Department of Medical Sciences, Uppsala University, UCR, Dag Hammarskjölds väg 38, SE-751 83, Uppsala, Sweden.
Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institute, Stockholm, Sweden.
Diabetologia. 2019 Nov;62(11):1998-2006. doi: 10.1007/s00125-019-4960-8. Epub 2019 Aug 24.
AIMS/HYPOTHESIS: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal.
In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of ≥7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.
Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, α-L-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.
CONCLUSIONS/INTERPRETATION: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.
目的/假设：2 型糖尿病的发病机制尚未完全阐明。我们研究了预先选择的蛋白质的循环水平是否与结局 '糖尿病' 相关，以及这些关联是否具有因果关系。
在基于人群的横断面 EpiHealth 研究中，对 2467 名 45-75 岁（50%为女性）个体的 249 种血浆蛋白进行了临近延伸测定技术分析。使用 Illumina HumanCoreExome-12 v1.0 BeadChip 对 DNA 进行基因分型。糖尿病的定义为服用降糖药物或空腹血糖≥7.0mmol/L。使用逻辑回归评估蛋白质与糖尿病之间的关联。为了研究蛋白质与糖尿病之间的因果关系，基于 DIAGRAM 和 MAGIC 联盟的大型全基因组关联研究以及 EpiHealth 研究中的全基因组关联研究，进行了双向两样本 Mendelian 随机化。
26 种蛋白质与糖尿病呈正相关，包括组织蛋白酶 D、视网膜脱氢酶 1、α-L-艾杜糖苷酸酶、羟基酸氧化酶 1 和半乳糖凝集素-4（前五项发现）。三种蛋白质，脂蛋白脂肪酶、胰岛素样生长因子结合蛋白 2 和对氧磷酶 3（PON-3）与糖尿病呈负相关。其中 14 种蛋白质为新发现。Mendelian 随机化研究未发现蛋白质与糖尿病之间存在任何有意义的因果关系，这与蛋白质水平与糖尿病之间的关系不一致。
结论/解释：与糖尿病相关的 29 种蛋白质参与了几个生理途径，但考虑到研究的力量，在 Mendelian 随机化中未发现对测试的蛋白质有因果关系。因此，这些鉴定出的蛋白质可能是 2 型糖尿病的生物标志物，而不是代表因果途径。
