Shitao Rao1, Alexandria Lau1, Hon-Cheong So2,3,4,5,6,7. 1. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong. 2. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong hcso@cuhk.edu.hk. 3. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. 4. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology and The Chinese University of Hong Kong, Shatin, Hong Kong. 5. Department of Psychiatry, The Chinese University of Hong Kong, Shatin, Hong Kong. 6. Margaret K.L. Cheung Research Centre for Management of Parkinsonism, The Chinese University of Hong Kong, Shatin, Hong Kong. 7. Brain and Mind Institute, The Chinese University of Hong Kong, Shatin, Hong Kong.
Abstract
OBJECTIVE: COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of ACE2 may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on ACE2 lung expression. RESEARCH DESIGN AND METHODS: We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant. RESULTS: The most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N = 898,130), T2DM was causally linked to raised ACE2 expression (P = 2.91E-03; MR-IVW). Significant associations (at nominal level; P < 0.05) with ACE2 expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor-positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. CONCLUSIONS: Our analysis suggested that diabetes and related traits may increase ACE2 expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.
OBJECTIVE:COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of ACE2 may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on ACE2 lung expression. RESEARCH DESIGN AND METHODS: We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant. RESULTS: The most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N = 898,130), T2DM was causally linked to raised ACE2 expression (P = 2.91E-03; MR-IVW). Significant associations (at nominal level; P < 0.05) with ACE2 expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor-positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. CONCLUSIONS: Our analysis suggested that diabetes and related traits may increase ACE2 expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.
Authors: Usman M Ashraf; Ahmed A Abokor; Jonnelle M Edwards; Emily W Waigi; Rachel S Royfman; Syed Abdul-Moiz Hasan; Kathryn B Smedlund; Ana Maria Gregio Hardy; Ritu Chakravarti; Lauren Gerard Koch Journal: Physiol Genomics Date: 2020-12-04 Impact factor: 3.107
Authors: Philip T James; Zakari Ali; Andrew E Armitage; Ana Bonell; Carla Cerami; Hal Drakesmith; Modou Jobe; Kerry S Jones; Zara Liew; Sophie E Moore; Fernanda Morales-Berstein; Helen M Nabwera; Behzad Nadjm; Sant-Rayn Pasricha; Pauline Scheelbeek; Matt J Silver; Megan R Teh; Andrew M Prentice Journal: J Nutr Date: 2021-07-01 Impact factor: 4.798