USDA Agricultural Research Service.
Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
Am J Clin Nutr. 2018 Jul 1;108(1):188-200. doi: 10.1093/ajcn/nqy081.
The putative functional variant -265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity.
The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction.
We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (<22 g/d) or high-SFA diet (≥22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites.
In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar results were observed in the GOLDN Study and the FHS. Additionally, in the FHS, cg04436964 methylation was negatively correlated with APOA2 expression in the blood of participants consuming a high-SFA diet. Furthermore, when consuming a high-SFA diet, CC carriers had lower APOA2 expression than those with the TT genotype. Lastly, metabolomic analysis identified 4 pathways as overrepresented by metabolite differences between CC and TT genotypes with high-SFA intake, including tryptophan and branched-chain amino acid (BCAA) pathways. Interestingly, these pathways were linked to rs5082-specific cg04436964 methylation differences in high-SFA consumers.
The epigenetic status of the APOA2 regulatory region is associated with SFA intake and APOA2 -265T>C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787.
APOA2 启动子内假定的功能性变体-265T>C(rs5082)与饱和脂肪酸(SFA)摄入有一致的相互作用，影响肥胖的风险。
本研究旨在采用综合方法来描述这种相互作用的分子基础。
我们对 80 名参与者进行了全基因组范围内的表观遗传学扫描，这些参与者携带 rs5082CC 或 TT 基因型，并分别摄入低 SFA(<22g/d)或高 SFA(≥22g/d)饮食，这些参与者在波士顿波多黎各健康研究(BPRHS)中按年龄、性别、BMI 和糖尿病状况匹配。然后，我们在基因脂质降低药物和饮食网络(GOLDN)研究(n=379)和弗雷明汉心脏研究(FHS)(n=243)中选择的参与者中验证了这些发现。进行转录和代谢组学分析，以确定表观遗传状态、APOA2mRNA 表达和血液代谢物之间的关系。
在 BPRHS 中，我们发现 cg04436964 甲基化位点在摄入高 SFA 的 CC 和 TT 参与者之间存在显著差异，但在摄入低 SFA 的参与者中没有差异。在 GOLDN 研究和 FHS 中也观察到了类似的结果。此外，在 FHS 中，cg04436964 甲基化与摄入高 SFA 饮食的参与者血液中的 APOA2 表达呈负相关。此外，当摄入高 SFA 饮食时，CC 携带者的 APOA2 表达低于 TT 基因型携带者。最后，代谢组学分析确定了 4 条途径，这些途径在高 SFA 摄入的 CC 和 TT 基因型之间的代谢物差异中表现过度，包括色氨酸和支链氨基酸(BCAA)途径。有趣的是，这些途径与高 SFA 消费者中 rs5082 特异性 cg04436964 甲基化差异有关。
APOA2 调节区域的表观遗传状态与 SFA 摄入和 APOA2-265T>C 基因型相关，在高 SFA 饮食中促进 APOA2 基因型之间的 APOA2 表达差异，并调节 BCAA 和色氨酸代谢途径。这些发现确定了这种高度可重复的基因-饮食相互作用影响肥胖风险的潜在机制，并为正在进行的 SFA 与人类健康之间关系的研究提供了新的见解。本研究在 clinicaltrials.gov 注册为 NCT03452787。
