Novel evidence revealed genetic association between COVID-19 infection, severity and endometrial cancer.

Dear Editor,

We were greatly fascinated with the unprecedented Mendelian randomization (MR) study in this journal by Gao and colleagues, which shed light on the positive association between genetic predisposition of COVID-19 infection and risk of endometrial cancer EC. Interestingly, findings from Qiu and colleagues revealed the expression rate of SARS-CoV-2 cell receptors might correlate with infection rates of COVID-19 in cancer patients. Taking together, questions arise regarding three aspects: firstly, due to the limited number of genetic variants, it is insufficient to elucidate a reliable correlation; secondly, it is unclear whether the association exists regarding the severity of COVID-19; and thirdly, whether the genetic variation associated with endometrial cancer is associated with susceptibility and severity of SARS-CoV-2 infection.

In explaining the positive association between COVID-19 and the risk of endometrial cancer, it may not be clear whether COVID-19 is causal to cancer, whether the presence of undetected cancer has a negative effect on COVID-19, or whether the correlation between the two is due to latent confounding. Bidirectional MR is capable of teasing apart these relationships. Herein, to address these questions, we introduced bidirectional two-sample MR analyses, utilizing the most comprehensive genetic proxies of COVID-19 to date.

Originated from the COVID-19 Host Genetics Initiative, nineteen host-specific single nucleotide polymorphisms (SNPs) were extracted from a large-scale genome-wide association study (GWAS) and summary online dataset (available at https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST010776/), comprising a huge sample size of 1,299,010 in European ancestries. (Supplementary Table 1). All the 19 SNPs were strongly associated with SARS-CoV-2 infection or severe COVID-19 manifestations (p < 5 × 10–8) and were selected as instrumental variables (IVs). None of them were excluded from observing linkage disequilibrium (r2 < 0.001). Given the large sample size and the type I error rate =0.05, all the selected IVs suggested noticeable correlativity for the MR analysis (Power = 1.00). Correspondingly, using the MR-Base platform (http://app.mrbase.org/), SNPs associated with endometrial cancer were selected from the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), and the UK Biobank, as published by O'Mara et al. (Supplementary Table 2).

The main MR results were obtained using the random-effects inverse variance weighted (IVW) estimator. Weighted median, weighted mode, simple mode, and MR-Egger methods were applied for sensitivity analysis. Leave-one-out analyses were to examine whether some SNPs had a significant independent influence on results. MR-Egger regression analysis and I² statistic were employed to selectively detect pleiotropic effects and heterogeneity. All summary data used in this work are publicly available, and they were obtained with relevant participant consent and ethical approval.

The primary MR analyses results suggested that the reported SARS-CoV-2 infection (odds ratio (OR) = 1.165, 95% confidence interval (CI) 1.012–1.340, P = 0.033), hospitalized COVID-19 (OR 1.145, 95% CI 1.002–1.309, P = 0.047), and critically ill COVID-19 (OR 1.075, 95% CI 1.006–1.148, P = 0.032) had a significant positive correlation with the risk of endometrial cancer (Fig. 1 ). Single MR analysis revealed that rs505922 and rs143334143 were significantly associated with endometrial cancer risk in both reported SARS-CoV-2 infection and hospitalized COVID-19 (Supplementary Table 3). The increased trend was observed using sensitivity analyses (Fig. 1), whereas bidirectional relationships were not revealed between both diseases by our study (OR 1.019, 95% CI 0.945–1.099, P = 0.625 for reported SARS-CoV-2 infection; OR 0.970, 95% CI 0.886–1.062, P = 0.512 for hospitalized COVID-19; OR 0.986, 95% CI 0.837–1.161, P = 0.865 for critically ill COVID-19) (Supplementary Fig. 1). Pleiotropy (Supplementary Table 4) and heterogeneity (Supplementary Table 5) did not exist in most of the study outcomes. Leave-one-out results indicated that no SNP could independently drive MR analysis results (Supplementary Table 6).

Fig. 1

Summary Mendelian randomization estimates of COVID-19 on the risks of endometrial cancer. (A) Schematic overview of the bidirectional Mendelian randomization (MR) design. (B) Summary MR estimates of genetically predisposed COVID-19 susceptibility/severity and endometrial cancer risk.

Based on the most comprehensive genetic proxies of COVID-19 to date, our study provides clear evidence in supporting the positive correlation between genetically predisposed SARS-CoV-2 susceptibility/severity and risk of endometrial cancer, further refining and validating the research studies by Gao and colleagues. Our findings may aid in a deeper understanding of the susceptibility and severity of SARS-CoV-2 infection to predict endometrial cancer risk in future observational studies. Although several possible pathways, for example, the Angiotensin Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine 2 (TMPRSS2) may provide a mechanistic link between SARS-CoV-2 susceptibility and malignancy, the underlying mechanism by which COVID-19 genetically increased the risk of endometrial cancer is still unclear and worth to be explored in the future.

Several deficiencies also existed in our study. As we only included participants from Europe, caution should also be taken when generalizing our findings. Besides, the reported positive association between COVID-19 and endometrial cancer entails verification in future observational studies. Still, our findings may aid in a deeper understanding of the susceptibility and severity of SARS-CoV-2 infection to predict endometrial cancer risk in future clinical practice.

Data availability statement

The authors acknowledge the efforts of the COVID-19 Host Genetics Initiative (COVID-19 HGI) in providing high-quality GWASs data in the MR-Base platform (https://www.mrbase.org/) for researchers.

Funding

This work was supported by China National Science Foundation (Grant number 81871893); Key Project of Guangzhou Scientific Research Project (Grant number 201804020030); Cultivation of Guangdong College Students' Scientific and Technological Innovation (“Climbing Program” Special Funds) (Grant number pdjh2020a0480, pdjh2021a0407).

Contributions

(I) Conception and design: XRW, HXP, and WHL.

(II) Administrative support: WHL.

(III) Provision of study materials or patients: All authors

(IV) Collection and assembly of data: XRW, HXP, and WHL.

(V) Data analysis and interpretation: XRW, HXP, and WHL.

(VI) Manuscript writing: All authors

(VII) Final approval of manuscript: All authors

Ethical approval and consent to participate

The study protocol was complied with the principles of the Declaration of Helsinki and was approved by the institutional review board of the National Clinical Research Center for Respiratory Disease of the First Affiliated Hospital of Guangzhou Medical University.

Consent for publication

Written informed consent for publication was obtained from all participants.

Declaration of Competing Interest

All authors declare no conflicts of interest.