Am J Epidemiol. 2022 Oct 20;191(11):1867-1876. doi: 10.1093/aje/kwac118.
Observational studies have revealed phenotypic associations between type 2 diabetes (T2D) and many biomarkers. However, causality between these conditions in East Asians is unclear. We leveraged genome-wide association study (GWAS) summary statistics on T2D (n = 77,418 cases; n = 356,122 controls) from the Asian Genetic Epidemiology Network (sample recruited during 2001-2011) and GWAS summary statistics on 42 biomarkers (n = 12,303-143,658) from BioBank Japan (sample recruited during 2003-2008) to investigate causal relationships between T2D and biomarkers. Applications of Mendelian randomization approaches consistently revealed genetically instrumented associations of T2D with increased serum potassium levels (liability-scale β = 0.04-0.10; P = 6.41 × 10-17-9.85 × 10-5) and decreased serum chloride levels (liability-scale β = -0.16 to -0.06; P = 5.22 × 10-27-3.14 × 10-5), whereas these 2 biomarkers showed no causal effects on T2D. Heritability Estimation Using Summary Statistics (ρ-HESS) and summary-data-based Mendelian randomization highlighted 27 genomic regions and 3 genes (α-1,3-mannosyl-glycoprotein 2-β-N-acetylglucosaminyltransferase (MGAT1), transducing-like enhancer (TLE) family member 1, transcriptional corepressor (TLE1), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)) that interactively associated with the shared genetics underlying T2D and the 2 biomarkers. Thus, T2D may causally affect serum potassium and chloride levels among East Asians. In contrast, the relationships of potassium and chloride with T2D are not causal, suggesting the importance of monitoring electrolyte disorders for T2D patients.
观察性研究揭示了 2 型糖尿病（T2D）与许多生物标志物之间的表型关联。然而，东亚人群中这些疾病之间的因果关系尚不清楚。我们利用亚洲遗传流行病学网络（2001-2011 年期间招募的样本）中 T2D 的全基因组关联研究（GWAS）汇总统计数据（n=77418 例病例；n=356122 名对照）和生物银行日本的 42 个生物标志物的 GWAS 汇总统计数据（2003-2008 年期间招募的样本）（n=12303-143658），以研究 T2D 与生物标志物之间的因果关系。孟德尔随机化方法的应用一致显示，T2D 与血清钾水平升高（ Liability-scale β=0.04-0.10；P=6.41×10-17-9.85×10-5）和血清氯水平降低（ Liability-scale β=-0.16 至-0.06；P=5.22×10-27-3.14×10-5）之间存在遗传上的关联，而这 2 个生物标志物对 T2D 没有因果作用。利用汇总统计数据进行遗传力估计（ρ-HESS）和基于汇总数据的孟德尔随机化强调了 27 个基因组区域和 3 个基因（α-1,3-甘露糖基-糖蛋白 2-β-N-乙酰氨基葡萄糖基转移酶（MGAT1）、转导样增强子（TLE）家族成员 1、转录核心抑制因子（TLE1）和 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）），这些区域和基因与 T2D 及这 2 个生物标志物的共同遗传基础相互作用。因此，T2D 可能在东亚人群中对血清钾和氯水平产生因果影响。相比之下，钾和氯与 T2D 的关系不是因果关系，这表明监测 T2D 患者的电解质紊乱非常重要。
