Genetic determinants of circulating sphingolipid concentrations in European populations.
Genetic determinants of circulating sphingolipid concentrations in European populations.
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DOI：
10.1371/journal.pgen.1000672
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发表时间：
2009-10
期刊：
影响因子：
4.5
通讯作者：
Campbell H
中科院分区：
文献类型：
--
作者：
Hicks AA;Pramstaller PP;Johansson A;Vitart V;Rudan I;Ugocsai P;Aulchenko Y;Franklin CS;Liebisch G;Erdmann J;Jonasson I;Zorkoltseva IV;Pattaro C;Hayward C;Isaacs A;Hengstenberg C;Campbell S;Gnewuch C;Janssens AC;Kirichenko AV;König IR;Marroni F;Polasek O;Demirkan A;Kolcic I;Schwienbacher C;Igl W;Biloglav Z;Witteman JC;Pichler I;Zaboli G;Axenovich TI;Peters A;Schreiber S;Wichmann HE;Schunkert H;Hastie N;Oostra BA;Wild SH;Meitinger T;Gyllensten U;van Duijn CM;Wilson JF;Wright A;Schmitz G;Campbell H
鞘脂作为细胞膜的结构成分和细胞信号传导具有重要作用，其代谢的破坏可导致多种疾病，具有不同的神经、精神和代谢后果。越来越多的研究发现，一些参与鞘脂代谢的酶编码基因的变异与复杂的疾病表型有关。直接实验证据支持特定鞘脂类在几种常见的复杂慢性疾病过程中的作用，包括动脉粥样硬化斑块形成、心肌梗死（MI）、心肌病、胰腺β细胞衰竭、胰岛素抵抗和2型糖尿病。因此，鞘脂代表了遗传分析中重要的新型中间表型，但对影响其在普通人群中循环水平的主要遗传变异知之甚少。我们进行了318237个单核苷酸多态性（snp）与循环鞘磷脂（SM）、二氢鞘磷脂（Dih-SM）、神经酰胺（Cer）和糖基神经酰胺（GluCer）单一脂质物种（33个性状）水平之间的全基因组关联研究（GWAS）；43个匹配的代谢物比率测量了来自5个不同欧洲人群的4400名受试者。鉴定出5个基因组区域的相关变异（32个），全基因组显著校正p值范围低至9.08×10−66。在功能上参与神经酰胺生物合成和运输的7个基因中观察到最强的相关性：SPTLC3， LASS4, SGPP1， ATP10D和FADS1-3。3个基因座（ATP10D、FADS3和SPTLC3）的变异在德国的一系列MI研究中与MI相关。涉及鞘脂代谢途径的23个候选基因中的另外70个变异也显示出相关性（p = 10−4或更小）。因此，鞘脂代谢中几个关键成分的循环浓度受到强烈的遗传控制，这些基因座的变异可以在常见的心血管、代谢、神经和精神疾病的发展中进行测试。尽管一些罕见的单基因疾病是由参与鞘脂生物合成和代谢的酶缺陷引起的，但对控制这些重要生物活性分子循环水平的主要变异知之甚少。鞘脂不仅是质膜和内体的重要组成部分，在细胞表面保护、蛋白质和脂质转运和分选以及细胞信号级联反应中起着至关重要的作用。实验证据支持鞘脂在几种常见的复杂慢性代谢、心血管或神经疾病过程中的作用。因此，鞘脂代表了遗传分析中重要的新型中间表型，发现影响其循环浓度的遗传变异是理解鞘脂遗传控制如何导致常见人类疾病的重要一步。我们已经确定了7个基因中的32个变体，这些基因对33种不同鞘脂的循环血浆水平和43种匹配的代谢物比率有强烈影响。在一系列的3个德国心肌梗死研究中，我们看到了与心肌梗死相关的3个被测试基因的变异。进一步的心血管、代谢、神经和精神疾病的关联可以用这里描述的变异来测试，这可能会确定额外的疾病风险和潜在有用的治疗靶点。
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 β-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 9.08×10−66. 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. Although several rare monogenic diseases are caused by defects in enzymes involved in sphingolipid biosynthesis and metabolism, little is known about the major variants that control the circulating levels of these important bioactive molecules. As well as being essential components of plasma membranes and endosomes, sphingolipids play critical roles in cell surface protection, protein and lipid transport and sorting, and cellular signalling cascades. Experimental evidence supports a role for sphingolipids in several common complex chronic metabolic, cardiovascular, or neurological disease processes. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, and discovering the genetic variants that influence their circulating concentrations is an important step towards understanding how the genetic control of sphingolipids might contribute to common human disease. We have identified 32 variants in 7 genes that have a strong effect on the circulating plasma levels of 33 distinct sphingolipids, and 43 matched metabolite ratios. In a series of 3 German MI studies, we see association with MI for variants in 3 of the genes tested. Further cardiovascular, metabolic, neurological, and psychiatric disease associations can be tested with the variants described here, which may identify additional disease risk and potentially useful therapeutic targets.
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影响因子：
9.8
作者：
Chen, Wei-Min;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
影响因子：
--
作者：
Pattaro, Cristian;Marroni, Fabio;Pramstaller, Peter P.
通讯作者：
Pramstaller, Peter P.
影响因子：
30.8
作者：
Kathiresan S;Willer CJ;Peloso GM;Demissie S;Musunuru K;Schadt EE;Kaplan L;Bennett D;Li Y;Tanaka T;Voight BF;Bonnycastle LL;Jackson AU;Crawford G;Surti A;Guiducci C;Burtt NP;Parish S;Clarke R;Zelenika D;Kubalanza KA;Morken MA;Scott LJ;Stringham HM;Galan P;Swift AJ;Kuusisto J;Bergman RN;Sundvall J;Laakso M;Ferrucci L;Scheet P;Sanna S;Uda M;Yang Q;Lunetta KL;Dupuis J;de Bakker PI;O'Donnell CJ;Chambers JC;Kooner JS;Hercberg S;Meneton P;Lakatta EG;Scuteri A;Schlessinger D;Tuomilehto J;Collins FS;Groop L;Altshuler D;Collins R;Lathrop GM;Melander O;Salomaa V;Peltonen L;Orho-Melander M;Ordovas JM;Boehnke M;Abecasis GR;Mohlke KL;Cupples LA
通讯作者：
Cupples LA
DOI：
10.1073/pnas.0704292104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Caspi, Avshalom;Williams, Benjamin;Moffitt, Terrie E.
通讯作者：
Moffitt, Terrie E.
影响因子：
--
作者：
Clark, Lorraine N.;Kartsaklis, Lykourgos A.;Gilbert, Rebecca Wolf;Dorado, Beatriz;Ross, Barbara M.;Kisselev, Sergey;Verbitsky, Miguel;Mejia-Santana, Helen;Cote, Lucien J.;Andrews, Howard;Vonsattel, Jean-Paul;Fahn, Stanley;Mayeux, Richard;Honig, Lawrence S.;Marder, Karen
通讯作者：
Marder, Karen