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Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk

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Abstract

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.

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Data availability

Summary statistics of GWAS for C-reactive protein and body mass index can be obtained from GWAS catalog (https://www.ebi.ac.uk/gwas) that for cigarettes per day and drinks per week from the Data Repository for University of Minnesota (DRUM) website(https://conservancy.umn.edu/drum), and those lung cancer GWAS data can be obtained from dbGaP (https://www.ncbi.nlm.nih.gov/gap/) under accession phs001273.v1.p1.

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Acknowledgements

We thank the TRICL-ILCCO, UK Biobank, GSCAN, GIANT, and CHARGE for providing valuable data resources for this study.

Funding

This work was supported in part by a grant from the National Cancer Institute R01CA249863 (to Qiuyin Cai and Jirong Long).

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Authors and Affiliations

  1. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37023, USA

    Jiajun Shi, Wanqing Wen, Jirong Long, Yaohua Yang, Xiao-Ou Shu & Qiuyin Cai

  2. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, 55455, USA

    Haoran Xue & Wei Pan

  3. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, 37023, USA

    Ran Tao

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37023, USA

    Ran Tao

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  1. Jiajun Shi
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Contributions

JS, WW, and QC conceived the study. JS and HX analyzed the data. JS, WW, HX, RT, and WP contributed to methodology. JS, JL, YY, and QC obtained resources. HX and WP contributed to software development. WW, XS, and QC supervised the study. JS drafted the manuscript. All authors edited and approved the final draft.

Corresponding author

Correspondence to Qiuyin Cai.

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Competing interests

The authors declare no competing interests.

Ethical approval

Our study is based on publicly available summary statistics from genome-wide association studies that had already obtained ethical approval from respective review boards or ethics committees. Therefore, obtaining a separate ethical approval for this study was not required.

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Shi, J., Wen, W., Long, J. et al. Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk. Cancer Causes Control (2024). https://doi.org/10.1007/s10552-024-01855-7

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