Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Section of Gerontology and Geriatrics; Leiden University Medical Center, Leiden, The Netherlands.
Int J Epidemiol. 2022 Dec 13;51(6):1874-1885. doi: 10.1093/ije/dyac119.
There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomization (MR) analyses in the UK Biobank.
We conducted Cox proportional hazard analyses in 451 232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13 247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect estimates of individual instruments (P-value for Q statistic = 4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by over-representation analyses.
In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes [hazard ratio (HR): 1.31; 95% CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth hormone signalling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity.
The IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
血清胰岛素样生长因子-1（IGF-1）浓度在人类年龄相关疾病（如 2 型糖尿病（T2D））的发病机制中起因果作用的证据并不一致。在这里，我们使用英国生物库中的（聚类）孟德尔随机化（MR）分析来研究 IGF-1 与 T2D 之间的关系。
我们对英国生物库中的 451232 名欧洲血统个体（55.3%为女性，招募时的平均年龄为 56.6 岁）进行 Cox 比例风险分析，其中 13247 人在 12 年的随访中患上了 2 型糖尿病。此外，我们还基于与 IGF-1 相关的独立单核苷酸多态性（SNP）进行了两样本 MR 分析。鉴于个体工具的 MR 效应估计值存在异质性（Q 统计量的 P 值=4.03e-145），我们还进行了聚类 MR 分析。通过过度代表分析对确定的聚类进行了生物途径分析。
在 Cox 比例风险模型中，我们将 IGF-1 浓度分层为五组，发现最低组的参与者患 2 型糖尿病的相对风险最高[风险比（HR）：1.31；95%置信区间（CI）：1.23-1.39）。相反，在两样本 MR 分析中，遗传上受影响的 IGF-1 水平较高与 2 型糖尿病的风险增加相关。基于个体工具的 MR 效应估计值的异质分布，确定了六个与 2 型糖尿病风险较低或较高相关的遗传决定的 IGF-1 聚类。与 2 型糖尿病风险较低相关的主要聚类中，IGF-1 水平较高的聚类包含映射到生长激素信号通路基因的工具，而与 2 型糖尿病风险较高相关的主要聚类中，IGF-1 水平较高的聚类包含映射到与氨基酸代谢和基因组完整性相关的途径的基因的工具。
MR 分析中用作遗传工具的 IGF-1 相关 SNP 对 2 型糖尿病风险的 MR 效应估计值呈异质分布。这可能是由于增加 IGF-1 浓度的潜在分子途径的差异以及 IGF-1 对 2 型糖尿病的影响的差异介导所致。
