Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis
Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis
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DOI：
10.1096/fj.12-219097
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Zeisel, Steven H.
中科院分区：
文献类型：
--
作者：
Corbin, Karen D.;Abdelmalek, Manal F.;Zeisel, Steven H.
胆碱代谢对极低密度脂蛋白分泌很重要，使这一营养途径成为肝脏脂质平衡的重要贡献者。本研究的目的是评估胆碱/1-碳代谢和功能相关途径基因的多个单核苷酸多态性（SNP）的累积效应是否增加发生肝脂肪变性的易感性。在非酒精性脂肪性肝病和对照组的活检特征病例中，我们评估了胆碱/1-碳代谢中21个基因的260个SNP。当使用逻辑回归单独检查SNP时，在调整混杂因素和多重比较后，我们仅确定了与肝脂肪变性严重程度显著相关的单个SNP（PNPLA 3 rs738409）（P=0.02）。然而，当使用无监督分层聚类定义相似代谢途径中的SNP分组时，我们确定了具有与脂肪变性负荷显著相关的共享SNP特征的受试者组（P=0.0002）。最低和最高脂肪变性集群也可以通过种族来区分。然而，独特的SNP模式定义了脂肪变性负担，与种族无关。我们的研究结果表明，胆碱/1-碳代谢基因中SNP模式的分析可能有助于预测特定人群脂肪变性的严重程度，应由这些SNP引起的代谢效率低下应进一步研究。Corbin，K. D、Abdelmalek，M. F.、斯宾塞，M。D、da Costa，K.-一、Galanko，J. A.，Sha，W.，铃木，A.，盖伊角D、Cardona，D. M.，Torquati，A.，Diehl，A. M.，Zeisel，S. H.胆碱和1-碳代谢的遗传特征与肝脂肪变性的严重程度相关。FASEB J.27，1674-1689（2013）。www.fasebj.org
Choline metabolism is important for very low-density lipoprotein secretion, making this nutritional pathway an important contributor to hepatic lipid balance. The purpose of this study was to assess whether the cumulative effects of multiple single nucleotide polymorphisms (SNPs) across genes of choline/1-carbon metabolism and functionally related pathways increase susceptibility to developing hepatic steatosis. In biopsy-characterized cases of nonalcoholic fatty liver disease and controls, we assessed 260 SNPs across 21 genes in choline/1-carbon metabolism. When SNPs were examined individually, using logistic regression, we only identified a single SNP (PNPLA3 rs738409) that was significantly associated with severity of hepatic steatosis after adjusting for confounders and multiple comparisons (P=0.02). However, when groupings of SNPs in similar metabolic pathways were defined using unsupervised hierarchical clustering, we identified groups of subjects with shared SNP signatures that were significantly correlated with steatosis burden (P=0.0002). The lowest and highest steatosis clusters could also be differentiated by ethnicity. However, unique SNP patterns defined steatosis burden irrespective of ethnicity. Our results suggest that analysis of SNP patterns in genes of choline/1-carbon metabolism may be useful for prediction of severity of steatosis in specific subsets of people, and the metabolic inefficiencies caused by these SNPs should be examined further.-Corbin, K. D., Abdelmalek, M. F., Spencer, M. D., da Costa, K.-A., Galanko, J. A., Sha, W., Suzuki, A., Guy, C. D., Cardona, D. M., Torquati, A., Diehl, A. M., Zeisel, S. H. Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis. FASEB J. 27, 1674-1689 (2013). www.fasebj.org