Relationship Between Nonalcoholic Fatty Liver Disease Susceptibility Genes and Coronary Artery Disease
Relationship Between Nonalcoholic Fatty Liver Disease Susceptibility Genes and Coronary Artery Disease
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DOI：
10.1002/hep4.1319
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发表时间：
2019-04-01
影响因子：
5.1
通讯作者：
Isaacs, Aaron
中科院分区：
文献类型：
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作者：
Brouwers, Martijn C. G. J.;Simons, Nynke;Isaacs, Aaron
冠状动脉疾病（CAD）是非酒精性脂肪性肝病（NAFLD）患者死亡的主要原因。本研究的目的是调查NAFLD是否与CAD的发病机制有因果关系。为此，对先前报道的NAFLD易感基因进行了聚类，并在冠状动脉疾病全基因组复制和荟萃分析加上冠状动脉疾病遗传学（CARDIOGRAMplusC 4D）联盟数据集中检测了其与CAD的相关性。通过使用来自全球脂质遗传学联盟的数据，探讨了血浆脂质作为潜在介质的作用。统计分析显示，在60，801例CAD病例和123，504例对照中，12个NAFLD基因的组合与CAD无关（每个NAFLD风险等位基因的比值比[OR]为1.0; 95%置信区间[CI]为0.99-1.00）。在随后的敏感性分析中，在排除通过受损的极低密度脂蛋白分泌（即，微粒体甘油三酯转移蛋白[MTTP]、含patatin样磷脂酶结构域3 [PNPLA 3]、磷脂酰乙醇胺N-甲基转移酶[PEMT]和跨膜6超家族成员2 [TM 6SF 2]）（OR，1.01; 95% CI，1.00-1.02）。排除基因的聚集显示与CAD显著负相关（OR，0.97; 95%CI，0.96-0.99）。观察到的个体NAFLD基因之间与CAD相关的异质性的很大一部分可以通过血浆脂质来解释，如血浆脂质与NAFLD易感基因赋予的CAD风险之间的强相关性所反映的（对于低密度脂蛋白胆固醇，r = 0.76; P = 0.004）。结论：NAFLD易感基因本身并不引起CAD。这些基因和CAD之间的关系似乎在很大程度上取决于血脂。这些观察结果强烈建议在设计靶向NAFLD的新药时考虑血脂。
Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genomc-Wide Replication and Meta-Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele, 1.0; 95% confidence interval [CI], 0.99-1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low-density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [MTTP], patatin-like phospholipase domain containing 3 [PNPLA3], phosphatidylethanolamine N-methyltransferase [PEMT], and transmembrane 6 superfamily member 2 [TM6SF2]) (OR, 1.01; 95% CI, 1.00-1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96-0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes (r = 0.76; P = 0.004 for low-density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se. The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD.