| 1. |
|
|
| 2. |
- Dixon-Suen, Suzanne C, et al.
(author)
-
Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
-
In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
-
Journal article (peer-reviewed)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.
|
|
| 3. |
- Ahearn, Thomas U., et al.
(author)
-
Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
-
In: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
-
Journal article (peer-reviewed)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.
|
|
| 4. |
- Escala-Garcia, Maria, et al.
(author)
-
A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
-
Journal article (peer-reviewed)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.
|
|
| 5. |
- Mueller, Stefanie H., et al.
(author)
-
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
-
In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
-
Journal article (peer-reviewed)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
|
|
| 6. |
- Shu, Xiang, et al.
(author)
-
Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
-
In: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
-
Journal article (peer-reviewed)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
|
|
| 7. |
- Hahn, Katharina, et al.
(author)
-
Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome
- 2017
-
In: Amyloid. - : TAYLOR & FRANCIS LTD. - 1350-6129 .- 1744-2818. ; 24:2, s. 78-86
-
Journal article (peer-reviewed)abstract
- Transthyretin-derived (ATTR) amyloidosis is a frequent finding in carpal tunnel syndrome. We tested the following hypotheses: the novel fluorescent amyloid ligand heptameric formic thiophene acetic acid (h-FTAA) has a superior sensitivity for the detection of amyloid compared with Congo red-staining; Amyloid load correlates with patient gender and/or patient age. We retrieved 208 resection specimens obtained from 184 patients with ATTR amyloid in the carpal tunnel. Serial sections were stained with Congo red, h-FTAA and an antibody directed against transthyretin (TTR). Stained sections were digitalized and forwarded to computational analyses. The amount of amyloid was correlated with patient demographics. Amyloid stained intensely with h-FTAA and an anti-TTR-antibody. Congo red-staining combined with fluorescence microscopy was significantly less sensitive than h-FTAA-fluorescence and TTR-immunostaining: the highest percentage area was found in TTR-immunostained sections, followed by h-FTAA and Congo red. The Pearson correlation coefficient was .8 (Congo red vs. h-FTAA) and .9 (TTR vs. h-FTAA). Amyloid load correlated with patient gender, anatomical site and patient age. h-FTAA is a highly sensitive method to detect even small amounts of ATTR amyloid in the carpal tunnel. The staining protocol is easy and h-FTAA may be a much more sensitive procedure to detect amyloid at an earlier stage.
|
|
| 8. |
- Kapoor, Pooja Middha, et al.
(author)
-
Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
-
In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
-
Journal article (peer-reviewed)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
|
|
| 9. |
- Middha, Pooja K., et al.
(author)
-
A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
-
In: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
-
Journal article (peer-reviewed)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
|
|
| 10. |
- Okada, Yukinori, et al.
(author)
-
Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
-
Journal article (peer-reviewed)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
|
|
| 11. |
- Andersson, Odd E., et al.
(author)
-
C-axis resistance of HgCl2 intercalated graphite as a function of temperature and pressure
- 1989
-
In: Synthetic Metals volume 34. - Lausanne : Elsevier Sequoia SA. ; , s. 485-490
-
Conference paper (peer-reviewed)abstract
- The c-axis resistance of stage 3 HgCl2 intercalated graphite has been measured as a function of temperature T and pressure p in the range 40 to 300 K and up to 1 GPa (10 kbar). The absolute resistivity and its T- and p- dependence are all in good agreement with data for other acceptor compounds. The measurements show that a previosly unknown phase transformation occurs above 0.4 GPa. Below 250 K the high pressure phase is metastable down to zero pressure, and an x-ray diffraction analysis of metastable material shows that no stage change occurs. The transition thus probably leads to a different in-plane structure characterized by a more densely packed intercalate layer.
|
|
| 12. |
- Arthur-Farraj, Peter J., et al.
(author)
-
c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration
- 2012
-
In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 75:4, s. 633-647
-
Journal article (peer-reviewed)abstract
- The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.
|
|
| 13. |
- Azour, Farivar, et al.
(author)
-
Invasion rate and population characteristics of the round goby Neogobius melanostomus: effects of density and invasion history
- 2015
-
In: Aquatic Biology. - : Inter-Research Science Center. - 1864-7782 .- 1864-7790. ; 24:1, s. 41-52
-
Journal article (peer-reviewed)abstract
- Round goby Neogobius melanostomus is currently one of the most wide-ranging invasive fish species in Europe and North America. The present study demonstrates how the distribution of round goby has expanded from 2008 to 2013 at a rate of about 30 km yr(-1) along the Danish coastline in the western Baltic Sea. Further analyses showed that fish from an established high-density round goby population were slow-growing and displayed poorer condition (weight at age and hepatosomatic index) compared to fish sampled from recently invaded locations (i.e. at the forefront of the distribution range). The established population revealed a broad age distribution and a 1:1 gender ratio, while fish from a recently invaded site were primarily of intermediate ages with a male-biased gender ratio. Otolith analyses suggested that the oldest individuals from the recently invaded area experienced superior growth conditions only in the most recent years, suggesting immigration into the area as adults. Our results suggest that intraspecific competition for food may cause continued dispersal of the species and that population demographics likely relate to invasion history.
|
|
| 14. |
- Behrens, Anders, et al.
(author)
-
CoGNIT Automated Tablet Computer Cognitive Testing in Patients With Mild Cognitive Impairment : Feasibility Study
- 2022
-
In: JMIR Formative Research. - : JMIR Publications Inc.. - 2561-326X. ; 6:3
-
Journal article (peer-reviewed)abstract
- Background: Early diagnosis of cognitive disorders is becoming increasingly important. Limited resources for specialist assessment and an increasing demographical challenge warrants the need for efficient methods of evaluation. In response, CoGNIT, a tablet app for automatic, standardized, and efficient assessment of cognitive function, was developed. Included tests span the cognitive domains regarded as important for assessment in a general memory clinic (memory, language, psychomotor speed, executive function, attention, visuospatial ability, manual dexterity, and symptoms of depression). Objective: The aim of this study was to assess the feasibility of automatic cognitive testing with CoGNIT in older patients with symptoms of mild cognitive impairment (MCI). Methods: Patients older than 55 years with symptoms of MCI (n=36) were recruited at the research clinic at the Blekinge Institute of Technology (BTH), Karlskrona, Sweden. A research nurse administered the Mini-Mental State Exam (MMSE) and the CoGNIT app on a tablet computer. Technical and testing issues were documented. Results: The test battery was completed by all 36 patients. One test, the four-finger-tapping test, was performed incorrectly by 42% of the patients. Issues regarding clarity of instructions were found in 2 tests (block design test and the one finger-tapping test). Minor software bugs were identified. Conclusions: The overall feasibility of automatic cognitive testing with the CoGNIT app in patients with symptoms of MCI was good. The study highlighted tests that did not function optimally. The four-finger-tapping test will be discarded, and minor improvements to the software will be added before further studies and deployment in the clinic. © 2022 JMIR Publications Inc.. All right reserved.
|
|
| 15. |
- Behrens, Anders, et al.
(author)
-
Sleep disturbance predicts worse cognitive performance in subsequent years : A longitudinal population-based cohort study
- 2023
-
In: Archives of gerontology and geriatrics (Print). - : Elsevier. - 0167-4943 .- 1872-6976. ; 106
-
Journal article (peer-reviewed)abstract
- Background: Poor sleep is a potential modifiable risk factor for later life development cognitive impairment. The aim of this study is to examine if subjective measures of sleep duration and sleep disturbance predict future cognitive decline in a population-based cohort of 60, 66, 72 and 78-year-olds with a maximal follow up time of 18 years. Methods: This study included participants from the Swedish National Study on Ageing and Care – Blekinge, with assessments 2001–2021. A cohort of 60 (n = 478), 66 (n = 623), 72 (n = 662) and 78 (n = 548) year-olds, were assessed at baseline and every 6 years until 78 years of age. Longitudinal associations between sleep disturbance (sleep scale), self-reported sleep duration and cognitive tests (Mini Mental State Examination and the Clock drawing test) were examined together with typical confounders (sex, education level, hypertension, hyperlipidemia, smoking status, physical inactivity and depression). Results: There was an association between sleep disturbance at age 60 and worse cognitive function at ages 60, 66 and 72 years in fully adjusted models. The association was attenuated after bootstrap-analysis for the 72-year-olds. The items of the sleep scale most predictive of later life cognition regarded nightly awakenings, pain and itching and daytime naps. Long sleep was predictive of future worse cognitive function. Conclusion: Sleep disturbance was associated with worse future cognitive performance for the 60-year-olds, which suggests poor sleep being a risk factor for later life cognitive decline. Questions regarding long sleep, waking during the night, pain and itching and daytime naps should be further explored in future research and may be targets for intervention.
|
|
| 16. |
- Chung, Sharon A., et al.
(author)
-
Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production
- 2011
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001323-
-
Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with (Pheterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
|
|
| 17. |
- Chung, Sharon A, et al.
(author)
-
European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus
- 2009
-
In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:8, s. 2448-2456
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease. METHODS: SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations. RESULTS: In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96). CONCLUSION: This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
|
|
| 18. |
- Demichev, Vadim, et al.
(author)
-
A time-resolved proteomic and prognostic map of COVID-19
- 2021
-
In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
-
Journal article (peer-reviewed)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
|
|
| 19. |
- Dupont, Daniel M, et al.
(author)
-
Protein-binding RNA aptamers affect molecular interactions distantly from their binding sites.
- 2015
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
-
Journal article (peer-reviewed)abstract
- Nucleic acid aptamer selection is a powerful strategy for the development of regulatory agents for molecular intervention. Accordingly, aptamers have proven their diligence in the intervention with serine protease activities, which play important roles in physiology and pathophysiology. Nonetheless, there are only a few studies on the molecular basis underlying aptamer-protease interactions and the associated mechanisms of inhibition. In the present study, we use site-directed mutagenesis to delineate the binding sites of two 2´-fluoropyrimidine RNA aptamers (upanap-12 and upanap-126) with therapeutic potential, both binding to the serine protease urokinase-type plasminogen activator (uPA). We determine the subsequent impact of aptamer binding on the well-established molecular interactions (plasmin, PAI-1, uPAR, and LRP-1A) controlling uPA activities. One of the aptamers (upanap-126) binds to the area around the C-terminal α-helix in pro-uPA, while the other aptamer (upanap-12) binds to both the β-hairpin of the growth factor domain and the kringle domain of uPA. Based on the mapping studies, combined with data from small-angle X-ray scattering analysis, we construct a model for the upanap-12:pro-uPA complex. The results suggest and highlight that the size and shape of an aptamer as well as the domain organization of a multi-domain protein such as uPA, may provide the basis for extensive sterical interference with protein ligand interactions considered distant from the aptamer binding site.
|
|
| 20. |
- Forslund, Tommie, et al.
(author)
-
El Apego Va a Juicio: Problemas de Custodia y Protección Infantil : [Attachment goes to court: Child protection and custody issues]
- 2021
-
In: Anuario de psicología jurídica. - : Colegio Oficial de la Psicologia de Madrid. - 1133-0740 .- 2174-0542. ; 32:1, s. 115-139
-
Journal article (peer-reviewed)abstract
- Attachment theory and research are drawn upon in many applied settings, including family courts, but misunderstandings are widespread and sometimes result in misapplications. The aim of this consensus statement is, therefore, to enhance understanding, counter misinformation, and steer family-court utilisation of attachment theory in a supportive, evidence-based direction, especially with regard to child protection and child custody decision-making. This article is divided into two parts. In the first part, we address problems related to the use of attachment theory and research in family courts, and discuss reasons for these problems. To this end, we examine family court applications of attachment theory in the current context of the best-interest-of-the-child standard, discuss misunderstandings regarding attachment theory, and identify factors that have hindered accurate implementation. In the second part, we provide recommendations for the application of attachment theory and research. To this end, we set out three attachment principles: the child's need for familiar, non-abusive caregivers; the value of continuity of good-enough care; and the benefits of networks of attachment relationships. We also discuss the suitability of assessments of attachment quality and caregiving behaviour to inform family court decision-making. We conclude that assessments of caregiver behaviour should take center stage. Although there is dissensus among us regarding the use of assessments of attachment quality to inform child custody and child-protection decisions, such assessments are currently most suitable for targeting and directing supportive interventions. Finally, we provide directions to guide future interdisciplinary research collaboration.
|
|
| 21. |
|
|
| 22. |
- Fragoulis, George E., et al.
(author)
-
2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases
- 2023
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82:6, s. 742-753
-
Journal article (peer-reviewed)abstract
- Objectives: To develop EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods: An international Task Force (TF) (22 members/15 countries) formulated recommendations, supported by systematic literature review findings. Level of evidence and grade of recommendation were assigned for each recommendation. Level of agreement was provided anonymously by each TF member. Results: Four overarching principles (OAP) and eight recommendations were developed. The OAPs highlight the need for infections to be discussed with patients and with other medical specialties, in accordance with national regulations. In addition to biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for which screening for latent tuberculosis (TB) should be performed, screening could be considered also before conventional synthetic DMARDs, glucocorticoids and immunosuppressants. Interferon gamma release assay should be preferred over tuberculin skin test, where available. Hepatitis B (HBV) antiviral treatment should be guided by HBV status defined prior to starting antirheumatic drugs. All patients positive for hepatitis-C-RNA should be referred for antiviral treatment. Also, patients who are non-immune to varicella zoster virus should be informed about the availability of postexposure prophylaxis should they have contact with this pathogen. Prophylaxis against Pneumocystis jirovecii seems to be beneficial in patients treated with daily doses >15-30 mg of prednisolone or equivalent for >2-4 weeks. Conclusions: These recommendations provide guidance on the screening and prevention of chronic and opportunistic infections. Their adoption in clinical practice is recommended to standardise and optimise care to reduce the burden of opportunistic infections in people living with AIIRD.
|
|
| 23. |
- Gateva, Vesela, et al.
(author)
-
A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus
- 2009
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:11, s. 1228-1233
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
|
|
| 24. |
- Graham, R. Robert, et al.
(author)
-
Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus
- 2007
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:16, s. 6758-6763
-
Journal article (peer-reviewed)abstract
- Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
|
|
| 25. |
- Granqvist, Pehr, et al.
(author)
-
Disorganized attachment in infancy : a review of the phenomenon and its implications for clinicians and policy-makers
- 2017
-
In: Attachment & Human Development. - : Informa UK Limited. - 1461-6734 .- 1469-2988. ; 19:6, s. 534-558
-
Research review (peer-reviewed)abstract
- Disorganized/Disoriented (D) attachment has seen widespread interest from policy makers, practitioners, and clinicians in recent years. However, some of this interest seems to have been based on some false assumptions that (1) attachment measures can be used as definitive assessments of the individual in forensic/child protection settings and that disorganized attachment (2) reliably indicates child maltreatment, (3) is a strong predictor of pathology, and (4) represents a fixed or static trait of the child, impervious to development or help. This paper summarizes the evidence showing that these four assumptions are false and misleading. The paper reviews what is known about disorganized infant attachment and clarifies the implications of the classification for clinical and welfare practice with children. In particular, the difference between disorganized attachment and attachment disorder is examined, and a strong case is made for the value of attachment theory for supportive work with families and for the development and evaluation of evidence-based caregiving interventions.
|
|
| 26. |
- Green, Leon, et al.
(author)
-
Sperm performance limits the reproduction of an invasive fish in novel salinities
- 2021
-
In: Diversity and Distributions. - : Wiley. - 1366-9516 .- 1472-4642. ; 27:6, s. 1091-1105
-
Journal article (peer-reviewed)abstract
- Aim: The few fish species able to reproduce across wide osmotic ranges either plastically acclimate sperm performance to, or are locally adapted to, different salinities. The invasive round goby (Neogobius melanostomus) is spreading in Eurasia and the Americas, into both fresh and brackish water. We aim to understand if reproduction in different salinities is affected by an ability to acclimate. Location: Brackish and freshwater systems of northern Europe and the Baltic Sea. Methods: We cross-exposed round gobies of freshwater and brackish origin to 0 and 16 practical salinity units (PSU), and the fish were given nest boxes in which to spawn. After 4weeks, we measured their sperm performance in both 0 and 16 PSU; fertilization success of each egg clutch was measured through visual analysis of eggs. Clutches were split and allowed to develop in both 0 and 16 PSU salinity, and reproductive success (zygote development) was measured 20±1days later. Responses were analysed using generalized mixed models. Results: After a month, the fish showed no plasticity in sperm performance to their acclimation salinity, regardless of their origin. Sperm velocity was highest in the salinity similar to the males’ origin. Significantly lower fertilization success was measured for individuals that reproduced outside their salinity of origin despite recurring spawning events in all treatment groups. Among fertilized eggs, zygote development was similar regardless of salinity treatment of either eggs or parents. Main Conclusions: Short-term acclimation to new salinities does not affect sperm performance in the round goby. Alternative hypotheses such as local adaption should be further investigated. Limits to the species’ reproductive success, and therefore invasion processes, are likely dependent on environment-phenotype matches. Fish of brackish origin spawned successfully in freshwater, pointing to an increased risk of introducing populations of brackish origin into freshwater.
|
|
| 27. |
- Harley, John B., et al.
(author)
-
Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci
- 2008
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:2, s. 204-10
-
Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
|
|
| 28. |
- Hom, Geoffrey, et al.
(author)
-
Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
- 2008
-
In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 358:9, s. 900-909
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4are established susceptibility genes; there is strong evidence for the existence of additional risk loci.METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10−10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10−11).
|
|
| 29. |
|
|
| 30. |
- Jung, Audrey Y, et al.
(author)
-
Distinct reproductive risk profiles for intrinsic-like breast cancer subtypes : pooled analysis of population-based studies
- 2022
-
In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:12, s. 1706-1719
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER) positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.METHODS: Analyses included up to 23,353 cases, and 71,072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative) and by invasiveness. All statistical tests were 2-sided.RESULTS: Compared to nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46; for multiparous women with luminal A-like tumors 20-<25 years after last birth and 45-<50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95%CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95%CI = 0.79 to 1.34, for multiparous women 25 to < 30 years after last birth). Older age at first birth (P-heterogeneity<.001 for triple-negative compared to luminal-A like) and breastfeeding (P-heterogeneity<.001 for triple-negative compared to luminal-A like) were associated with lower risk of triple-negative but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.CONCLUSION: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared to other subtypes, with implications for the understanding of disease etiology and risk prediction.
|
|
| 31. |
- Kapoor, Pooja Middha, et al.
(author)
-
Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium
- 2020
-
In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 49:1, s. 216-232
-
Journal article (peer-reviewed)abstract
- Background: Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions. Methods: Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions. Results: Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth. Conclusions: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.
|
|
| 32. |
- Langefeld, Carl D., et al.
(author)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
|
|
| 33. |
|
|
| 34. |
- Wang, Li-San, et al.
(author)
-
Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
-
In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
-
Journal article (peer-reviewed)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
|
|
| 35. |
- Wang, Ning, et al.
(author)
-
Selective IgA deficiency in autoimmune diseases
- 2011
-
In: Molecular Medicine. - Baltimore, Md. : Johns Hopkins University Press. - 1076-1551 .- 1528-3658. ; 17:11-12, s. 1383-
-
Research review (peer-reviewed)abstract
- Selective IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves' disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) based both on our own, recent, large scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the MHC region has been reported. In addition, non-MHC genes, such as IFIH1 and CLEC16A, are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.
|
|
