Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

被引：172

作者：

Hicks, Andrew A. ^{[1
,2
]}

Pramstaller, Peter P. ^{[1
,2
,3
,4
]}

Johansson, Asa ^{[5
]}

Vitart, Veronique ^{[6
]}

Rudan, Igor ^{[7
,8
,9
]}

Ugocsai, Peter ^{[10
]}

Aulchenko, Yurii ^{[11
]}

Franklin, Christopher S. ^{[7
]}

Liebisch, Gerhard ^{[10
]}

Erdmann, Jeanette ^{[12
]}

Jonasson, Inger ^{[5
]}

Zorkoltseva, Irina V. ^{[13
]}

Pattaro, Cristian ^{[1
,2
]}

Hayward, Caroline ^{[6
]}

Isaacs, Aaron ^{[11
]}

Hengstenberg, Christian ^{[14
]}

Campbell, Susan ^{[6
]}

Gnewuch, Carsten ^{[10
]}

Janssens, A. Cecile J. W. ^{[11
]}

Kirichenko, Anatoly V. ^{[13
]}

Koenig, Inke R. ^{[15
]}

Marroni, Fabio ^{[1
,2
]}

Polasek, Ozren ^{[9
,16
]}

Demirkan, Ayse ^{[11
]}

Kolcic, Ivana ^{[16
]}

Schwienbacher, Christine ^{[1
,2
,17
]}

Igl, Wilmar ^{[5
]}

Biloglav, Zrinka ^{[16
]}

Witteman, Jacqueline C. M. ^{[11
]}

Pichler, Irene ^{[1
,2
]}

Zaboli, Ghazal ^{[5
]}

Axenovich, Tatiana I. ^{[13
]}

Peters, Annette ^{[18
]}

Schreiber, Stefan ^{[19
]}

Wichmann, H. -Erich ^{[18
,20
]}

Schunkert, Heribert ^{[12
]}

Hastie, Nick ^{[6
]}

Oostra, Ben A. ^{[21
]}

Wild, Sarah H. ^{[7
]}

Meitinger, Thomas ^{[22
]}

Gyllensten, Ulf ^{[5
]}

van Duijn, Cornelia M. ^{[11
]}

Wilson, James F. ^{[7
]}

Wright, Alan ^{[6
]}

Schmitz, Gerd ^{[10
]}

Campbell, Harry ^{[7
]}

机构：

[1] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy

[2] Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany

[3] Gen Cent Hosp, Dept Neurol, Bolzano, Italy

[4] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany

[5] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden

[6] Western Gen Hosp, IGMM, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[7] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[8] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split, Croatia

[9] Gen Info Ltd, Zagreb, Croatia

[10] Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany

[11] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[12] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[13] RAS, Inst Cytol & Genet, SD, Novosibirsk, Russia

[14] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[15] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[16] Univ Zagreb, Fac Med, Andrija Stampar Sch Publ Hlth, Zagreb 41000, Croatia

[17] Univ Ferrara, Dept Expt & Diagnost Med, I-44100 Ferrara, Italy

[18] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[19] Univ Kiel, Inst Klin Mol Biol, Kiel, Germany

[20] Ludwig Maximilians Univ Munchen, Chair Epidemiol, Inst Med Informat Sci Biometry & Epidemiol, Munich, Germany

[21] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands

[22] Helmholtz Zentrum Munchen, Munich, Germany

来源：

PLOS GENETICS | 2009年 / 5卷 / 10期

基金：

俄罗斯基础研究基金会; 英国医学研究理事会;

关键词：

TANDEM MASS-SPECTROMETRY; CORONARY-ARTERY-DISEASE; GENOMEWIDE ASSOCIATION SCANS; METABOLISM; ACID; MUTATIONS; CERAMIDE; ONSET; SUSCEPTIBILITY; VARIANTS;

D O I：

10.1371/journal.pgen.1000672

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页数：11

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