Absence of causal association between CD40–CD40L signaling and cervical cancer risk - A Mendelian randomization study

Sep 22, 2026

Two-sample Mendelian randomization (MR) was used to test whether CD40–CD40L signaling causally affects cervical cancer risk and to examine CD40/CD40L expression and immune relationships. Genetic instruments for CD40–CD40L were taken from plasma protein quantitative trait loci, while outcome data came from five independent GWAS datasets. Inverse-variance weighted estimates with MR-Egger, weighted median, and sensitivity analyses showed no significant causal effect. Expression and bioinformatics analyses indicate no tumor-versus-normal mRNA difference and no link to overall survival, yet expression correlates positively with stromal, immune, and ESTIMATE tumor microenvironment scores, suggesting immune-regulatory relevance despite lack of causal genetic evidence.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

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Abstract

Abbreviations

Introduction

Background on cervical cancer and HPV

Immunological role of CD40–CD40L axis

MR study design and methods

Results: causal inference findings

Results: expression and immune correlation

Discussion and implications

® Observational Study Absence of causal association between CD40– CD40L signaling and cervical cancer risk A Mendelian randomization study Huifang Liu, MMa , Fan Huang, MMa , Huini Da, MMa , Qinghua Yin, MMa , Jieyu Liu, MBa , Yan Peng, MMa ,* | Abstract
To investigate the potential causal relationship between cluster of differentiation 40 (CD40)–cluster of differentiation 40 ligand (CD40L) signaling and cervical cancer risk using a two-sample Mendelian randomization (MR) approach and to explore the expression and immune correlation of CD40/CD40L in cervical cancer. A two-sample MR framework was used in this study. Genetic instruments for CD40–CD40L (exposure) were derived from the plasma protein quantitative trait loci data. Summary-level data for cervical cancer (outcome) were obtained from 5 independent genome-wide association study datasets. Instrumental variable selection adhered to the core MR assumptions. Causal estimates were primarily generated using the inverse-variance weighted method supplemented by MR-Egger, weighted median, and other sensitivity analyses. Heterogeneity and pleiotropy were assessed. Bioinformatics analyses using the Sangerbox 3.0 and Gene Expression Profiling Interactive Analysis 2 databases were used to evaluate the expression, prognostic value, and immune infiltration correlation of CD40 and CD40L in cervical squamous cell carcinoma and endocervical adenocarcinoma. MR analyses found no significant causal effect of CD40–CD40L signaling on cervical cancer risk across all datasets (e.g. , for CD40: inverse-variance weighted OR = 1.014, P = .838) . Sensitivity analyses, including leave-one-out validation and tests for heterogeneity and horizontal pleiotropy, supported the robustness of null findings. Expression analysis showed no significant difference in CD40/CD40L mRNA levels between tumor and normal tissues and no correlation with overall survival. However, their expression was positively correlated with stromal, immune, and ESTIMATE scores in the tumor microenvironment. This MR study found no genetic evidence to support a causal role for CD40–CD40L signaling in cervical cancer etiology. Although not a causal risk factor, the positive correlation of CD40/CD40L expression with immune microenvironment scores suggests a potential role in local immune regulation, warranting further investigation. | | --- | | Abbreviations: CD40 = cluster of differentiation 40 , CD40L = cluster of differentiation 40 ligand , CESC = cervical squamous cell carcinoma and endocervical adenocarcinoma, GEPIA2 = Gene Expression Profiling Interactive Analysis 2, GWAS = genomewide association studies, HLA = human leukocyte antigen, HPV = human papillomavirus, IV = instrumental variable, IVW = inverse-variance weighted, LD = linkage disequilibrium, LOO = leave-one-out, MR = Mendelian randomization, pQTL = protein quantitative trait loci, SNP = single nucleotide polymorphism. | | Keywords: causal inference, CD40–CD40L signaling, cervical cancer, Mendelian randomization, protein quantitative trait loci (pQTL) | 1. Introduction Cervical cancer is the 4th most common malignancy in women worldwide. Its pathogenesis is inextricably linked to persistent infection with high-risk human papillomavirus (HPV) genotypes. [1] Nevertheless, critical knowledge gaps persist regarding the precise mechanisms by which the host immune system governs viral clearance and exerts tumor immune surveillance. [2,3] The cluster of differentiation 40 (CD40)–cluster HL and FH contributed to this article equally. The authors have no funding and conflicts of interest to disclose. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. No further ethical approval was required, because the present study was based on publicly available GWAS data. All methods were performed in accordance with relevant guidelines. Supplemental Digital Content is available in t

FAQs

Does CD40–CD40L signaling have a causal genetic association with cervical cancer risk?

MR analyses found no significant causal effect across the included datasets, with sensitivity analyses supporting the robustness of the null findings.

How were genetic instruments and outcome data obtained in the study?

Genetic instruments for CD40–CD40L exposure were derived from plasma protein quantitative trait loci, and cervical cancer outcome summary data were taken from five independent GWAS datasets.

What did the expression analysis show for CD40 and CD40L?

CD40/CD40L mRNA levels did not differ significantly between tumor and normal tissues and showed no correlation with overall survival.

If not causal, how do CD40/CD40L relate to the tumor microenvironment?

CD40/CD40L expression was positively correlated with stromal, immune, and ESTIMATE scores, suggesting a potential role in local immune regulation and warranting further investigation.

Sep 22, 2026

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