Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma

孟德尔随机化 单核苷酸多态性 全基因组关联研究 蛋白质组 肺癌 生物 腺癌 肿瘤科 生物信息学 计算生物学 内科学 遗传学 医学 癌症 基因 基因型 遗传变异
作者
Long Zhang,Yajun Xiong,Jie Zhang,Yuying Feng,Aiguo Xu
出处
期刊:Journal of Translational Medicine [BioMed Central]
卷期号:22 (1) 被引量:15
标识
DOI:10.1186/s12967-024-04919-z
摘要

Abstract Background Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies. Methods This study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein–protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications. Results We identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72–0.87), 0.39 (95% CI 0.28–0.55), 0.91 (95% CI 0.72–0.87), and 0.85 (95% CI 0.79–0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08–1.19), NTM (OR, 1.12; 95% CI 1.09–1.16), PMM2 (OR, 1.35; 95% CI 1.18–1.53), RNASET2 (OR, 1.15; 95% CI 1.08–1.21), and TFPI (OR, 4.58; 95% CI 3.02–6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets. Conclusions Our proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.
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