Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study,Diabetes Care

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Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study
Diabetes Care ( IF 14.8 ) Pub Date : 2021-11-10 , DOI: 10.2337/dc21-1049
Nahid Yazdanpanah ₁ , Mojgan Yazdanpanah ₁ , Ye Wang ₂ , Vincenzo Forgetta ₂ , Michael Pollak _{2,

3,

4} , Constantin Polychronakos _{5,

6,

7} , J Brent Richards _{2,

3,

6,

8,

9} , Despoina Manousaki _{1,

10}

Affiliation

OBJECTIVE

To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR).

RESEARCH DESIGN AND METHODS

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.

RESULTS

We found that a genetically predicted SD increase in signal regulatory protein (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 x 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 x 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 x 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).

CONCLUSIONS

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.

中文翻译：

1 型糖尿病临床相关循环蛋白生物标志物：来自两样本孟德尔随机研究的证据

客观的

使用孟德尔随机化 (MR) 识别影响 1 型糖尿病易感性的循环蛋白。

研究设计与方法

我们使用了一项大规模的两样本 MR 研究，使用来自五个大型全基因组关联研究的多达 1,611 个循环蛋白质的顺式遗传决定因素（蛋白质数量性状基因座 [pQTL]）来筛选这些蛋白质与类型的因果关联9,684 名 1 型糖尿病病例和 15,743 名对照受试者的 1 糖尿病风险。此外，多效性强的 MR 方法用于敏感性分析，同时使用cis和trans -pQTL。

结果

我们发现，遗传预测的信号调节蛋白 (SIRPG) 水平的 SD 增加与 1 型糖尿病风险增加相关（MR 优势比 [OR] 1.66 [95% 1.36–2.03]；^P= 7.1 x 10–7 ） . 白细胞介素 27 Epstein-Barr 病毒诱导的 3 (IL27-EBI3) 蛋白水平每增加一个基因预测的标准差 (SD)，1 型糖尿病的风险就会增加近两倍（MR OR 1.97 [95% CI 1.48–2.62]；P = 3.7 x 10 ^–6 )。^{然而，胰凝乳蛋白酶原 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 x 10–6）。使用 MR 方法测试多效性同时包括反式-pQTL 的敏感性分析显示出类似的结果。虽然 MR-Egger 表明没有多效性（P值 MR-Egger 截距 = 0.31），但在 MR-PRESSO 中存在多效性证据（P值全局检验 = 0.006）。