1Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada.
2Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Diabetes Care. 2022 Jan 1;45(1):169-177. doi: 10.2337/dc21-1049.
To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR).
We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL.
We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 × 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 × 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 × 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006).
We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.
使用孟德尔随机化（MR）方法鉴定影响 1 型糖尿病易感性的循环蛋白。
我们使用了一项大型两样本 MR 研究，使用来自五个大型全基因组关联研究的多达 1611 种循环蛋白的顺式遗传决定因素（蛋白质数量性状基因座 [pQTL]），筛选这些蛋白与 9684 例 1 型糖尿病患者和 15743 例对照者 1 型糖尿病风险的因果关联。此外，还使用 cis 和 trans-pQTL 的多效性稳健 MR 方法进行了敏感性分析。
我们发现，信号调节蛋白γ（SIRPG）水平的遗传预测 SD 增加与 1 型糖尿病风险增加相关（MR 比值比 [OR] 1.66 [95% 1.36-2.03]；P = 7.1×10-7）。与遗传预测的 IL27-EBI3 蛋白水平每增加一个 SD 相比，1 型糖尿病的风险几乎增加了两倍（MR OR 1.97 [95% CI 1.48-2.62]；P = 3.7×10-6）。然而，糜蛋白酶原 B1（CTRB1）的 SD 增加与 1 型糖尿病风险降低相关（MR OR 0.84 [95% CI 0.77-0.90]；P = 6.1×10-6）。在包括 trans-pQTL 的情况下测试多效性的 MR 方法的敏感性分析显示了类似的结果。尽管 MR-Egger 表明没有多效性影响（P 值 MR-Egger 截距=0.31），但在 MR-PRESSO 中存在多效性的证据（全局检验 P 值=0.006）。
我们使用 MR 方法鉴定了三个与 1 型糖尿病风险相关的新型循环蛋白生物标志物。这些生物标志物是开发药物和/或用于早期预测 1 型糖尿病的筛选工具的有前途的靶点。
