Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
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DOI：
10.1371/journal.pgen.1001324
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发表时间：
2011-03
期刊：
影响因子：
4.5
通讯作者：
GOLD Consortium
中科院分区：
文献类型：
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作者：
Speliotes EK;Yerges-Armstrong LM;Wu J;Hernaez R;Kim LJ;Palmer CD;Gudnason V;Eiriksdottir G;Garcia ME;Launer LJ;Nalls MA;Clark JM;Mitchell BD;Shuldiner AR;Butler JL;Tomas M;Hoffmann U;Hwang SJ;Massaro JM;O'Donnell CJ;Sahani DV;Salomaa V;Schadt EE;Schwartz SM;Siscovick DS;NASH CRN;GIANT Consortium;MAGIC Investigators;Voight BF;Carr JJ;Feitosa MF;Harris TB;Fox CS;Smith AV;Kao WH;Hirschhorn JN;Borecki IB;GOLD Consortium
非酒精性脂肪性肝病（NAFLD）在家庭中聚集，但唯一已知的影响风险的常见遗传变异是PNPLA 3附近。我们试图在大规模人群样本中使用计算机断层扫描（CT）测量的肝脂肪变性（NAFLD的非侵入性测量）的全基因组关联（GWA）分析来确定影响NAFLD的其他遗传变异。使用方差分量法，我们发现CT肝脂肪变性是遗传性的（约26%-27%），在家庭为基础的阿米什人，家庭心脏，心脏病研究（n = 880至3,070）。 通过对来自旧秩序阿米什人、年龄、基因/环境易感性-雷克雅未克研究（AGES）、家族心脏和心脏病研究的7，176名个体中CT肝脂肪变性和1240万个插补或基因分型SNP之间的全基因组关联（GWA）结果进行固定效应荟萃分析，我们确定了在全基因组显著水平上相关的变异。（p<5×10−8）在PNPLA 3、NCAN和PPP 1 R3 B中或附近。我们对来自NASH临床研究网络（NASH CRN）的592名经活检证实的NAFLD受试者进行了这些和其他42个顶级CT肝脂肪变性相关SNP的基因分型。与来自心肌遗传学联盟（MIGen）的1，405名健康对照相比，我们观察到NCAN，GCKR，LYPLAL 1和PNPLA 3中或附近的变异与组织学NAFLD显著相关，但不是PPP 1 R3 B。在这五个位点的变异表现出不同的模式与血脂，以及血糖和人体测量性状。我们确定了影响CT评估的脂肪变性和NAFLD风险的常见遗传变异。肝脂肪变性相关变体与NASH/纤维化或导致血脂或血糖和人体测量特征异常并不一致，表明影响这些特征的途径存在遗传异质性。NAFLD是一系列疾病，范围从脂肪变性到脂肪性肝炎（非酒精性脂肪性肝炎或NASH：脂肪周围的炎症）到纤维化/肝硬化。肝脂肪变性可以使用计算机断层扫描（CT）非侵入性地测量，而NASH/纤维化则通过组织学评估。NAFLD的遗传基础仍有待确定。我们估计，CT测量的肝脂肪变性的变异中有26%-27%是遗传性的。我们确定了与CT肝脂肪变性相关的PNPLAL 3、NCAN和PPP 1 R3 B附近的三种变体，并表明NCAN、GCKR、LYPLAL 1和PNPLA 3中或附近的变体，而不是PPP 1 R3 B，与组织学小叶炎症/纤维化相关。NCAN、GCKR和PPP 1 R3 B中或附近的变体与血清脂质水平的改变有关，而LYPLAL 1和PNPLA 3中或附近的变体则与血清脂质水平的改变无关。GCKR和PPP 1 R3 B附近的变体也影响血糖性状。因此，我们表明NAFLD受遗传影响，并扩大了与此特征相关的常见遗传变异的数量。我们的研究结果表明，肝脂肪变性、NASH/纤维化或代谢特征异常的发生可能受到不同代谢途径的影响，这些代谢途径可能代表不同的治疗靶点。
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.
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与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
DOI：
10.1111/j.1440-1746.2005.04058.x
发表时间：
2005-12-01
影响因子：
4.1
作者：
Fan, JG;Zhu, JN;Chen, SY
通讯作者：
Chen, SY
影响因子：
5.1
作者：
Harrison, Stephen A;Neuschwander-Tetri, Brent A
通讯作者：
Neuschwander-Tetri, Brent A
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
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
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