School of Biomedical Informatics The University of Texas Health Science Center at Houston, Houston, TX 77030.
Departments of Epidemiology University of Alabama at Birmingham, Birmingham, AL 35233.
J Lipid Res. 2018 Apr;59(4):722-729. doi: 10.1194/jlr.P080333. Epub 2018 Feb 20.
Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in , , and are significantly associated with fasting LDL cholesterol response to FFB ( = 1.24E-07), triglyceride postprandial area under the increase (AUI) ( = 2.31E-06), and triglyceride postprandial AUI response to FFB ( = 1.88E-06), respectively. We sought to replicate the association for in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of is associated with triglyceride postprandial AUI ( < 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.
我们对遗传因素影响特定干预措施下脂质反应的理解是有限的。在这项研究中，我们使用外显子组测序关联研究，试图阐明罕见遗传变异对高脂餐挑战和非诺贝特（FFB）治疗下脂质反应的影响，该研究来自于降脂药物和饮食网络遗传学（GOLDN）队列。我们的研究结果表明，在 、 和 中罕见的编码变异与 FFB 治疗后空腹 LDL 胆固醇反应（ = 1.24E-07）、餐后甘油三酯 AUC 增加（AUI）（ = 2.31E-06）和 FFB 治疗后甘油三酯餐后 AUI 反应（ = 1.88E-06）显著相关。我们试图在包括高脂餐挑战但不包括 FFB 治疗的遗传与表型干预（HAPI）心脏研究中复制 与 FFB 治疗后 LDL 胆固醇反应之间的关联。在 HAPI 心脏研究中未观察到 GOLDN 中与 相关的罕见变异，因此该基因座结果未得到复制。为了进行功能验证，我们发现 GOLDN 中 基因的转录水平与餐后甘油三酯 AUI 相关（ < 0.05）。我们的研究表明，独特的遗传机制有助于对高脂餐挑战和 FFB 治疗的脂质反应。
