| 1. |
- Ellinghaus, David, et al.
(author)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 2. |
- Erdmann, Jeanette, et al.
(author)
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New susceptibility locus for coronary artery disease on chromosome 3q22.3
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:3, s. 280-282
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Journal article (peer-reviewed)abstract
- We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in similar to 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).
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| 3. |
- Gasman, Danny, et al.
(author)
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MINDS Abundant water and varying C/O across the disk of Sz 98 as seen by JWST/MIRI
- 2023
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 679
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Journal article (peer-reviewed)abstract
- Context. The Mid-InfraRed Instrument (MIRI) Medium Resolution Spectrometer (MRS) on board the James Webb Space Telescope (JWST) allows us to probe the inner regions of protoplanetary disks, where the elevated temperatures result in an active chemistry and where the gas composition may dictate the composition of planets forming in this region. The disk around the classical T Tauri star Sz 98, which has an unusually large dust disk in the millimetre with a compact core, was observed with the MRS, and we examine its spectrum here.Aims. We aim to explain the observations and put the disk of Sz 98 in context with other disks, with a focus on the H2O emission through both its ro-vibrational and pure rotational emission. Furthermore, we compare our chemical findings with those obtained for the outer disk from Atacama Large Millimeter/submillimeter Array (ALMA) observations.Methods. In order to model the molecular features in the spectrum, the continuum was subtracted and local thermodynamic equilibrium (LTE) slab models were fitted. The spectrum was divided into different wavelength regions corresponding to H2O lines of different excitation conditions, and the slab model fits were performed individually per region.Results. We confidently detect CO, H2O, OH, CO2, and HCN in the emitting layers. Despite the plethora of H2O lines, the isotopo-logue (H2O)-O-18 is not detected. Additionally, no other organics, including C2H2, are detected. This indicates that the C/O ratio could be substantially below unity, in contrast with the outer disk. The H2O emission traces a large radial disk surface region, as evidenced by the gradually changing excitation temperatures and emitting radii. Additionally, the OH and CO2 emission is relatively weak. It is likely that H2O is not significantly photodissociated, either due to self-shielding against the stellar irradiation, or UV shielding from small dust particles. While H2O is prominent and OH is relatively weak, the line fluxes in the inner disk of Sz 98 are not outliers compared to other disks.Conclusions. The relative emitting strength of the different identified molecular features points towards UV shielding of H2O in the inner disk of Sz 98, with a thin layer of OH on top. The majority of the organic molecules are either hidden below the dust continuum, or not present. In general, the inferred composition points to a sub-solar C/O ratio (<0.5) in the inner disk, in contrast with the larger than unity C/O ratio in the gas in the outer disk found with ALMA.
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| 4. |
- Kamp, Inga, et al.
(author)
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The chemical inventory of the inner regions of planet-forming disks - the JWST/MINDS program
- 2023
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In: Faraday discussions. - 1359-6640 .- 1364-5498. ; 245, s. 112-137
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Journal article (peer-reviewed)abstract
- The understanding of planet formation has changed recently, embracing the new idea of pebble accretion. This means that the influx of pebbles from the outer regions of planet-forming disks to their inner zones could determine the composition of planets and their atmospheres. The solid and molecular components delivered to the planet-forming region can be best characterized by mid-infrared spectroscopy. With Spitzer low-resolution (R = 100, 600) spectroscopy, this approach was limited to the detection of abundant molecules, such as H2O, C2H2, HCN and CO2. This contribution will present the first results of the MINDS (MIRI mid-INfrared Disk Survey, PI:Th Henning) project. Due do the sensitivity and spectral resolution provided by the James Webb Space Telescope (JWST), we now have a unique tool to obtain the full inventory of chemistry in the inner disks of solar-type stars and brown dwarfs, including also less-abundant hydrocarbons and isotopologues. The Integral Field Unit (IFU) capabilities will enable at the same time spatial studies of the continuum and line emission in extended sources such as debris disks, the flying saucer and also the search for mid-IR signatures of forming planets in systems such as PDS 70. These JWST observations are complementary to ALMA and NOEMA observations of outer-disk chemistry; together these datasets will provide an integral view of the processes occurring during the planet-formation phase.
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| 5. |
- Martin, Carlos, et al.
(author)
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Combination of water extraction with dilute-sulphuric acid pretreatment for enhancing the enzymatic hydrolysis of jatropha curcas shells
- 2015
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In: Industrial crops and products (Print). - : Elsevier BV. - 0926-6690 .- 1872-633X. ; 64, s. 233-241
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Journal article (peer-reviewed)abstract
- Jatropha curcas shells were extracted with water in a pilot-scale reactor and then pretreated with dilute sulphuric acid. The pretreatment was initially investigated with a Box-Behnken experimental design in the range of 110-180 degrees C, 0.1-1.5% H2SO4 and 20-60 min, and then with complementary experiments at 190 degrees C. The glucan recovery was above 87% in all the experimental runs. Xylan solubilisation was 13-20% in the milder pretreatments and up to 45% in the most severe runs. Around 70% cellulose enzymatic conversion, evaluated with commercial cellulases during 72-h hydrolysis, was achieved for the pretreatments at 180 degrees C, and a region with maximal conversion was predicted for around 190 degrees C. For confirming that estimation, a 2(2)-experiment augmented by one central point and parallel pretreatments of pre-extracted and non-extracted shells were performed. The highest cellulose conversion, reached at the central point, was 16.5% higher for the pre-extracted and pretreated material than for the directly pretreated one. The low cellulose crystallinity index (0.79) of the pre-extracted and pretreated shells correlated well with their better enzymatic convertibility.
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| 6. |
- Schunkert, Heribert, et al.
(author)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Journal article (peer-reviewed)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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| 7. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 8. |
- Wild, Philipp S., et al.
(author)
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A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
- 2011
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In: Circulation: Cardiovascular Genetics. - : American Heart Association/Lippincott, Williams & Wilkins. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
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Journal article (peer-reviewed)abstract
- Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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