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Genetic determinants of circulating sphingolipid concentrations in European populations.

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 9.08x10(-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.

SUBMITTER: Hicks AA

PROVIDER: S-EPMC2745562 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Genetic determinants of circulating sphingolipid concentrations in European populations.

Hicks Andrew A AA Pramstaller Peter P PP Johansson Asa A Vitart Veronique V Rudan Igor I Ugocsai Peter P Aulchenko Yurii Y Franklin Christopher S CS Liebisch Gerhard G Erdmann Jeanette J Jonasson Inger I Zorkoltseva Irina V IV Pattaro Cristian C Hayward Caroline C Isaacs Aaron A Hengstenberg Christian C Campbell Susan S Gnewuch Carsten C Janssens A Cecilej W AC Kirichenko Anatoly V AV König Inke R IR Marroni Fabio F Polasek Ozren O Demirkan Ayse A Kolcic Ivana I Schwienbacher Christine C Igl Wilmar W Biloglav Zrinka Z Witteman Jacqueline C M JC Pichler Irene I Zaboli Ghazal G Axenovich Tatiana I TI Peters Annette A Schreiber Stefan S Wichmann H-Erich HE Schunkert Heribert H Hastie Nick N Oostra Ben A BA Wild Sarah H SH Meitinger Thomas T Gyllensten Ulf U van Duijn Cornelia M CM Wilson James F JF Wright Alan A Schmitz Gerd G Campbell Harry H

PLoS genetics 20091002 10

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 ...[more]

PMID: 19798445

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Dataset Information

Genetic determinants of circulating sphingolipid concentrations in European populations.

Publications

Genetic determinants of circulating sphingolipid concentrations in European populations.

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