Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations
| العنوان: | Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations |
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| المؤلفون: | Ozren Polasek, Thomas Meitinger, Wilmar Igl, Heribert Schunkert, Andrew A. Hicks, Stefan Schreiber, Cornelia M. van Duijn, Cristian Pattaro, Alan F. Wright, Aaron Isaacs, Tatiana I. Axenovich, A. CecileJ.W. Janssens, H.-Erich Wichmann, Zrinka Biloglav, Annette Peters, Inke R. König, Susan Campbell, Christopher S. Franklin, Irina V. Zorkoltseva, Jeanette Erdmann, Irene Pichler, Ghazal Zaboli, Jacqueline C. M. Witteman, Igor Rudan, Inger Jonasson, Ayse Demirkan, Yurii S. Aulchenko, Veronique Vitart, Åsa Johansson, Anatoly V. Kirichenko, Harry Campbell, Ivana Kolcic, Gerhard Liebisch, Caroline Hayward, Ben A. Oostra, Ulf Gyllensten, James F. Wilson, Sarah H. Wild, Peter Ugocsai, Peter P. Pramstaller, Christine Schwienbacher, Nicholas D. Hastie, Christian Hengstenberg, Fabio Marroni, Gerd Schmitz, Carsten Gnewuch |
| المساهمون: | Epidemiology, Clinical Genetics |
| المصدر: | PLoS Genetics, Vol 5, Iss 10, p e1000672 (2009) PLoS Genetics; Vol 5 PLoS Genetics Hicks, A A, Pramstaller, P P, Johansson, A, Vitart, V, Rudan, I, Ugocsai, P, Aulchenko, Y, Franklin, C S, Liebisch, G, Erdmann, J, Jonasson, I, Zorkoltseva, I V, Pattaro, C, Hayward, C, Isaacs, A, Hengstenberg, C, Campbell, S, Gnewuch, C, Janssens, A C W, Kirichenko, A V, König, I R, Marroni, F, Polsek, O, Demirkan, A, Kolcic, I, Schwienbacher, C, Igl, W, Biloglav, Z, Witteman, J C M, Pichler, I, Zaboli, G, Axenovich, T I, Peters, A, Schreiber, S, Wichmann, H-E, Schunkert, H, Hastie, N, Oostra, B A, Wild, S H, Meitinger, T, Gyllensten, U, van Duijn, C M, Wilson, J F, Wright, A, Schmitz, G & Campbell, H 2009, ' Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations ', PLoS Genetics, vol. 5, no. 10, e1000672 . https://doi.org/10.1371/journal.pgen.1000672Test PLoS Genetics (print), 5(10). Public Library of Science PLoS Genetics, 5 (10). PLoS Genet. 5:e1000672 (2009) |
| بيانات النشر: | Public Library of Science (PLoS), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, Cancer Research, Candidate gene, sphingolipids, isolate, genetic, association, Genome-wide association study, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, Neuroscience/Motor Systems, 80 and over, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Aged, 80 and over, Genetics and Genomics/Medical Genetics, Genetics, 0303 health sciences, education.field_of_study, Single Nucleotide, Middle Aged, Phenotype, Pedigree, 3. Good health, Female, Neuroscience/Neurobiology of Disease and Regeneration, Sphingomyelin, Cardiovascular Disorders/Myocardial Infarction, Research Article, Adult, Ceramide, Adolescent, Genotype, lcsh:QH426-470, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, White People, single-nucleotide polymorphisms (SNPs), Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, blood, Genetics and Genomics/Population Genetics, Humans, Sphingolipids, genome-wide association study (GWAS), single-nucleotide polymorphisms (SNPs), Polymorphism, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, Sphingolipids, genome-wide association study (GWAS), Sphingolipid, lcsh:Genetics, chemistry, 030217 neurology & neurosurgery, Adolescent, Adult, Aged, Aged, 80 and over, European Continental Ancestry Group, genetics, Female, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Sphingolipids, blood, Young Adult, Genome-Wide Association Study |
| الوصف: | Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases. Author Summary Although several rare monogenic diseases are caused by defects in enzymes involved in sphingolipid biosynthesis and metabolism, little is known about the major variants that control the circulating levels of these important bioactive molecules. As well as being essential components of plasma membranes and endosomes, sphingolipids play critical roles in cell surface protection, protein and lipid transport and sorting, and cellular signalling cascades. Experimental evidence supports a role for sphingolipids in several common complex chronic metabolic, cardiovascular, or neurological disease processes. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, and discovering the genetic variants that influence their circulating concentrations is an important step towards understanding how the genetic control of sphingolipids might contribute to common human disease. We have identified 32 variants in 7 genes that have a strong effect on the circulating plasma levels of 33 distinct sphingolipids, and 43 matched metabolite ratios. In a series of 3 German MI studies, we see association with MI for variants in 3 of the genes tested. Further cardiovascular, metabolic, neurological, and psychiatric disease associations can be tested with the variants described here, which may identify additional disease risk and potentially useful therapeutic targets. |
| وصف الملف: | application/pdf; text |
| تدمد: | 1553-7404 1553-7390 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b67d1904303b1d3b0e7255a32284de11Test https://doi.org/10.1371/journal.pgen.1000672Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b67d1904303b1d3b0e7255a32284de11 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537404 15537390 |
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