美国国立心肺血液研究所血脂降低药物与饮食网络（GOLDN）参与者中甘油三酯对高脂餐反应的全基因组关联研究。
Genome-wide association study of triglyceride response to a high-fat meal among participants of the NHLBI Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
作者信息
Wojczynski Mary K, Parnell Laurence D, Pollin Toni I, Lai Chao Q, Feitosa Mary F, O'Connell Jeff R, Frazier-Wood Alexis C, Gibson Quince, Aslibekyan Stella, Ryan Kathy A, Province Michael A, Tiwari Hemant K, Ordovas Jose M, Shuldiner Alan R, Arnett Donna K, Borecki Ingrid B
机构信息
Department of Genetics, Washington University School of Medicine, St. Louis, MO.
Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
出版信息
Metabolism. 2015 Oct;64(10):1359-71. doi: 10.1016/j.metabol.2015.07.001. Epub 2015 Jul 3.
OBJECTIVE
The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
METHODS
The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN.
RESULTS
GOLDN revealed 111 suggestive (p < 1E-05) associations, with two SNPs meeting GWA significance level (p < 5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG.
CONCLUSION
This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics.
目的
甘油三酯（TG）对高脂餐的反应（餐后血脂异常，PPL）影响心血管疾病风险，且受基因和环境的影响。参与脂质代谢的基因在PPL TG反应的遗传研究中占据主导地位。我们试图通过脂质降低药物和饮食网络遗传学（GOLDN）中的全基因组关联（GWA）研究来阐明常见的基因变异。
方法
GOLDN GWAS发现样本由872名欧洲血统家族中的参与者组成。对2,543,887个变异的基因型进行测量或从HapMap中推算。在遗传与表型干预（HAPI）心脏研究（n = 843）中对我们的顶级结果进行重复验证。使用随机系数回归模型，根据高脂餐后基线（空腹，0小时）、3.5小时和6小时测量的血浆TG构建PPL TG反应表型。在使用亲属关系矩阵的线性混合模型中，必要时对协变量和主成分进行关联分析调整；还进行了进一步针对空腹TG进行调整的其他模型分析。对GOLDN中的顶级单核苷酸多态性（SNP）进行发现和重复研究（n = 1715）的荟萃分析。
结果
GOLDN揭示了111个提示性关联（p < 1E - 05），其中两个SNP达到GWA显著性水平（p < 5E - 08）。在这两个显著的SNP中，rs964184在HAPI心脏研究中显示出重复验证的证据（p = 1.20E - 03），在联合分析中具有GWA显著性（p = 1.26E - 09）。Rs964184与空腹血脂（TG和HDL）相关，且靠近ZPR1（原ZNF259），接近APOA1/C3/A4/A5簇。在进一步调整空腹TG后，这种关联减弱。
结论
这是首次针对一种新表型，即PPL TG反应，进行全基因组显著性关联并重复验证的报告。有必要使用通路分析或更新的遗传技术如代谢组学对反应表型进行未来研究。
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