Hicks, Andrew A. and Pramstaller, Peter P. and Johansson, Asa and Vitart, Veronique and Rudan, Igor and Ugocsai, Peter and Aulchenko, Yurii and Franklin, Christopher S. and Liebisch, Gerhard and Erdmann, Jeanette and Jonasson, Inger and Zorkoltseva, Irina V. and Pattaro, Cristian and Hayward, Caroline and Isaacs, Aaron and Hengstenberg, Christian and Campbell, Susan and Gnewuch, Carsten and Janssens, A. Cecile J. W. and Kirichenko, Anatoly V. and Koenig, Inke R. and Marroni, Fabio and Polasek, Ozren and Demirkan, Ayse and Kolcic, Ivana and Schwienbacher, Christine and Igl, Wilmar and Biloglav, Zrinka and Witteman, Jacqueline C. M. and Pichler, Irene and Zaboli, Ghazal and Axenovich, Tatiana I. and Peters, Annette and Schreiber, Stefan and Wichmann, H. -Erich and Schunkert, Heribert and Hastie, Nick and Oostra, Ben A. and Wild, Sarah H. and Meitinger, Thomas and Gyllensten, Ulf and van Duijn, Cornelia M. and Wilson, James F. and Wright, Alan and Schmitz, Gerd and Campbell, Harry (2009) Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations. PLOS GENETICS, 5 (10): e1000672. ISSN 1553-7390,
Full text not available from this repository. (Request a copy)Abstract
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 beta-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 x 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TANDEM MASS-SPECTROMETRY; CORONARY-ARTERY-DISEASE; GENOMEWIDE ASSOCIATION SCANS; METABOLISM; ACID; MUTATIONS; CERAMIDE; ONSET; SUSCEPTIBILITY; VARIANTS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Sep 2020 05:18 |
| Last Modified: | 07 Sep 2020 05:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28379 |
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