常见遗传变异及血清代谢物与聚乙二醇洛塞那肽的降糖疗效的关联研究

Intensive glycemic control can delay the occurrence and development of chronic complications of diabetes and is of crucial importance for the prognosis of diabetes patients. Patients with type 2 diabetes respond individually to hypoglycemic agents with individual heterogeneity, and there is an urgent need to develop individualized glucose-lowering regimens based on the patient's own characteristics. As the main approach to explore the variability of drug response, pharmacogenomics is committed to studying the impact of genetic factors on drug response, but only explains 15-30% of the differences between individual drug responses. By studying the reaction and change of the small molecule metabolites of the body under various factors, metabolomics has been used in the early diagnosis, evaluation and prediction of several diseases, and is expected to become a new method to study the individual's response to hypoglycemic drugs. PEX168 is a new long-acting glucagon-like peptide 1 receptor agonist. This program intends to carry out pharmacogenomics and metabolomics studies with samples enrolled in the phase Ⅲb clinical trial of PEX168. In stage 1, we aim to find the genetic variants and serum metabolites related to the therapeutic efficacy of PEX168, then we construct the prediction model of PEX168 efficacy. In stage 2, we verify the prediction model in independent samples. This study is expected to provide new evidence for the clinical application of PEX168, and may provide new research ideas and theoretical basis for the accurate treatment of type 2 diabetes.

血糖控制可延缓糖尿病并发症的发生发展，对患者的预后至关重要。2型糖尿病患者对降糖药物的反应具有个体异质性，因此亟需制定个体化降糖方案。药物基因组学研究遗传因素对药物反应的影响，是目前探讨个体对药物反应差异性的主要手段，但仅解释15-30%的个体间药物反应的差异。代谢组学研究机体在各种因素作用下的小分子代谢物的反应及变化，已用于疾病的早期诊断、疗效评估及预测，有望成为研究个体对降糖药物反应的新方法。聚乙二醇洛塞那肽（PEX168）是一种新型的人高血糖素样肽1（GLP-1）受体激动剂。本项目拟利用该药的Ⅲb期临床研究样本，同时开展药物基因组学及代谢组学研究。第一阶段寻找与PEX168降糖疗效相关的遗传变异及血清代谢物，并利用二者构建PEX168疗效的预测模型；第二阶段对预测模型进行验证。本研究的开展，有望为PEX168的临床应用提供新证据，并可能2型糖尿病的精准治疗提供新的研究思路及理论依据。

2型糖尿病是一种复杂代谢疾病，患者对于降糖药的反应具有个体差异性。研究影响降糖药物的遗传因素及血清代谢物有助于指导药物的临床应用及开展个体化治疗，本项目通过血清代谢物检测及分析，发现2型糖尿病患者使用聚乙二醇洛塞那肽（PEX168）治疗具有异质性，可分为持续响应组、早期响应-晚期抵抗组、持续不响应组，治疗异质性与患者BMI及胰岛功能等因素相关。加权基因共表达网络分析（WGCNA）发现6个与PEX168降糖疗效有关的模块，最终，我们发现了6个模块，其中包含2个酰化肉碱相关模块、3个氨基酸相关模块和1个血红蛋白相关模块。并且，我们发现酰化肉碱根据是否含有羟基被明显分成了两个模块。进一步通过spearman相关分析和ROC分析发现，羟基类酰化肉碱和药物响应显著相关。同时，利用关联规则分析找到与药物响应相关的24条关联规则。其中，“高HbA1c、高空腹C肽、低甘油三酯”与药物持续响应相关。此外，项目还开展了血清猪胆酸类胆汁酸（HCAs）与糖脂代谢的相关性研究，发现超重/肥胖2型糖尿病患者的血清HCAs水平降低；HCAs水平降低与血脂异常、胰岛β细胞功能受损以及胰岛素抵抗密切相关。人群遗传关联研究发现，IAPP通路有关基因的常见变异与中国人群2型糖尿病风险相关；药物基因组研究发现，rs8094402和rs4693646和二甲双胍的降糖疗效有关。

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