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dc.contributor.authorHicks AA
dc.contributor.authorPramstaller PP
dc.contributor.authorJohansson A
dc.contributor.authorVitart V
dc.contributor.authorRudan I
dc.contributor.authorUgocsai P
dc.contributor.authorAulchenko Y
dc.contributor.authorFranklin CS
dc.contributor.authorLiebisch G
dc.contributor.authorErdmann J
dc.contributor.authorJonasson I
dc.contributor.authorZorkoltseva IV
dc.contributor.authorPattaro C
dc.contributor.authorHayward C
dc.contributor.authorIsaacs A
dc.contributor.authorHengstenberg C
dc.contributor.authorCampbell S
dc.contributor.authorGnewuch C
dc.contributor.authorJanssens AC
dc.contributor.authorKirichenko AV
dc.contributor.authorKönig IR
dc.contributor.authorMarroni F
dc.contributor.authorPolasek O
dc.contributor.authorDemirkan A
dc.contributor.authorKolcic I
dc.contributor.authorSchwienbacher C
dc.contributor.authorIgl W
dc.contributor.authorBiloglav Z
dc.contributor.authorWitteman JC
dc.contributor.authorPichler I
dc.contributor.authorZaboli G
dc.contributor.authorAxenovich TI
dc.contributor.authorPeters A
dc.contributor.authorSchreiber S
dc.contributor.authorWichmann HE
dc.contributor.authorSchunkert H
dc.contributor.authorHastie N
dc.contributor.authorOostra BA
dc.contributor.authorWild SH
dc.contributor.authorMeitinger T
dc.contributor.authorGyllensten U
dc.contributor.authorvan Duijn CM
dc.contributor.authorWilson JF
dc.contributor.authorWright A
dc.contributor.authorSchmitz G
dc.contributor.authorCampbell H
dc.date.accessioned2018-10-30T14:04:24Z
dc.date.available2018-10-30T14:04:24Z
dc.date.issued2009
dc.identifier.issn1553-7390
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pgen.1000672
dc.identifier.urihttp://hdl.handle.net/10863/6771
dc.description.abstractSphingolipids 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.en_US
dc.language.isoenen_US
dc.rights
dc.titleGenetic determinants of circulating sphingolipid concentrations in European populationsen_US
dc.typeArticleen_US
dc.date.updated2018-10-30T12:11:09Z
dc.language.isiEN-GB
dc.journal.titlePLoS genetics
dc.description.fulltextopenen_US


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