The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.
The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.
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DOI：
10.1016/j.atherosclerosis.2013.01.038
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发表时间：
2013-05
期刊：
影响因子：
5.3
通讯作者：
Borecki, Ingrid B.
中科院分区：
文献类型：
--
作者：
Feitosa, Mary F.;Wojczynski, Mary K.;North, Kari E.;Zhang, Qunyuan;Province, Michael A.;Carr, Jeffrey J.;Borecki, Ingrid B.
关键词：
非酒精性脂肪性肝病(NAFLD)的范围从单纯性脂肪变性到肝脏炎症再到肝硬变。我们试图利用CT测量的脂肪肝(FL)和丙氨酸氨基转移酶水平(ALT)作为肝脏炎症的生化标记物，来识别导致NAFLD的常见基因变异。我们使用相关荟萃分析(CMA)来测试结合FL和ALT全基因组关联(GWA)结果，使用大约250万个SNP，是否可以提高检测影响这两个性状的变异的能力。ERLIN1-Chuk-CWF19L1基因簇变异与FL和ALT的伴随变异相关。9个变异体(rs2862954、rs1408579、rs10883451、rs11597086、rs11591741、rs17729876、rs17668255、rs17668357、rs12784396)对FL和ALT有显著影响(2.47×10−9≤cma-p≤4.29×10−10)，而边际检验(4.11×10−5≤gwa-p≤2.34×10−6)对FL和ALT有显著影响。例如，ERLIN1-rs2862954的错义变异对于FL和ALT的组合具有全基因组意义(Cma-p=4.88×10−10)，而各自的单变量关联是提示的(FL：P=5.74×10−6，ALT：P=3.71×10−6)。此外，我们还调查了伴发关联是否主要由ALT水平驱动。当我们用ALT调整FL时，相关联系减少但没有消失(CmA-p≤3.3×10−7)。我们的发现表明ERLIN1-Chuk-CWF19L1变异与FL堆积的早期阶段(通过CT测量)和肝脏炎症(ALT水平)相关，当考虑到它们之间的相关性时，这种相关性增强。CMA方法增强了识别ERLIN1-Chuk-CWF19L1影响单纯性脂肪变性和伴有炎症的肝脏脂肪变性的新变体的能力，这表明该基因簇可能调节广泛疾病范围内NAFLD的易感性。
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation. We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using ~2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits. Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47×10−9≤CMA-p≤4.29×10−10) as compared with the suggestive significance of marginal tests (4.11×10−5≤GWA-p≤2.34×10−6). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p=4.88×10−10) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p=5.74×10−6, ALT:p=3.71×10−6). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p≤3.3×10−7). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans. CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease.
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影响因子：
4.5
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
通讯作者：
GOLD Consortium
影响因子：
13.5
作者：
Rotman, Yaron;Koh, Christopher;Zmuda, Joseph M.;Kleiner, David E.;Liang, T. Jake
通讯作者：
Liang, T. Jake
影响因子：
5
作者：
Boyce, Cody J.;Pickhardt, Perry J.;Hinshaw, J. Louis
通讯作者：
Hinshaw, J. Louis
影响因子：
5
作者：
Higgins, M;Province, M;Williams, R
通讯作者：
Williams, R
影响因子：
8.2
作者：
Kotronen, A.;Johansson, L. E.;Yki-Jarvinen, H.
通讯作者：
Yki-Jarvinen, H.