
  • Goodrich, Katherine A., et al. (författare)
  • MMS Multipoint electric field observations of small-scale magnetic holes
  • 2016
  • Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:12, s. 5953-5959
  • Tidskriftsartikel (refereegranskat)abstract
    • Small-scale magnetic holes (MHs), local depletions in magnetic field strength, have been observed multiple times in the Earth's magnetosphere in the bursty bulk flow (BBF) braking region. This particular subset of MHs has observed scale sizes perpendicular to the background magnetic field (B) less than the ambient ion Larmor radius (rho(i)). Previous observations by Time History of Events and Macroscale Interactions during Substorms (THEMIS) indicate that this subset of MHs can be supported by a current driven by the E x B drift of electrons. Ions do not participate in the E x B drift due to the small-scale size of the electric field. While in the BBF braking region, during its commissioning phase, the Magnetospheric Multiscale (MMS) spacecraft observed a small-scale MH. The electric field observations taken during this event suggest the presence of electron currents perpendicular to the magnetic field. These observations also suggest that these currents can evolve to smaller spatial scales.
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26.
  • Goodrich, Katherine A., et al. (författare)
  • MMS Observations of Electrostatic Waves in an Oblique Shock Crossing
  • 2018
  • Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 123:11, s. 9430-9442
  • Tidskriftsartikel (refereegranskat)abstract
    • High-resolution particle and wave measurements taken during an oblique bow shock crossing by the Magnetospheric Multiscale (MMS) mission are analyzed. Two regions of differing magnetic behavior are identified within the shock, one with active magnetic fluctuations and one with laminar interplanetary magnetic field topology. A prominent reflected ion population is observed in both regions. The active magnetic region is characterized by large-amplitude (>100 mV/m) electrostatic solitary waves, electron Bernstein waves, and ion acoustic waves, along with intermittent current activity and localized electron heating. In the region of laminar magnetic field, ion acoustic waves are prominently observed. Solar wind ion deceleration is observed in both regions of active and laminar magnetic field. All observations suggest that solar wind deceleration can occur as a result of multiple independent processes, in this case current and ion-ion instabilities.
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27.
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28.
  • Granberg, Åsa, 1977- (författare)
  • Microbotryum violaceum on Silene dioica : understanding traits that influence plant-pathogen interactions
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The dynamics of a plant-pathogen interaction vary both within and among species. Both spatial structuring and specific genetic and life-history characteristics will affect the interaction and the outcome of a potential co-evolution between the two organisms. In this thesis I have studied the interaction between the wild perennial herb Silene dioica and its automictic, obligate anther smut Microbotryum violaceum MvSd. From the plant perspective, I have examined different aspects of biochemical resistance in S. dioica to M. violaceum MvSd. From the pathogen perspective, I have focused on the breeding system of M. violaceum MvSd and its connection to fitness and distribution of genetic diversity. I have used varying methods; glasshouse trails involving inoculation of plants with the pathogen, classical Mendelian analysis involving controlled crosses between plants, microscopic studies of spores and molecular DNA-analysis. With the results I demonstrate that resistance to M. violaceum MvSd in S. dioica can be specific to the attacking pathogen strain and also spatially highly diverse both within and among populations within a metapopulation. Together, these factors are likely to delay the establishment of the disease within host populations and reduce the spread and amount of disease, once it has been established. The results also suggest that the specific resistance expressed against two different M. violaceum MvSd strains were determined by separate gene systems and that, in both cases, the resistance was simply inherited. This implies a potential for relatively rapid response to M. violaceum-induced selection in S. dioica populations variable for resistance. My results also show that automixis clearly is the predominating breeding system of M. violaceum MvSd, similarly to what earlier has been shown for M. violaceum MvSl. Furthermore, I found lower levels of neutral genetic diversity in M. violaceum MvSd in the northern parts of Sweden, compared to what has been found in populations in more southern Europe. This result is consistent with predictions that populations in the outer regions of a species distribution have lower levels of genetic variation. Moreover, populations were highly differentiated in northern Sweden, which could have been generated by high selfing rates, genetic drift and high population turnover rates, all factors that coincide with life-history and ecology of M. violaceum MvSd. However, despite the general low variability in neutral genetic markers, I did find variation in fitness related traits, both within and among populations, as well as differences in infection ability between strains, suggesting there is a potential for co-evolution between S. dioica and M. violaceum MvSd in the area. To summarize, this thesis reflect a plant-pathogen system that is highly influenced by constant colonisation-extinction dynamics, which is likely to have influenced both the genetics of resistance in the plant and the breeding system of the pathogen and thus also the interaction between the two organisms.
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29.
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30.
  • Granberg, Åsa, et al. (författare)
  • Variation in breeding system traits within and among populations of Microbotryum violaceum on Silene dioica
  • 2008
  • Ingår i: International journal of plant sciences. - : University of Chicago Press. - 1058-5893 .- 1537-5315. ; 169:2, s. 293-303
  • Tidskriftsartikel (refereegranskat)abstract
    • Breeding systems exert profound effects on the amount and distribution of genetic diversity within and among populations. Knowledge of breeding systems is also important for understanding dynamics between coevolving organisms, e.g., pathogen‐host interactions. Here we study the breeding system of the obligate anther smut Microbotryum violaceum on Silene dioica. Microbotryum violaceum is capable of both inbreeding and outcrossing, but several recent studies on other host races have indicated that automixis via intrapromycelial mating is the predominant breeding system. Compared with conjugations between cells from different meioses, automixis results in slower loss of heterozygosity and faster production of infectious hypha. However, high rates of intrapromycelial matings have been suggested to invoke a fitness cost due to production of fewer infectious dikaryons. Working with single strains under standardized laboratory conditions, we studied traits that could influence the distribution of genetic variability and pathogen fitness. We found that intrapromycelial mating is the dominant conjugation form for M. violaceum var. dioica but that the breeding system varies, partly because of genetic differences, both within and among populations. Further, we did not find the predicted fitness reduction for intrapromycelial matings, suggesting that intrapromycelial mating is a highly favorable breeding system for M. violaceum.
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31.
  • Huyghe, Jeroen R, et al. (författare)
  • Genetic architectures of proximal and distal colorectal cancer are partly distinct
  • 2021
  • Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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32.
  • Imamura, Fumiaki, et al. (författare)
  • Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes : A pooled analysis of prospective cohort studies
  • 2018
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 15:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.
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33.
  • Imamura, Fumiaki, et al. (författare)
  • Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes : A pooled analysis of prospective cohort studies
  • 2020
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:6
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and findingsSeventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.ConclusionsConcentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.
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34.
  • Johlander, Andreas, 1990-, et al. (författare)
  • Shock ripples observed by the MMS spacecraft : ion reflection and dispersive properties
  • 2018
  • Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 60
  • Tidskriftsartikel (refereegranskat)abstract
    • Shock ripples are ion-inertial-scale waves propagating within the front region of magnetized quasi-perpendicular collisionless shocks. The ripples are thought to influence particle dynamics and acceleration at shocks. With the four magnetospheric multiscale (MMS) spacecraft, it is for the first time possible to fully resolve the small scale ripples in space. We use observations of one slow crossing of the Earth's non-stationary bow shock by MMS. From multi-spacecraft measurements we show that the non-stationarity is due to ripples propagating along the shock surface. We find that the ripples are near linearly polarized waves propagating in the coplanarity plane with a phase speed equal to the local Alfvén speed and have a wavelength close to 5 times the upstream ion inertial length. The dispersive properties of the ripples resemble those of Alfvén ion cyclotron waves in linear theory. Taking advantage of the slow crossing by the four MMS spacecraft, we map the shock-reflected ions as a function of ripple phase and distance from the shock. We find that ions are preferentially reflected in regions of the wave with magnetic field stronger than the average overshoot field, while in the regions of lower magnetic field, ions penetrate the shock to the downstream region.
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35.
  • Khankari, Nikhil K, et al. (författare)
  • Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.
  • 2020
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 29:4, s. 860-870
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.METHODS: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.RESULTS: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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36.
  • Kirchhoff, Tomas, et al. (författare)
  • Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
  • 2012
  • Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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37.
  • Labadie, Julia D., et al. (författare)
  • Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location
  • 2020
  • Ingår i: JNCI Cancer Spectrum. - : Oxford University Press. - 2515-5091. ; 4:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2sided. Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR = 0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P-het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P-het = .01) tumors. Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.
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38.
  • Lai, Heidi T. M., et al. (författare)
  • Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes : Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE)
  • 2022
  • Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:4, s. 854-863
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.RESEARCH DESIGN AND METHODS: We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged >= 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.RESULTS: During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P >= 0.1).CONCLUSIONS: Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
  •  
39.
  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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40.
  • Lewis, Harry C., et al. (författare)
  • Magnetospheric Multiscale measurements of turbulent electric fields in earth's magnetosheath : How do plasma conditions influence the balance of terms in generalized Ohm's law?
  • 2023
  • Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 30:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Turbulence is ubiquitous within space plasmas, where it is associated with numerous nonlinear interactions. Magnetospheric Multiscale (MMS) provides the unique opportunity to decompose the electric field (E) dynamics into contributions from different linear and nonlinear processes via direct measurements of the terms in generalized Ohm's law. Using high-resolution multipoint measurements, we compute the magnetohydrodynamic ( E MHD ), Hall ( E Hall ), electron pressure ( E P e ), and electron inertia ( E inertia ) terms for 60 turbulent magnetosheath intervals, to uncover the varying contributions to the dynamics as a function of scale for different plasma conditions. We identify key spectral characteristics of the Ohm's law terms: the Hall scale, k Hall , where E Hall becomes dominant over E MHD ; the relative amplitude of E P e to E Hall , which is constant in the sub-ion range; and the relative scaling of the nonlinear and linear components of E MHD and of E Hall , which are independent of scale. We find expressions for the characteristics as a function of plasma conditions. The underlying relationship between turbulent fluctuation amplitudes and ambient plasma conditions is discussed. Depending on the interval, we observe that E MHD and E Hall can be dominated by either nonlinear or linear dynamics. We find that E P e is dominated by its linear contributions, with a tendency for electron temperature fluctuations to dominate at small scales. The findings are not consistent with existing linear kinetic Alfvén wave theory for isothermal fluctuations. Our work shows how contributions to turbulent dynamics change in different plasma conditions, which may provide insight into other turbulent plasma environments.
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41.
  • Lindberg, Martin, et al. (författare)
  • Electron Kinetic Entropy across Quasi-Perpendicular Shocks
  • 2022
  • Ingår i: Entropy. - : MDPI AG. - 1099-4300. ; 24:6, s. 745-
  • Tidskriftsartikel (refereegranskat)abstract
    • We use Magnetospheric Multiscale (MMS) data to study electron kinetic entropy per particle Se across Earth's quasi-perpendicular bow shock. We have selected 22 shock crossings covering a wide range of shock conditions. Measured distribution functions are calibrated and corrected for spacecraft potential, secondary electron contamination, lack of measurements at the lowest energies and electron density measurements based on plasma frequency measurements. All crossings display an increase in electron kinetic entropy across the shock Delta S-e being positive or zero within their error margin. There is a strong dependence of Delta S-e on the change in electron temperature, Delta T-e, and the upstream electron plasma beta, beta(e). Shocks with large Delta T-e have large Delta S-e. Shocks with smaller beta(e) are associated with larger Delta S-e. We use the values of Delta S-e, Delta Te and density change Delta n(e) to determine the effective adiabatic index of electrons for each shock crossing. The average effective adiabatic index is = 1.64 +/- 0.07.
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42.
  • Marklund, Matti, et al. (författare)
  • Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
  • 2019
  • Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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43.
  • Mavaddat, Nasim, et al. (författare)
  • Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
  • 2015
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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44.
  • Murphy, Neil, et al. (författare)
  • Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
  • 2020
  • Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1300-1312.e20
  • Tidskriftsartikel (refereegranskat)abstract
    • Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
  •  
45.
  • Nakamura, Rumi, et al. (författare)
  • Multiscale Currents Observed by MMS in the Flow Braking Region
  • 2018
  • Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 123:2, s. 1260-1278
  • Tidskriftsartikel (refereegranskat)abstract
    • We present characteristics of current layers in the off-equatorial near-Earth plasma sheet boundary observed with high time-resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn-dusk direction. Field-aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field-aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field-aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold ExB drifting ions, and magnetized electrons. Our observations show that both the near-Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field-aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field-aligned currents in the off-equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field-aligned current system.
  •  
46.
  • Nakamura, Rumi, et al. (författare)
  • Near-Earth plasma sheet boundary dynamics during substorm dipolarization
  • 2017
  • Ingår i: Earth Planets and Space. - : Springer Berlin/Heidelberg. - 1343-8832 .- 1880-5981. ; 69
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on the large-scale evolution of dipolarization in the near-Earth plasma sheet during an intense (AL similar to -1000 nT) substorm on August 10, 2016, when multiple spacecraft at radial distances between 4 and 15 RE were present in the night-side magnetosphere. This global dipolarization consisted of multiple short-timescale (a couple of minutes) Bz disturbances detected by spacecraft distributed over 9 MLT, consistent with the large-scale substorm current wedge observed by ground-based magnetometers. The four spacecraft of the Magnetospheric Multiscale were located in the southern hemisphere plasma sheet and observed fast flow disturbances associated with this dipolarization. The high-time-resolution measurements from MMS enable us to detect the rapid motion of the field structures and flow disturbances separately. A distinct pattern of the flow and field disturbance near the plasma boundaries was found. We suggest that a vortex motion created around the localized flows resulted in another fieldaligned current system at the off-equatorial side of the BBF-associated R1/R2 systems, as was predicted by the MHD simulation of a localized reconnection jet. The observations by GOES and Geotail, which were located in the opposite hemisphere and local time, support this view. We demonstrate that the processes of both Earthward flow braking and of accumulated magnetic flux evolving tailward also control the dynamics in the boundary region of the near-Earth plasma sheet.
  •  
47.
  • Pan, Dong-Xiao, et al. (författare)
  • Rippled Electron-Scale Structure of a Dipolarization Front
  • 2018
  • Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:22, s. 12116-12124
  • Tidskriftsartikel (refereegranskat)abstract
    • We use the Magnetospheric Multiscale mission to investigate electron-scale structures at a dipolarization front. The four spacecraft are separated by electron scales and observe large differences in plasma and field parameters within the dipolarization front, indicating strong deviation from typically assumed plane or slightly curved front surface. We attribute this to ripples generated by the lower hybrid drift instability (LHDI) with wave number of k(rho e)similar or equal to 0.4 and maximum wave potential of similar to 1 kV similar to k(B)T(e). Power law-like spectra of E-perpendicular to with slope of -3 indicates the turbulent cascade of LHDI. LHDI is observed together with bursty high-frequency parallel electric fields, suggesting coupling of LHDI to higher-frequency electrostatic waves. Plain Language Summary Dipolarization fronts (DFs) are narrow boundaries with sharp enhancement of magnetic field, located at the leading part of fast plasma jets observed in Earth's magnetotail. DFs are typically assumed to be smooth boundaries at scales comparable to the ion gyroradius and below. In this study, we use the four Magnetospheric Multiscale spacecraft separated by several electron gyroradii to investigate fine structure of a DF. Surprisingly, we observe significant differences in the fields and plasma measurements between the spacecraft despite their small separation. We attribute these signatures to electron-scale disturbances propagating along the DF surface, and thus the DF surface is not smooth as expected but rather rippled. The ripples develop as a result of a plasma instability driven by the strong inhomogeneities present at the DF. The fact that the ripples have such small scales means that they can effectively interact with plasma electrons.
  •  
48.
  • Papadimitriou, Nikos, et al. (författare)
  • Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis
  • 2020
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value=0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value=0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
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49.
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50.
  • Peedu, Elisabet, 1985- (författare)
  • Metapopulations dynamics and sex-specific resource allocation in Silene dioica
  • 2018
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Rising archipelagos provide unique settings for the study of the temporal and spatial dynamics of their biota. This offers the possibility to study the ecology and genetics of early successional processes; both between islands that differ in age and within islands when already established organisms have to keep pace with the changing environment. I have worked in the Skeppsvik Archipelago housing about 100 islands that due to land uplift vary in age, thus representing various stages of primary succession. I have utilized a naturally created metapopulation of Silene dioica, which in this archipelago is a dominant plant of the deciduous border, offering the possibility to study subpopulations on islands of different ages and in different phases of primary succession. Many plant species exist as metapopulations, which consists of many local populations which may differ in size and degree of connectivity. Metapopulations are further characterized by recurrent colorizations and extinctions of local populations, meaning that a species continually must disperse and relocate to allow for persistence in this system. For a dioecious plant species, gene flow is in the shape of seeds and pollen and to allow for the persistence of populations, it is necessary that levels of seed dispersal and pollen gene flow are enough to ensure both colonisation, establishment and subsequent population growth. Levels of seed dispersal and pollen gene flow is in turn influenced by how the two sexes partition resources between reproduction, growth and survival.In paper I, I combined a field survey, a common garden experiment and a nine-year demographic study to assess the demographic consequences of sex-specific resource allocation and to investigate if differential costs of reproduction may be a driver in the evolution of sexual dimorphism in dioecious Silene dioica. Significant somatic intersexual dimorphism was found with females being the larger sex, both in terms of above – and belowground biomass. Furthermore, the reproductive effort of females exceeds that of males across a growing season which largely confirms what has been observed earlier in dioecious, herbaceous plant species. According to the cost of reproduction hypothesis, high reproductive investment should result in trade-offs with somatic and/or life-history traits. Somatic trade-offs were not observed, and instead I found strong, positive associations between reproductive investment and vegetative growth in both males and females. Compensation mechanisms were found in both sexes although females are generally more efficient at compensating their reproductive costs. At the end of a flowering season, after having paid the current costs of reproduction, females are better than males at provisioning perennial roots and rosettes potentially influencing the ability to set future flower buds and winter survival. Trade-offs were found between current and future reproduction and survival, but this is condition dependent and compensation through frequency of flowering plays an important role. The cost of reproduction hypothesis appears to play some role in driving the somatic and demographic sexual dimorphisms observed in this system but sexual selection acting on males will be a fruitful avenue for future research.In paper II, I investigated the population genetic consequences of metapopulation dynamics in Silene dioica. The occurrence of islands in different phases of primary succession together with successional gradients across islands, makes it possible to investigate the genetic dynamics occurring in an age-structured metapopulation across several hierarchical levels. Genetic diversity and differentiation were estimated in eight young, recently colonised populations and in ten populations of an intermediate successional stage. Young populations were less genetically diverse compared to older populations, indicating that bottlenecks, created by small founding groups derived from a limited number of source populations, reduce the genetic diversity within newly founded populations. The observation of strong genetic structure both between islands and between patches with islands, indicates that gene flow is restricted across several spatial levels in this system. However, the lack of statistically significant differences in genetic differentiation between young and intermediate populations, indicates that levels of gene flow may not be high enough to reduce the genetic differentiation that arise from the initial founder event.The patterns of sexual dimorphism and the roles of males and females in Silene dioica have evolved to allow persistence in an ecological and population context of this species. The nature of this habitat, where islands rise up from the sea creating new environments for colonisation while at the same time, autogenic primary succession processes eventually leads to extinction, means that S. dioica continuously must relocate within successional phases for its persistence. The obvious success of this dioecious plant is apparent as it is one of the few dominant species in the deciduous border. This suggests that levels of seed dispersal and gene flow are sufficient enough to allow for establishment and persistence of island populations and that the sexual dimorphisms that have evolved in this metapopulation system act to increase levels of gene flow. The "live hard – die young" strategy, with extensive flowering bouts, which we find in the males may have evolved as a way of maintaining sufficient levels of genetic diversity in the metapopulation but will only be a possible strategy if there are continuous opportunities for re-establishments. Thus, the continuous land uplift that is occurring in the northern part of the Gulf of Bothnia may very well be a prerequisite for the long-term persistence of this dioecious, perennial plant species.
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