Demirkan, Ayse and van Duijn, Cornelia M. and Ugocsai, Peter and Isaacs, Aaron and Pramstaller, Peter P. and Liebisch, Gerhard and Wilson, James F. and Johansson, Asa and Rudan, Igor and Aulchenko, Yurii S. and Kirichenko, Anatoly V. and Janssens, A. Cecile J. W. and Jansen, Ritsert C. and Gnewuch, Carsten and Domingues, Francisco S. and Pattaro, Cristian and Wild, Sarah H. and Jonasson, Inger and Polasek, Ozren and Zorkoltseva, Irina V. and Hofman, Albert and Karssen, Lennart C. and Struchalin, Maksim and Floyd, James and Igl, Wilmar and Biloglav, Zrinka and Broer, Linda and Pfeufer, Arne and Pichler, Irene and Campbell, Susan and Zaboli, Ghazal and Kolcic, Ivana and Rivadeneira, Fernando and Huffman, Jennifer and Hastie, Nicholas D. and Uitterlinden, Andre and Franke, Lude and Franklin, Christopher S. and Vitart, Veronique and Nelson, Christopher P. and Preuss, Michael and Bis, Joshua C. and O'Donnell, Christopher J. and Franceschini, Nora and Witteman, Jacqueline C. M. and Axenovich, Tatiana and Oostra, Ben A. and Meitinger, Thomas and Hicks, Andrew A. and Hayward, Caroline and Wright, Alan F. and Gyllensten, Ulf and Campbell, Harry and Schmitz, Gerd (2012) Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations. PLOS GENETICS, 8 (2): e1002490. ISSN 1553-7390,
Full text not available from this repository. (Request a copy)Abstract
Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TANDEM MASS-SPECTROMETRY; HIGH-THROUGHPUT QUANTIFICATION; FATTY-ACIDS; SUSCEPTIBILITY LOCI; MEMBRANE-LIPIDS; HUMAN PLATELETS; LYSOPHOSPHATIDYLCHOLINE; DISEASE; PHOSPHATIDYLCHOLINE; ATHEROSCLEROSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 May 2020 05:02 |
| Last Modified: | 20 May 2020 05:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19292 |
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