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Genetic determinants of circulating sphingolipid concentrations in European populations.
PLoS Genet. 5:e1000672 (2009)
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 9.08x10(-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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
8.883
1.120
130
131
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
TANDEM MASS-SPECTROMETRY; CORONARY-ARTERY-DISEASE; GENOMEWIDE ASSOCIATION SCANS; METABOLISM; ACID; MUTATIONS; CERAMIDE; ONSET; SUSCEPTIBILITY; VARIANTS
Sprache
englisch
Veröffentlichungsjahr
2009
HGF-Berichtsjahr
0
ISSN (print) / ISBN
1553-7390
e-ISSN
1553-7404
Zeitschrift
PLoS Genetics
Quellenangaben
Band: 5,
Heft: 10,
Artikelnummer: e1000672
Verlag
Public Library of Science (PLoS)
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
Institute of Epidemiology (EPI)
POF Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er)
Genetics and Epidemiology
PSP-Element(e)
G-500700-001
G-503900-005
G-503900-005
PubMed ID
19798445
WOS ID
000272032100010
Scopus ID
73449117605
Erfassungsdatum
2009-12-11