Diabetes maybe a risk factor for COVID-19 through increased ACE2 expression

Results of a recent phenome-wide Mendelian randomization (MR) study by researchers at the Chinese University Hong Kong (CUHK) reveals that diabetes may be a risk factor for increased susceptibility to or severity of coronavirus disease 2019 (COVID-19) through increased expression of ACE2, the putative receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“There is great potential in using genomic big data to uncover risk factors and treatments of COVID-19. MR studies are better at delineating the causal relationships between diseases, risk factors, blood proteins and ACE2 expression than observational studies,” remarked Dr Hon-Cheong So of the School of Biomedical Sciences, CUHK. “[Although] our study is exploratory and the results are preliminary, we believe this work is of value given the urgency in addressing the COVID-19 outbreak. It is hoped that the current work will shed light on new research strategies and lead to more confirmatory studies in the future [on the underlying mechanism of ACE2 expression and guide drug repositioning].”

In the study, the researchers extracted all genome-wide association study (GWAS) data from publicly available databases. Exposure data labelled as “diseases”, “risk factor” and “protein” were retrieved from the latest Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) GWAS database, which contains more than 30,000 summary data sets, and the UK Biobank (UKBB), the largest source of GWAS data worldwide. Data were predominantly based on European samples. Outcome data, namely pulmonary expression of ACE2, was retrieved from the Genotype-Tissue Expression (GTEx) database, one of the largest databases to date with both genotype and expression data of a variety of tissues samples, with samples mainly of European ancestry. [Diabetes Care 2020;43:1416-1426]

Overall, diabetes-related traits, including doctor-diagnosed diabetes, self-reported cases of diabetes, diagnosis of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), and early use of insulin <1 year of diabetes diagnosis, were significantly associated with increased ACE2 expression (nominal significance, p<0.05). A consistent association was demonstrated for T2DM based on large-scale GWAS (n=898,130) (p=0.00291). [Nat Genet 2018;50:1505-1513]

Other diseases and traits, such as oestrogen receptor-positive breast and lung cancer, inflammatory bowel disease, asthma, tobacco use and elevated alanine aminotransferase, were also found to be significantly associated with increased ACE2 expression (nominal level, p<0.05).

Exploratory analysis showed significant associations of blood proteins within cytokine-cytokine receptor interaction, VEGFA-VEGFR2 signalling and JAK-STAT signalling pathways with altered ACE2 expression (p=1.82e-06, p=7.79e-06, p=5.61e-04, respectively).

Subsequent drug repositioning analysis revealed the presence of ≥3 protein targets with significance in ACE2 expression in fostamatinib, copper, zinc and zonisamide.

Recent evidence showed that more than one-quarter of confirmed cases of COVID-19 had a history of comorbid conditions, such as diabetes and respiratory diseases, with more severe infection commonly seen in patients with chronic conditions. Establishing causality is important in planning effective intervention. [Zhonghua Liu Xing Bing Xue Za Zhi 2020;41:145-151; N Engl J Med 2020;382:1708-1720; Lancet 2020;395:497-506]

In addition, ACE2 has been suggested in a number of studies as a key receptor of SARS-CoV-2, with overexpression of ACE2 protein leading to increased SARS-CoV-2 replication and its action blocked by anti-ACE2 antibodies in a dose-dependent manner. [J Virol 2020;94:e00127-20; Nature 2020;579:270-273; Science 2020;367:1260-1263]