| 121. |
- Lopez-Isac, E, et al.
(författare)
-
GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4955-
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
|
|
| 122. |
- Mahajan, Anubha, et al.
(författare)
-
Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
- 2015
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
|
|
| 123. |
- Major, B., et al.
(författare)
-
Investigation of high harmonic generation using a high-power, 5-fs laser in a loose-focusing geometry
- 2017
-
Ingår i: 2017 Conference on Lasers and Electro-Optics Europe & European Quantum Electronics Conference (CLEO/Europe-EQEC). - : IEEE. - 9781509067367
-
Konferensbidrag (refereegranskat)abstract
- Summary form only given. Since its first observation almost three decades ago high-order harmonic generation (HHG) in gases became a reliable source of extreme ultraviolet (XUV) pulses, which gave the possibility to study electronic processes on their natural timescale [1, 2]. While the main building blocks of the experimental setups for gas HHG are the same in almost all cases, the focusing or medium geometry varies from realization to realization based on, for example, the available laser power [3, 4].In this work we study HHG in a loose focusing geometry by focusing a ~50-mm diameter (FWHM) beam with a mirror of 16-m focal length (f-number ~320). The main subject of this analysis is to compare low pressure - long interaction length (few millibars and tens of centimeters) with high pressure - short medium (hundreds of millibars and a few millimeters) scenarios and understand the underlying reasons for the observed XUV radiation parameters. The experiments are carried out with on target 35 mJ, sub-5 fs, 740 nm central wavelength pulses provided by an optical parametric synthesizer [5], producing high-energy pulses at the 100 eV spectral region [6]. The theoretical analysis is performed by simulation code based on a three-dimensional nonadiabatic model [7,8]. The good agreement between the experimental and simulation data (see Fig. 1) allows us to use the theoretical findings to gain better insight on the exact phase-matching processes providing the observed features. This detailed description is used to draw general conclusions of the high-harmonic generation process.
|
|
| 124. |
- Manning, Alisa, et al.
(författare)
-
A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
-
Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
-
Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
|
|
| 125. |
- Mariscal-Arcas, M., et al.
(författare)
-
Dietary exposure assessment of pregnant women to bisphenol-A from cans and microwave containers in Southern Spain
- 2009
-
Ingår i: Food and Chemical Toxicology. - : Elsevier. - 0278-6915 .- 1873-6351. ; 47:2, s. 506-510
-
Tidskriftsartikel (refereegranskat)abstract
- Bisphenol-A (BPA), material for polycarbonate and epoxy resin synthesis, has been detected in canned food, among other food containers. In mammal studies, BPA transferred from mother to fetus, caused abnormality of reproductive organs, and advanced female puberty. BPA from canned food and microwave containers was analyzed using high performance liquid chromatography and gas chromatography-mass spectrometry. Population was cohort of mother-son pairs established at Granada University Hospital. Frequency of food consumption (including canned food) was studied with a semi-quantitative questionnaire. The most frequently consumed products were fish and juice cans, consumed 1-3 times/week by 34.7% and 22.3% of the study population, respectively. The women made little use of polymer microwave containers, 52.8% never using them and 45.9% using them <3 times/month. Estimated mean (standard deviation) intake of BPA was 1.1(0.839) microgram/day. No relationship was found between BPA exposure and maternal socio-demographic variables or newborn characteristics. This study offers the first estimate of BPA dietary intake by pregnant women in Southern Spain. The consumption of canned foods and drinks by these women means that their exposure was lower than EFSA estimates for the European population. Nevertheless it remains of concern, given the proven undesirable effects of low-level exposure and higher susceptibility of pregnant women.
|
|
| 126. |
- Matricardi, PM, et al.
(författare)
-
EAACI Molecular Allergology User's Guide
- 2016
-
Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley. - 1399-3038. ; 2727 Suppl 23, s. 1-250
-
Tidskriftsartikel (refereegranskat)
|
|
| 127. |
- Monteagudo, Celia, 1984-, et al.
(författare)
-
Effects of maternal diet and environmental exposure to organochlorine pesticides on newborn weight in Southern Spain
- 2016
-
Ingår i: Chemosphere. - Oxford, United Kingdom : Elsevier. - 0045-6535 .- 1879-1298. ; 156, s. 135-142
-
Tidskriftsartikel (refereegranskat)abstract
- An appropriate eating pattern is essential during childbearing years and pregnancy to ensure a healthy pregnancy and newborn. Our group developed a Mediterranean Diet Score for Pregnancy (MDS-P) based on the MD and the specific need of pregnant women for Fe, Ca, and folic acid. Humans are daily exposed to endocrine disruptors, which may alter body weight and hormone system regulation. This study analyzed the relationship of maternal diet and in utero exposure to organochlorine pesticides (OCPs) with newborn weight in mothers and newborns from Southern Spain. Higher MDS-P score, folic acid supplementation, and greater in utero exposure to endosulfan-diol and endosulfan-1 were related to higher newborn weight. MDS-P score was not associated with maternal weight gain during pregnancy (above or below 12 Kg). Residues from one or more OCPs were detected in 96.5% of umbilical cord serum samples from 320 newborns. The most frequent residues were endosulfans (96.5%). The presence of endosulfan-diol, endosulfan-I, p-p´DDT, folic acid supplementation, and a higher MDS-P (>8) were predictive factors for newborn overweight (>3500 g). Conversely, smoking during pregnancy, shorter gestation time (32-36 vs. 37-39 weeks), and lesser maternal weight gain during pregnancy predicted lower newborn weight (<2500 g). These results indicate prenatal exposure to OCPs in Southern Spain and its possible impact on the weight of healthy full-term newborns. Further studies are warranted to interpret the consequences of this exposure and identify preventive measures. Adherence to the MD and folic acid supplementation during pregnancy emerged as predictive factors for overweight in newborns.
|
|
| 128. |
- Neale, Benjamin M., et al.
(författare)
-
Testing for an Unusual Distribution of Rare Variants
- 2011
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:3
-
Tidskriftsartikel (refereegranskat)abstract
- Technological advances make it possible to use high-throughput sequencing as a primary discovery tool of medical genetics, specifically for assaying rare variation. Still this approach faces the analytic challenge that the influence of very rare variants can only be evaluated effectively as a group. A further complication is that any given rare variant could have no effect, could increase risk, or could be protective. We propose here the C-alpha test statistic as a novel approach for testing for the presence of this mixture of effects across a set of rare variants. Unlike existing burden tests, C-alpha, by testing the variance rather than the mean, maintains consistent power when the target set contains both risk and protective variants. Through simulations and analysis of case/control data, we demonstrate good power relative to existing methods that assess the burden of rare variants in individuals.
|
|
| 129. |
|
|
| 130. |
- Papadopoulos, Nikolaos G, et al.
(författare)
-
Research needs in allergy: an EAACI position paper, in collaboration with EFA.
- 2012
-
Ingår i: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 2:1
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
|
|
