Genetic Associations With Plasma Angiotensin Converting Enzyme 2 Concentration
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.120.049007
ISSN1524-4539
AutoresChristopher P. Nelson, Iziah E Sama, Veryan Codd, Tom R. Webb, Shu Ye, Chim C. Lang, Adriaan A. Voors, Leong L. Ng, Nilesh J. Samani,
Tópico(s)COVID-19 Clinical Research Studies
ResumoHomeCirculationVol. 142, No. 11Genetic Associations With Plasma Angiotensin Converting Enzyme 2 Concentration Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBGenetic Associations With Plasma Angiotensin Converting Enzyme 2 ConcentrationPotential Relevance to COVID-19 Risk Christopher P. Nelson, Iziah E. Sama, Veryan Codd, Thomas R. Webb, Shu Ye, Chim C. Lang, Adriaan A. Voors, Leong L. Ng and Nilesh J. Samani Christopher P. NelsonChristopher P. Nelson Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). , Iziah E. SamaIziah E. Sama Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (I.E.S., A.A.V.). , Veryan CoddVeryan Codd Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). , Thomas R. WebbThomas R. Webb Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). , Shu YeShu Ye Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). , Chim C. LangChim C. Lang Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee Ninewells Hospital and Medical School, United Kingdom (C.C..) , Adriaan A. VoorsAdriaan A. Voors Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (I.E.S., A.A.V.). , Leong L. NgLeong L. Ng https://orcid.org/0000-0002-6553-5749 Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). and Nilesh J. SamaniNilesh J. Samani Nilesh J Samani, MD, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom. Email E-mail Address: [email protected] Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.). Originally published7 Jul 2020https://doi.org/10.1161/CIRCULATIONAHA.120.049007Circulation. 2020;142:1117–1119Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 7, 2020: Ahead of Print Male sex has emerged as a major independent risk factor for severe disease and death from severe acute respiratory syndrome coronavirus–related coronavirus disease 2019 (COVID-19).1 Severe acute respiratory syndrome coronavirus 2 infects cells via the angiotensin converting enzyme 2 (ACE2) receptor, a widely distributed cell-surface receptor.2 In 2 cohorts of patients with heart failure (BIOSTAT-CHF [Biology Study to Tailored Treatment in Chronic Heart Failure]), we recently showed that age-adjusted plasma concentrations of ACE2 are higher in men than in women.3To explore whether there are sex-specific genotype effects on plasma ACE2 concentrations, we undertook sex-specific and combined genome-wide associations studies of plasma ACE2, measured using the Olink platform (which provides results expressed in the form of relative quantification without units), in the combined index and validation cohorts of BIOSTAT-CHF (2420 men and 1022 women, mean age 70.9±11.6 years).3 The BIOSTAT-CHF study was approved by institutional review boards at participating centers. Further details on the cohorts are available in Sama et al.3 Mean plasma ACE2 concentrations were 5.41 (SD 0.74) in men and 5.13 (0.75) in women (P=2.6×10–26). Genotyping was performed using the Affymetrix Axiom Genome-Wide UKB WCSG Genotyping Array and variants imputed to 1000G Phase 1 v3. Further details on imputation and quality control are available on request. We tested variants with a minor allele frequency >1% and an imputation quality score >0.5 and adjusted the analyses for BIOSTAT-CHF cohort, age, and the first 5 principal components.We identified 3 loci associated with plasma ACE2 concentrations at genome-wide significance in men, but none in women (Figure A). No additional genome-wide significance loci were identified in the combined analysis.Download figureDownload PowerPointFigure. Association of genetic variants with plasma ACE2 concentration.A, Miami plot showing genome-wide association analysis of genetic variants with plasma ACE2 concentration. Chromosomal location of the variants is shown on the x axis and –log10 (P value) of the association on the y axis for men (blue, Upper) and women (red, Lower). Dashed reference line shows the genome-wide significance threshold of P=5×10–8. B through D, Regional plots showing association with plasma ACE2 concentration of genetic variants on the X-chromosome (chrX) around the ACE2 gene (B), on chromosome 12 (chr12) around the HNF1α gene (C), and on chromosome 21 (chr21) around the ERG gene (D). Each plot shows associations for men in the upper half and women in the lower half. The top signals for chromosome 12 (rs71076692) and for chromosome 21 (chr21:39834295) are both indels. Therefore, proxy single-nucleotide polymorphisms (rs7139079 and rs2186346, respectively) in high-linkage disequilibrium with these lead variants were used to generate the linkage disequilibrium relationships with other variants for signals on chromosomes 12 and 21.The strongest association was with an X-chromosome locus (lead single-nucleotide polymorphism rs12551879, minor allele frequency 27.2%, beta 0.13±0.02, P=5.93×10–15), which includes the ACE2 gene (Figure B). The strongest association in women was rs4646131 (P=1.58×10–3) with a R2=0.16 and D′=0.86 with the lead single-nucleotide polymorphism in men (Figure B). The lead variant (rs71076692, minor allele frequency 48.4%, beta 0.14±0.02, P=1.49×10–9) at the second locus in men on chromosome 12 (Figure C) is an insertion-deletion (indel) variant located proximate to HNF1α that encodes a transcription factor known to regulate ACE2 expression.4 The lead variant (chr21:39834295, minor allele frequency 24.8%, beta 0.13±0.03, P=2.87×10–9) at the third locus in men on chromosome 21 (Figure D) is also an indel located within the ERG gene which encodes a transcription factor involved in vascular development and remodeling. Fusion of ERG with the nearby gene TMPRSS2, encoding a transmembrane serine protease involved in ACE2 cleavage and entry of severe acute respiratory syndrome coronavirus 2 into the cell, is a frequent event in prostate cancer.2,5A sex interaction analysis showed a significant interaction for the third locus on chromosome 21 (P=0.001) but not for the loci on chromosomes X (P=0.25) or 12 (P=0.15). Because of the smaller sample size in women, we estimated the power to detect the effects seen in men. The power to detect the smallest effect size seen in men (chromosome 21) was 53.9% at 5×10–8 and 93.5% at 5×10–5. The 3 loci explained 4.91% of variation in plasma ACE2 concentration in men and 1.14% in women. The associations were independent of other clinical or demographic factors or medication.The lack of association signals in women at the 3 identified loci may reflect smaller sample size and lower power; however, the >4-fold difference in variation in ACE2 concentration explained by these loci between men and women supports an hypothesized sex-specific genotype effect on plasma ACE2 concentration. The association of X-chromosome variants is probably mediated by cis-effects on ACE2 transcription. Although there are strong candidate genes that may explain the associations at the other 2 loci (see earlier), causal genes underlying genome-wide association study loci are often neither the nearest nor the strongest putative candidate genes and further investigation of their involvement is necessary.Plasma ACE2 arises from shedding of the receptor from cells through the effect of several enzymes including TMPRSS2 and ADAM17.2 Any association between ACE2 levels and severity of COVID-19 and the extent to which plasma ACE2 concentration correlates with expression in tissues are both unclear. The genotype effects observed for plasma ACE2 concentration could reflect a similar effect on tissue expression or on receptor shredding, at least in some sites. In turn, this could possibly influence susceptibility to the severity of infection by severe acute respiratory syndrome coronavirus 2.Our analyses were performed in relatively elderly subjects of primarily European Caucasian ancestry with heart failure.3 These results require replication in other cohorts. As suitable cohorts collected during the COVID-19 pandemic become available, our findings provide an opportunity to determine whether these genetic markers associated with ACE2 concentrations in BIOSTAT-CHF are also associated with differences in outcomes from COVID-19, especially in men. If this is the case, genotyping may help inform future personalized prevention strategies against COVID-19. More broadly, a primarily protective role for ACE2 has been proposed in several cardiovascular diseases, and our findings provide new genetic instruments to investigate its precise involvement.AcknowledgmentsWe acknowledge the contribution of members of the BIOSTAT-CHF consortium.Sources of FundingThe BIOSTAT-CHF project (Biology Study to Tailored Treatment in Chronic Heart Failure) was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF). Drs Nelson, Webb, and Ye are funded by the British Heart Foundation.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circNilesh J Samani, MD, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom. Email [email protected]ac.ukReferences1. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell L, Chernyak Y, Tobin KA, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.BMJ. 2020; 369:m1966. doi: 10.1136/bmj.m1966CrossrefMedlineGoogle Scholar2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181:271–280.e8. doi: 10.1016/j.cell.2020.02.052CrossrefMedlineGoogle Scholar3. Sama IE, Ravera A, Santema BT, van Goor H, ter Maaten JM, Cleland JGF, Rienstra M, Friedrich AW, Samani NJ, Ng LL, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.Eur Heart J. 2020; 41:1810–1817. doi:10.1093/eurheartj/ehaa373CrossrefMedlineGoogle Scholar4. Pedersen KB, Chhabra KH, Nguyen VK, Xia H, Lazartigues E. The transcription factor HNF1α induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs.Biochim Biophys Acta. 2013; 1829:1225–1235. doi: 10.1016/j.bbagrm.2013.09.007CrossrefMedlineGoogle Scholar5. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310:644–648. doi: 10.1126/science.1117679CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lott N, Gebhard C, Bengs S, Haider A, Kuster G, Regitz-Zagrosek V and Gebhard C (2022) Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?, Nature Reviews Endocrinology, 10.1038/s41574-022-00780-6, 19:4, (217-231), Online publication date: 1-Apr-2023. Li J, Wang Y, Liu Y, Zhang Z, Zhai Y, Dai Y, Wu Z, Nie X and Du L (2022) Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review, European Journal of Medical Research, 10.1186/s40001-022-00647-6, 27:1, Online publication date: 1-Dec-2022. Sulentic R, Seferovic M, Aagaard K and Valentine G (2020) Perinatal COVID-19 outcomes: evaluating the strength of current evidence, The Journal of Maternal-Fetal & Neonatal Medicine, 10.1080/14767058.2020.1849101, 35:22, (4250-4257), Online publication date: 17-Nov-2022. Fan J, Long Q, Ren J, Chen H, Li M, Cheng Z, Chen J, Zhou L and Huang A (2022) Genome-wide association study of SARS-CoV-2 infection in Chinese population, European Journal of Clinical Microbiology & Infectious Diseases, 10.1007/s10096-022-04478-5 Yang Z, Macdonald-Dunlop E, Chen J, Zhai R, Li T, Richmond A, Klarić L, Pirastu N, Ning Z, Zheng C, Wang Y, Huang T, He Y, Guo H, Ying K, Gustafsson S, Prins B, Ramisch A, Dermitzakis E, Png G, Eriksson N, Haessler J, Hu X, Zanetti D, Boutin T, Hwang S, Wheeler E, Pietzner M, Raffield L, Kalnapenkis A, Peters J, Viñuela A, Gilly A, Elmståhl S, Dedoussis G, Petrie J, Polašek O, Folkersen L, Chen Y, Yao C, Võsa U, Pairo-Castineira E, Clohisey S, Bretherick A, Rawlik K, Esko T, Enroth S, Johansson Å, Gyllensten U, Langenberg C, Levy D, Hayward C, Assimes T, Kooperberg C, Manichaikul A, Siegbahn A, Wallentin L, Lind L, Zeggini E, Schwenk J, Butterworth A, Michaëlsson K, Pawitan Y, Joshi P, Baillie J, Mälarstig A, Reiner A, Wilson J and Shen X (2022) Genetic Landscape of the ACE2 Coronavirus Receptor, Circulation, 145:18, (1398-1411), Online publication date: 3-May-2022. Chamnanphon M, Pongpanich M, Suttichet T, Jantarabenjakul W, Torvorapanit P, Putcharoen O, Sodsai P, Phokaew C, Hirankarn N, Chariyavilaskul P and Shotelersuk V (2022) Host genetic factors of COVID-19 susceptibility and disease severity in a Thai population, Journal of Human Genetics, 10.1038/s10038-021-01009-6, 67:5, (295-301), Online publication date: 1-May-2022. Kushwaha S, Khanna P, Rajagopal V and Kiran T (2021) Biological attributes of age and gender variations in Indian COVID-19 cases: A retrospective data analysis, Clinical Epidemiology and Global Health, 10.1016/j.cegh.2021.100788, 11, (100788), Online publication date: 1-Jul-2021. Savoia C, Volpe M and Kreutz R (2021) Hypertension, a Moving Target in COVID-19, Circulation Research, 128:7, (1062-1079), Online publication date: 2-Apr-2021. Gaziano L, Giambartolomei C, Pereira A, Gaulton A, Posner D, Swanson S, Ho Y, Iyengar S, Kosik N, Vujkovic M, Gagnon D, Bento A, Barrio-Hernandez I, Rönnblom L, Hagberg N, Lundtoft C, Langenberg C, Pietzner M, Valentine D, Gustincich S, Tartaglia G, Allara E, Surendran P, Burgess S, Zhao J, Peters J, Prins B, Angelantonio E, Devineni P, Shi Y, Lynch K, DuVall S, Garcon H, Thomann L, Zhou J, Gorman B, Huffman J, O'Donnell C, Tsao P, Beckham J, Pyarajan S, Muralidhar S, Huang G, Ramoni R, Beltrao P, Danesh J, Hung A, Chang K, Sun Y, Joseph J, Leach A, Edwards T, Cho K, Gaziano J, Butterworth A and Casas J (2021) Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19, Nature Medicine, 10.1038/s41591-021-01310-z, 27:4, (668-676), Online publication date: 1-Apr-2021. Leso V, Fontana L and Iavicoli I (2021) Susceptibility to Coronavirus (COVID-19) in Occupational Settings: The Complex Interplay between Individual and Workplace Factors, International Journal of Environmental Research and Public Health, 10.3390/ijerph18031030, 18:3, (1030) Calcagnile M, Forgez P, Iannelli A, Bucci C, Alifano M and Alifano P (2021) Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein, Biochimie, 10.1016/j.biochi.2020.11.004, 180, (143-148), Online publication date: 1-Jan-2021. Bienvenu L, Noonan J, Wang X and Peter K (2020) Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities, Cardiovascular Research, 10.1093/cvr/cvaa284, 116:14, (2197-2206), Online publication date: 1-Dec-2020. September 15, 2020Vol 142, Issue 11 Advertisement Article InformationMetrics © 2020 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.120.049007PMID: 32795093 Originally publishedJuly 7, 2020 Keywordsgenome-wide association studyangiotensin converting enzyme 2severe acute respiratory syndromeCOVID-19PDF download Advertisement SubjectsBiomarkersGenetic, Association StudiesVascular Biology
Referência(s)