Purpose

We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC).

Methods

Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses.

Results

Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01–1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03–1.09), SCC (OR 1.06, 95% CI 1.02–1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03–1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations.

Conclusion

There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

中文翻译：

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循环C反应蛋白水平与肺癌风险之间的遗传相关性和因果关系

目的

我们的目的是表征循环 C 反应蛋白 (CRP) 水平与肺癌 (LC) 风险之间的遗传相关性和因果关系。

方法

利用对 575,531 名欧洲血统个体的循环 CRP 水平以及 29,266 例病例和 56,450 名对照者的 LC 风险进行的全基因组关联研究的汇总统计数据，我们研究了循环 CRP 水平与整体肺癌及其组织学亚型风险的遗传关联，通过使用连锁不平衡评分 (LDSC) 回归和孟德尔随机化 (MR) 分析。

结果

从 LDSC 回归中发现，循环 CRP 水平与 LC 及其组织学亚型风险之间存在显着的正遗传相关性，相关系数范围为 0.12 至 0.26，所有错误发现调整后p  < 0.05。单变量 MR 证明 CRP 水平与肺鳞状细胞癌 (SCC) 风险增加之间存在名义相关性（反方差加权 OR = 1.15，95% CI 1.01–1.30）。然而，当多变量 MR 包括每天的香烟数量和/或体重指数时，这种关联就消失了。通过使用我们最近开发的基于约束最大似然的 MR 方法，我们确定了 CRP 水平与总体 LC（OR 1.06，95% CI 1.03–1.09）、SCC（OR 1.06，95% CI 1.02–1.09）风险的显着相关性和小细胞肺癌（SCLC，OR 1.09，95% CI 1.03–1.15）。此外，大多数单变量和多变量 MR 分析也揭示了一致的 CRP-SCLC 关联。

结论

循环 CRP 水平与 SCLC 风险之间可能存在遗传和因果关系，这与之前基于人群的观察性研究一致。