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Sökning: WFRF:(Koch Beate)

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1.
  • Agarwal, Pallavi, et al. (författare)
  • Collagen XII and XIV, New Partners of Cartilage Oligomeric Matrix Protein in the Skin Extracellular Matrix Suprastructure
  • 2012
  • Ingår i: Journal of Biological Chemistry. - ASBMB. - 1083-351X. ; 287:27, s. 22549-22559
  • Tidskriftsartikel (refereegranskat)abstract
    • The tensile and scaffolding properties of skin rely on the complex extracellular matrix (ECM) that surrounds cells, vasculature, nerves, and adnexus structures and supports the epidermis. In the skin, collagen I fibrils are the major structural component of the dermal ECM, decorated by proteoglycans and by fibril-associated collagens with interrupted triple helices such as collagens XII and XIV. Here we show that the cartilage oligomeric matrix protein (COMP), an abundant component of cartilage ECM, is expressed in healthy human skin. COMP expression is detected in the dermal compartment of skin and in cultured fibroblasts, whereas epidermis and HaCaT cells are negative. In addition to binding collagen I, COMP binds to collagens XII and XIV via their C-terminal collagenous domains. All three proteins codistribute in a characteristic narrow zone in the superficial papillary dermis of healthy human skin. Ultrastructural analysis by immunogold labeling confirmed colocalization and further revealed the presence of COMP along with collagens XII and XIV in anchoring plaques. On the basis of these observations, we postulate that COMP functions as an adapter protein in human skin, similar to its function in cartilage ECM, by organizing collagen I fibrils into a suprastructure, mainly in the vicinity of anchoring plaques that stabilize the cohesion between the upper dermis and the basement membrane zone.
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2.
  • Artigas Soler, María, et al. (författare)
  • Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
  • 2011
  • Ingår i: Nature genetics. - 1546-1718. ; 43:11, s. 1082-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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3.
  • Hancock, Dana B, et al. (författare)
  • Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
  • 2012
  • Ingår i: PLoS genetics. - 1553-7404. ; 8:12, s. e1003098
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV<sub>1</sub>), and its ratio to forced vital capacity (FEV<sub>1</sub>/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV<sub>1</sub> and FEV<sub>1</sub>/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near <em>DNER</em> (smallest <em>P</em><sub>JMA = </sub>5.00×10<sup>−11</sup>), <em>HLA-DQB1</em> and <em>HLA-DQA2</em> (smallest <em>P</em><sub>JMA = </sub>4.35×10<sup>−9</sup>), and <em>KCNJ2</em> and <em>SOX9</em> (smallest <em>P</em><sub>JMA = </sub>1.28×10<sup>−8</sup>) were associated with FEV<sub>1</sub>/FVC or FEV<sub>1</sub> in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated <em>DNER</em>, <em>KCNJ2</em>, and <em>SOX9</em> and found them to be expressed in human lung tissue. <em>DNER</em> and <em>SOX9</em> further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.</p>
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4.
  • Obeidat, Ma'en, et al. (författare)
  • A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample
  • 2011
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 6:5, s. e19382
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Rationale: </strong></p> <p>Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).</p> <p><strong>Objectives:</strong></p> <p>To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.</p> <p><strong>Methods:</strong></p> <p>We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.</p> <p><strong>Results:</strong></p> <p>The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3 x 10(-5). The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81 x 10(-5)), CNTN5 (P = 4.37 x 10(-4)), and TRPV4 (P = 1.58 x 10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41 x 10(-5)), followed by PDE4D (P = 1.22 x 10(-4)). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38 x 10(-4)), and ESR1 (P = 5.42 x 10(-4)) among ever-smokers.</p> <p><strong>Conclusions: </strong></p> <p>Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.</p>
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5.
  • Repapi, Emmanouela, et al. (författare)
  • Genome-wide association study identifies five loci associated with lung function.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:1, s. 36-44
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
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6.
  • Repapi, Emmanouela, et al. (författare)
  • Genome-wide association study identifies five loci associated with lung function
  • 2010
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 42:1, s. 36-44
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV<sub>1</sub>) and the ratio of FEV<sub>1</sub> to forced vital capacity (FVC) in the SpiroMeta consortium (<em>n</em> = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (<em>n</em> ≤ 32,184 additional individuals) and <em>in silico</em> summary association data from the CHARGE Consortium (<em>n</em> = 21,209) and the Health 2000 survey (<em>n</em> ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV<sub>1</sub> or FEV<sub>1</sub>/FVC and common variants at five additional loci: 2q35 in <em>TNS1</em> (<em>P</em> = 1.11 × 10<sup>−12</sup>), 4q24 in <em>GSTCD</em> (2.18 × 10<sup>−23</sup>), 5q33 in <em>HTR4</em> (<em>P</em> = 4.29 × 10<sup>−9</sup>), 6p21 in <em>AGER</em> (<em>P</em> = 3.07 × 10<sup>−15</sup>) and 15q23 in <em>THSD4</em> (<em>P</em> = 7.24 × 10<sup>−15</sup>). mRNA analyses showed expression of <em>TNS1</em>, <em>GSTCD</em>, <em>AGER</em>, <em>HTR4</em> and <em>THSD4</em> in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.</p>
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7.
  • Thun, Gian Andri, et al. (författare)
  • Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
  • 2013
  • Ingår i: PLOS Genetics. - 1553-7390 .- 1553-7404. ; 9:8, s. e1003585
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs defined by showing minor allele frequencies (MAFs) &gt;5% reached genome-wide significance all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of beta = 20.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis as well as exon-sequencing in a subsample (N = 410) suggested that AAT serum level is causally determined at this locus by rare (MAF&lt;1%) and low-frequent (MAF 1-5%) variants only in particular by the well-documented protein inhibitor S and Z (PI S PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P&lt;0.0001) as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397) associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.</p>
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