key: cord-1032586-a7uzsdup
authors: Wu, Xiangrong; Peng, Haoxin; Xiong, Shan; Li, Caichen; Zhong, Ran; He, Jianxing; Liang, Wenhua
title: Novel evidence revealed genetic association between COVID-19 infection, severity and endometrial cancer: COVID-19 infection, severity and risk of endometrial cancer
date: 2022-05-10
journal: J Infect
DOI: 10.1016/j.jinf.2022.05.005
sha: 5a8b1997b4beddfee283fc9a26c4ab4ca1dbd8bb
doc_id: 1032586
cord_uid: a7uzsdup

nan

(2). Taking together, questions arise regarding three aspects: firstly, due to the limited number of genetic variants, it 23 is insufficient to elucidate a reliable correlation; secondly, it is unclear whether the association exists regarding the 24 severity of COVID-19; and thirdly, whether the genetic variation associated with endometrial cancer is associated 25 with susceptibility and severity of SARS-CoV-2 infection. 26

In explaining the positive association between COVID-19 and the risk of endometrial cancer, it may not be 27 clear whether COVID-19 is causal to cancer, whether the presence of undetected cancer has a negative effect on 28 COVID-19, or whether the correlation between the two is due to latent confounding. Bidirectional MR is capable of 29 teasing apart these relationships (3). Herein, to address these questions, we introduced bidirectional two-sample 30 MR analyses, utilizing the most comprehensive genetic proxies of COVID-19 to date. 31

Originated from the COVID-19 Host Genetics Initiative (4), nineteen host-specific single nucleotide 32 polymorphisms (SNPs) were extracted from a large-scale genome-wide association study (GWAS) (5) and Table 1 ). All the 19 SNPs were strongly 35 associated with SARS-CoV-2 infection or severe COVID-19 manifestations (p < 5*10-8) and were selected as 36 instrumental variables (IVs). None of them were excluded from observing linkage disequilibrium (r 2 < 0.001). 37

Given the large sample size and the type I error rate =0.05, all the selected IVs suggested noticeable correlativity 38 for the MR analysis (Power = 1.00) (6). Correspondingly, using the MR-Base platform (http://app.mrbase.org/) (7), 39

SNPs associated with endometrial cancer were selected from the Endometrial Cancer Association Consortium 40 Table 2) . 42

The main MR results were obtained using the random-effects inverse variance weighted (IVW) estimator. 43

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. 45 MR-Egger regression analysis and I² statistic were employed to selectively detect pleiotropic effects and 46 heterogeneity. All summary data used in this work are publicly available, and they were obtained with relevant 47 participant consent and ethical approval. Table 3 ). The increased trend was observed using sensitivity analysis 54 ( Fig. 1) , whereas bidirectional relationships were not revealed between both diseases by our study (OR 1.019, 95% 55 Table 4 ) and heterogeneity (Supplementary Table 5 ) did not exist in most of the 58 study outcomes. Leave-one-out results indicated that no SNP could independently drive MR analysis results 59 (Supplementary Table 6) . 60

Based on the most comprehensive genetic proxies of COVID-19 to date, our study provides clear evidence in 61 supporting the positive correlation between genetically predisposed SARS-CoV-2 susceptibility/severity and risk of 62 endometrial cancer, further refining and validating the research studies by Gao and colleagues (1). Our findings 63 may aid in a deeper understanding of the susceptibility and severity of SARS-CoV-2 infection to predict 64 endometrial cancer risks in future observational studies. Although several possible pathways, for example, the 65 Angiotensin Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine 2 (TMPRSS2) may provide a mechanistic link between SARS-CoV-2 susceptibility and malignancy (9), the underlying mechanism by which 67 COVID-19 genetically increased the risk of endometrial cancer is still unclear and worth to be explored in the 68

Several deficiencies also existed in our study. As we only included participants from Europe, caution should 70 also be taken when generalizing our findings. Besides, the reported positive association between COVID-19 and 71 endometrial cancer entails verification in future observational studies. Still, our findings may aid in a deeper 72 understanding of the susceptibility and severity of SARS-CoV-2 infection to predict endometrial cancer risks in 73 future clinical practice. 74 

Genetic variation associated with COVID-19 is also associated 85 with endometrial cancer

The high expression of SARS-CoV-2 cell receptors might lead to higher COVID-19 87 infection rates in cancer patients

The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in 91 susceptibility and severity of the SARS-CoV-2 virus pandemic

Avoiding bias from weak instruments in Mendelian randomization studies. International 94 journal of epidemiology

The MR-Base platform supports systematic 96 causal inference across the human phenome. eLife

Identification of nine new susceptibility loci 98 for endometrial cancer

Which cancer type has the highest risk of COVID-19 infection?

The authors acknowledge the efforts of the COVID-19 Host Genetics Initiative (COVID-19 HGI) in providing 111 high-quality GWASs data in the MR-Base platform (https://www.mrbase.org/) for researchers. 

Written informed consent for publication was obtained from all participants. 134 135

All authors declare no conflicts of interest. 137