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Causal inference between rheumatoid arthritis and prostate cancer

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Abstract

It is unclear if the association between rheumatoid arthritis (RA) and a higher risk of prostate cancer (Pca) reflects a causal relationship. We conducted a meta-analysis and used the Mendelian randomization method (MR) to evaluate the association between RA and Pca risk. A meta-analysis and subgroup analysis of the incidence of Pca in patients with RA was conducted. To determine whether genetically elevated RA levels were causally linked to Pca, two MR samples were employed. To eliminate gender-related bias, we conducted a stratified analysis of the GWAS data for RA by gender, specifically including 140,254 males. Additional MR analysis was also performed to determine potential confounding factors influencing the association between genetically susceptible RA and Pca. In total, 409,950 participants were enrolled in 20 trials to investigate the Pca risk in patients with RA. The meta-analysis suggested that RA was unrelated to the Pca risk (SIR = 1.072, 95% CI, 0.883–1.261). However, a subgroup analysis showed that low smoking rates might increase the Pca risk in patients with RA by 24%. The MR analysis showed that increased genetic susceptibility to RA was related to a high Pca risk (OR = 36.20, 95%CI = 1.24–1053.12, P = 0.037). The causality estimation of MR-Egger, Weighted mode, Simple mode, and Weighted median method were similar in direction and magnitude. Although our meta-analysis found no correlation between RA and Pca risk, MR analyses supported a causal relationship between genetic susceptibility to RA and increased prostate risk. Early attention to Pca risk in patients with RA may be important for improving prognosis and mortality in such patients. Further research is needed to determine the etiology of RA attributed to Pca and its underlying mechanisms.

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Availability of data and materials

The data of RA in males can be obtained from the Wget command https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/20002_1464.gwas.imputed_v3.male.tsv.bgz or AWS file https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/20002_1464.gwas.imputed_v3.male.tsv.bgz. The datasets GWAS for this study can be found in the GWAS Catalog [https://www.ebi.ac.uk/gwas/]. GWAS ID details can be found in methods or Supplementary Material.

Abbreviations

RA:

Rheumatoid arthritis

Pca:

Prostate cancer

MR:

Mendelian randomization

GWASs:

Genome-wide association studies

MOOSE:

Meta-analysis of observational studies in epidemiology

MeSH:

Medical subject headings

QATSO:

Quality assessment tool for systematic reviews of observational studies

RCTs:

Randomized controlled trials

ACR:

Criteria: American College of Rheumatology criteria

ARA:

Criteria: American Rheumatism Association criteria

SIR:

Standardized incidence rate

OR:

Odds ratio

HR:

Hazard ratio

RR:

Relative risk

CI:

Confidence interval

SNP:

Single nucleotide polymorphism

LD:

Linkage disequilibrium

PRACTICAL:

Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome

GIANT:

Genetic Investigation of Anthropometric Traits consortium

MRC-IEU:

MRC Integrative Epidemiology Unit

IVs:

Instrumental variables

IVW:

Inverse variance-weighted

PRESSO:

Pleiotropy Residual Sum and Outlier

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Acknowledgements

We would like to express our sincere gratitude to the National Natural Science Foundation of China for providing financial support for this study [Grant Numbers 82070778, 82272876, 82102975]. The authors thank for Editage (www.editage.cn) helping with the editing of the manuscript. The authors acknowledge the efforts of the genome-wide association study consortia (GWAS) for providing high-quality resources for researchers.

Funding

This work was supported by the National Natural Science Foundation of China [Grant Numbers: 82070778, 82272876, 81972381, 82102975].

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Author notes

  1. Hai Bi and Cheng Liu have contributed equally to this work and should be considered as co-corresponding authors.

Authors and Affiliations

  1. Department of Urology, Peking University Third Hospital, Peking University Health Science Center, 49 North Garden Road, Beijing, 100191, China

    Junyong Ou, Lang Zou, Yaqian Wu, Qiming Zhang, Yangyi Fang, Min Qiu, Xiaojun Tian, Lulin Ma & Hai Bi

  2. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai, 200080, China

    Hai Bi & Cheng Liu

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Contributions

Conceptualization: JYO, CL, LZ. Search and evaluation: JYO, LZ. Data Analysis: JYO, YQW, YYF, QMZ, LZ. Writing—original draft and Visualization: JYO, LZ,HB. Writing—Review and Revision: CL, JYO, YQW, YYF, QMZ, MQ, HB. Supervision and Project Management: CL, LLM, HB, XJT, MQ, LZ, HB. Resources: CL, LLM, HB, XJT, MQ.

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Correspondence to Hai Bi or Cheng Liu.

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Ou, J., Zou, L., Wu, Y. et al. Causal inference between rheumatoid arthritis and prostate cancer. Clin Exp Med 23, 4681–4694 (2023). https://doi.org/10.1007/s10238-023-01151-9

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