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Background <p>Cytoskeleton-associated protein 2 (CKAP2) plays a role in tumor proliferation, but its causal relationship with lung cancer remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate this association.</p> Methods <p>Using genome-wide association and FinnGen data, we assessed the potential causal relationship between genetically predicted plasma CKAP2 levels and lung cancer risk, including its subtypes. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger and weighted median. Sensitivity analyses included leave-one-out, Cochran’s Q, MR-Egger intercept, and MR-PRESSO. To assess generalizability, we replicated the forward MR analysis using an independent deCODE pQTL dataset.</p> Results <p>Forward MR showed a nominal association between elevated CKAP2 and lung squamous cell carcinoma (LUSC) risk (IVW: OR = 1.18; 95% CI = 1.01–1.38; <i>P</i> = 0.033). However, this did not survive Bonferroni correction (α = 0.0125) and was not replicated in an independent deCODE dataset (OR = 0.875; <i>P</i> = 0.493). No significant associations were found for overall lung cancer, lung adenocarcinoma, or small cell lung cancer. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy. Reverse MR found no causal effect of lung cancer on CKAP2 levels.</p> Conclusions <p>This study provides nominally significant genetic evidence for an association between elevated CKAP2 levels and LUSC risk, but the finding does not survive multiple-testing correction and was not replicated in an independent dataset. Further validation in larger cohorts with harmonized proteomic platforms is required before CKAP2 can be considered a therapeutic target.</p>

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Genetic evidence for a potential role of cytoskeleton-associated protein 2 in lung squamous cell carcinoma: a bidirectional mendelian randomization study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月19日

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  • Qiang Xie,
  • Yuzuo Lin,
  • Qingtong Wu,
  • Ziyan Lin,
  • Yanhong Cheng,
  • Guodong Zhong,
  • Lei Wang

摘要

Background

Cytoskeleton-associated protein 2 (CKAP2) plays a role in tumor proliferation, but its causal relationship with lung cancer remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate this association.

Methods

Using genome-wide association and FinnGen data, we assessed the potential causal relationship between genetically predicted plasma CKAP2 levels and lung cancer risk, including its subtypes. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger and weighted median. Sensitivity analyses included leave-one-out, Cochran’s Q, MR-Egger intercept, and MR-PRESSO. To assess generalizability, we replicated the forward MR analysis using an independent deCODE pQTL dataset.

Results

Forward MR showed a nominal association between elevated CKAP2 and lung squamous cell carcinoma (LUSC) risk (IVW: OR = 1.18; 95% CI = 1.01–1.38; P = 0.033). However, this did not survive Bonferroni correction (α = 0.0125) and was not replicated in an independent deCODE dataset (OR = 0.875; P = 0.493). No significant associations were found for overall lung cancer, lung adenocarcinoma, or small cell lung cancer. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy. Reverse MR found no causal effect of lung cancer on CKAP2 levels.

Conclusions

This study provides nominally significant genetic evidence for an association between elevated CKAP2 levels and LUSC risk, but the finding does not survive multiple-testing correction and was not replicated in an independent dataset. Further validation in larger cohorts with harmonized proteomic platforms is required before CKAP2 can be considered a therapeutic target.