基于孟德尔随机化的方法来识别疾病的早期和敏感诊断生物标志物。

A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease.

机构信息

Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

出版信息

Clin Chem. 2019 Mar;65(3):427-436. doi: 10.1373/clinchem.2018.291104. Epub 2018 Oct 18.

DOI:10.1373/clinchem.2018.291104

PMID:30337280

Abstract

BACKGROUND

Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative "reverse Mendelian randomization" (MR) approach.

METHODS

We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFR) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFR on 238 serum biomarkers.

RESULTS

With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFR (β = 1.86 SD per SD decrease eGFR; 95% CI, 0.95-2.76; = 8.0 × 10). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18-1.38; = 4.58 × 10). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFR alone (net reclassification improvement = 0.211; = 9.56 × 10) and in models including additional risk factors.

CONCLUSIONS

Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases.

CLINICALTRIALSGOV IDENTIFIER

NCT00069784.

摘要

背景

识别慢性肾脏病（CKD）早期发生的标志物，这些标志物特异性地与肾功能丧失有关，而不是与其他疾病的潜在原因有关，可能会更早、更准确地识别出将发展为 CKD 的患者。因此，我们试图通过一种创新的“反向孟德尔随机化（MR）”方法来识别由肾功能丧失引起的早期 CKD 的诊断性血液标志物。

方法

我们将这项技术应用于来自 Outcome Reduction with Initial Glargine Intervention（ORIGIN）试验的 4147 名参与者的遗传和生物标志物数据，所有参与者均患有 2 型糖尿病、空腹血糖受损或糖耐量受损。使用 CKDGen 联盟（n = 133814）与肌酐 eGFR（eGFR）相关的变异进行两样本 MR，以估计遗传上 eGFR 降低对 238 种血清生物标志物的影响。

结果

通过反向 MR，三叶因子 3（TFF3）被确定为一种由于 eGFR 降低而增加的蛋白质（β = 1.86 SD 每 SD 降低 eGFR；95%CI，0.95-2.76； = 8.0×10）。反向 MR 的发现与 ORIGIN 中 CKD 发病的流行病学关联一致（OR = 1.28 每 SD 增加 TFF3；95%CI，1.18-1.38； = 4.58×10）。与单独使用 eGFR 相比，TFF3 的添加显著改善了对 CKD 发病的区分（净重新分类改善 = 0.211； = 9.56×10），并且在包含其他危险因素的模型中也是如此。