Association of Renin-Angiotensin Pathway Gene Polymorphisms with COVID-19 Susceptibility and Severity in Moroccans: A Case-Control Study.
COVID-19
Genetic association
Moroccan population
Polymorphisms
Renin-angiotensin system
Journal
Biochemical genetics
ISSN: 1573-4927
Titre abrégé: Biochem Genet
Pays: United States
ID NLM: 0126611
Informations de publication
Date de publication:
08 May 2024
08 May 2024
Historique:
received:
10
01
2024
accepted:
15
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
8
5
2024
Statut:
aheadofprint
Résumé
Infection by the recent SARS-CoV-2 virus causes the COVID-19 disease with variable clinical manifestations ranging from asymptomatic or mild respiratory symptoms to severe respiratory distress and multiorgan failure. The renin-angiotensin system, responsible for maintaining homeostasis and governing several critical processes, has been considered the main system involved in the pathogenesis and progression of COVID-19. Here, we aimed to assess the possible association between variants in the RAS-related genes and COVID-19 susceptibility and severity in a sample of the Moroccan population. A total of 325 individuals were recruited in this study, with 102 outpatients, 105 hospitalized patients, and 118 healthy controls negative for SARS-CoV-2 infection, and subjected to NGS gene panel sequencing containing eleven RAS pathway genes. A total of 65 functional variants were identified, including 63 missenses, 1 splice, and 1 INDEL. Most of them were rare, with 47 (72%) found in a single individual. According to the common disease/common variant hypothesis, five common candidate variants with MAF > 10% were identified (ACE2 rs2285666, TMPRSS2 rs12329760, AGT rs699 genes, ACE rs4341, and ACE rs4343). Statistical analysis showed that the ACE rs4343 AA genotype was associated with a 2.5-fold increased risk of severe COVID-19 (p = 0.026), and the T genotype of the ACE2 rs2285666 variant showed a borderline association with susceptibility to SARS-CoV-2 in males (p = 0.097). In conclusion, our results showed that the RAS pathway genes are highly conserved among Moroccans, and most of the identified variants are rare. Among the common variants, the ACE rs4343 polymorphism would lead to a genetic predisposition for severe COVID-19.
Identifiants
pubmed: 38717614
doi: 10.1007/s10528-024-10813-6
pii: 10.1007/s10528-024-10813-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Abdel Ghafar MT (2020) An overview of the classical and tissue-derived renin-angiotensin-aldosterone system and its genetic polymorphisms in essential hypertension. Steroids 163:108701. https://doi.org/10.1016/j.steroids.2020.108701
doi: 10.1016/j.steroids.2020.108701
pubmed: 32717198
Adimulam T, Arumugam T, Gokul A, Ramsuran V (2023) Genetic variants within SARS-CoV-2 human receptor genes may contribute to variable disease outcomes in different ethnicities. Int J Mol Sci 10:8711. https://doi.org/10.3390/ijms24108711
doi: 10.3390/ijms24108711
Alaa A, Sarhan N, Lotfy El-Ansary MG, Bazan NS, Farouk K, Ismail RS, Schalaan MF, Abd-Allah ARA (2023) Association between genetic polymorphism, severity, and treatment response among COVID-19 infected Egyptian patients. Front Pharmacol 14:1209286. https://doi.org/10.3389/fphar.2023.1209286
doi: 10.3389/fphar.2023.1209286
pubmed: 37426824
pmcid: 10323191
Alabsi S, Dhole A, Hozayen S, Chapman SA (2023) Angiotensin-converting enzyme 2 expression and severity of SARS-CoV-2 infection. Microorganisms 11(3):612. https://doi.org/10.3390/microorganisms11030612
doi: 10.3390/microorganisms11030612
pubmed: 36985188
pmcid: 10054549
Alimoradi N, Sharqi M, Firouzabadi D, Sadeghi MM, Moezzi MI, Firouzabadi N (2022) SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease. Virol J 19(1):48. https://doi.org/10.1186/s12985-022-01782-6
doi: 10.1186/s12985-022-01782-6
pubmed: 35305693
pmcid: 8934128
Araujo FC, Milsted A, Watanabe IK, Del Puerto HL, Santos RA, Lazar J, Reis FM, Prokop JW (2015) Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters. Physiol Genomics 47(5):177–186. https://doi.org/10.1152/physiolgenomics.00138.2014
doi: 10.1152/physiolgenomics.00138.2014
pubmed: 25759379
pmcid: 4421791
Atiku SM, Kasozi D, Campbell K (2023) Single nucleotide variants (SNVs) of Angiotensin-Converting enzymes (ACE1 and ACE2): a plausible explanation for the global variation in COVID-19 prevalence. J Renin Angiotensin Aldosterone Syst 2023:9668008. https://doi.org/10.1155/2023/9668008
doi: 10.1155/2023/9668008
pubmed: 37051471
pmcid: 10085651
Cafiero C, Rosapepe F, Palmirotta R, Re A, Ottaiano MP, Benincasa G, Perone R, Varriale E, D’Amato G, Cacciamani A, Micera A, Pisconti S (2021) Angiotensin system polymorphisms’ in SARS-CoV-2 positive patients: assessment between symptomatic and asymptomatic patients: a pilot study. Pharmgenomics Pers Med 14:621–629. https://doi.org/10.2147/PGPM.S303666
doi: 10.2147/PGPM.S303666
pubmed: 34079337
pmcid: 8166347
Cantero-Navarro E, Fernández-Fernández B, Ramos AM, Rayego-Mateos S, Rodrigues-Diez RR, Sánchez-Niño MD, Sanz AB, Ruiz-Ortega M, Ortiz A (2021) Renin-angiotensin system and inflammation update. Mol Cell Endocrinol 529:111254. https://doi.org/10.1016/j.mce.2021.111254
doi: 10.1016/j.mce.2021.111254
pubmed: 33798633
Chappell MC (2023) Renin-angiotensin system and sex differences in COVID-19: a critical assessment. Circ Res 132(10):1320–1337. https://doi.org/10.1161/CIRCRESAHA.123.321883
doi: 10.1161/CIRCRESAHA.123.321883
pubmed: 37167353
pmcid: 10171311
Cooper SL, Boyle E, Jefferson SR, Heslop CRA, Mohan P, Mohanraj GGJ, Sidow HA, Tan RCP, Hill SJ, Woolard J (2021) Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein systems in the cardiovascular complications of COVID-19 and long COVID. Int J Mol Sci 22(15):8255. https://doi.org/10.3390/ijms22158255
doi: 10.3390/ijms22158255
pubmed: 34361021
pmcid: 8347967
Devaux CA, Fantini J (2023) ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus. Front Microbiol 14:1199561. https://doi.org/10.3389/fmicb.2023.1199561
doi: 10.3389/fmicb.2023.1199561
pubmed: 37520374
pmcid: 10373931
Dieter C, Brondani LA, Leitão CB, Gerchman F, Lemos NE, Crispim D (2022) Genetic polymorphisms associated with susceptibility to COVID-19 disease and severity: a systematic review and meta-analysis. PLoS One 17(7):e0270627. https://doi.org/10.1371/journal.pone.0270627
doi: 10.1371/journal.pone.0270627
pubmed: 35793369
pmcid: 9258831
El-Arif G, Farhat A, Khazaal S, Annweiler C, Kovacic H, Wu Y, Cao Z, Fajloun Z, Khattar ZA, Sabatier JM (2021) The Renin–Angiotensin system: a key role in SARS-CoV-2-induced COVID-19. Molecules 26(22):6945. https://doi.org/10.3390/molecules26226945
doi: 10.3390/molecules26226945
pubmed: 34834033
pmcid: 8622307
Evangelho VGO, Bello ML, Castro HC, Amorim MR (2021) Possible pleiotropic effect of SRY gene may increase male susceptibility to COVID-19. Am J Hypertens 34(11):1241–1242. https://doi.org/10.1093/ajh/hpab093
doi: 10.1093/ajh/hpab093
pubmed: 34125890
Firouzabadi N, Shafiei M, Bahramali E, Ebrahimi SA, Bakhshandeh H, Tajik N (2012) Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an iranian population. Psychiatry Res 200:336–342. https://doi.org/10.1016/j.psychres.2012.05.002
doi: 10.1016/j.psychres.2012.05.002
pubmed: 22688325
Fujikura K, Uesaka K (2021) Genetic variations in the human severe acute respiratory syndrome coronavirus receptor ACE2 and serine protease TMPRSS2. J Clin Pathol 74(5):307
doi: 10.1136/jclinpath-2020-206867
pubmed: 32690544
Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V (2020) COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males? Int J Mol Sci 1(10):3474. https://doi.org/10.3390/ijms21103474
doi: 10.3390/ijms21103474
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2):271-280 e8. https://doi.org/10.1016/j.cell.2020.02.052
doi: 10.1016/j.cell.2020.02.052
pubmed: 32142651
pmcid: 7102627
Íñiguez M, Pérez-Matute P, Villoslada-Blanco P, Recio-Fernandez E, Ezquerro-Pérez D, Alba J, Ferreira-Laso ML, Oteo JA (2021) ACE gene variants rise the risk of severe COVID-19 in patients with hypertension, dyslipidemia or diabetes: a spanish pilot study. Front Endocrinol (Lausanne) 12:688071. https://doi.org/10.3389/fendo.2021.688071
doi: 10.3389/fendo.2021.688071
pubmed: 34489863
Khazaal S, Harb J, Rima M, Annweiler C, Wu Y, Cao Z, Abi Khattar Z, Legros C, Kovacic H, Fajloun Z, Sabatier JM (2022) The pathophysiology of long COVID throughout the Renin–Angiotensin system. Molecules 27(9):2903. https://doi.org/10.3390/molecules27092903
doi: 10.3390/molecules27092903
pubmed: 35566253
pmcid: 9101946
Kirtipal N, Bharadwaj S, Kang SG (2020) From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses. Infect Genet Evol 85:104502. https://doi.org/10.1016/j.meegid.2020.104502
doi: 10.1016/j.meegid.2020.104502
pubmed: 32798769
pmcid: 7425554
Kouhpayeh HR, Tabasi F, Dehvari M, Naderi M, Bahari G, Khalili T, Clark C, Ghavami S, Taheri M (2021) Association between angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin-II receptor 1 (AGTR1) polymorphisms and COVID-19 infection in the southeast of Iran: a preliminary case-control study. Transl Med Commun 6(1):26. https://doi.org/10.1186/s41231-021-00106-0
doi: 10.1186/s41231-021-00106-0
pubmed: 34805533
pmcid: 8596349
Mir MM, Mir R, Alghamdi MAA, Alsayed BA, Elfaki I, Al Bshabshe A et al (2022) Differential impact of the angiotensin-converting enzyme-2 (ACE2 rs4343 G>A) and miR-196a2 rs11614913 C>T gene alterations in COVID-19 disease severity and mortality. Exp Ther Med 23(6):418. https://doi.org/10.3892/etm.2022.11345
doi: 10.3892/etm.2022.11345
pubmed: 35601073
pmcid: 9117950
Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, Hou C, Wang H, Liu J, Yang D, Xu Y, Cao Z, Gao Z (2020) Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 24(1):422. https://doi.org/10.1186/s13054-020-03120-0
doi: 10.1186/s13054-020-03120-0
pubmed: 32660650
pmcid: 7356137
Niehues RV, Wozniak J, Wiersch F, Lilienthal E, Tacken N, Schumertl T, Garbers C, Ludwig A, Düsterhöft S (2022) The collectrin-like part of the SARS-CoV-1 and -2 receptor ACE2 is shed by the metalloproteinases ADAM10 and ADAM17. FASEB J 36(3):e22234. https://doi.org/10.1096/fj.202101521R
doi: 10.1096/fj.202101521R
pubmed: 35199397
Pecoraro V, Cuccorese M, Trenti T (2023) Genetic polymorphisms of ACE1, ACE2, IFTM3, TMPRSS2 and TNFα genes associated with susceptibility and severity of SARS-CoV-2 infection: a systematic review and meta-analysis. Clin Exp Med 23(7):3251–3264. https://doi.org/10.1007/s10238-023-01038-9
doi: 10.1007/s10238-023-01038-9
pubmed: 37055652
Penna C, Mercurio V, Tocchetti CG, Pagliaro P (2020) Sex-related differences in COVID-19 lethality. Br J Pharmacol 177(19):4375–4385. https://doi.org/10.1111/bph.15207
doi: 10.1111/bph.15207
pubmed: 32698249
pmcid: 7405496
Prokop JW, Watanabe IK, Turner ME, Underwood AC, Martins AS, Milsted A (2012) From rat to human: regulation of Renin–Angiotensin system genes by sry. Int J Hypertens 2012:724240. https://doi.org/10.1155/2012/724240
doi: 10.1155/2012/724240
pubmed: 22315667
pmcid: 3270428
Ranjan J, Ravindra A, Mishra B (2021) Gender and genetic factors impacting COVID-19 severity. J Fam Med Prim Care 10:3956–3963. https://doi.org/10.4103/jfmpc.jfmpc_769_21
doi: 10.4103/jfmpc.jfmpc_769_21
Schüler R, Osterhoff MA, Frahnow T, Seltmann AC, Busjahn A, Kabisch S et al (2017) High-saturated-fat diet increases circulating angiotensin-converting enzyme, which is enhanced by the rs4343 polymorphism defining persons at risk of nutrient-dependent increases of blood pressure. J Am Heart Assoc 6(1):e004465. https://doi.org/10.1161/jaha.116.004465
doi: 10.1161/jaha.116.004465
pubmed: 28096099
pmcid: 5523633
Strobelt S, Adler J, Shaul Y (2023) The Transmembrane protease serine 2 (TMPRSS2) non-protease domains regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-mediated virus entry. Viruses 15(10):2124. https://doi.org/10.3390/v15102124
doi: 10.3390/v15102124
pubmed: 37896901
pmcid: 10612036
Sun K, Gu L, Ma L, Duan Y (2021) Atlas of ACE2 gene expression reveals novel insights into transmission of SARS-CoV-2. Heliyon 7(1):e05850. https://doi.org/10.1016/j.heliyon.2020.e05850
doi: 10.1016/j.heliyon.2020.e05850
pubmed: 33392409
Vadgama N, Kreymerman A, Campbell J, Shamardina O, Brugger C, Research Consortium GE, Deaconescu AM, Lee RT, Penkett CJ, Gifford CA, Mercola M, Nasir J, Karakikes I (2022) SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds. Front Genet 13:888025. https://doi.org/10.3389/fgene.2022.888025
doi: 10.3389/fgene.2022.888025
pubmed: 35571054
pmcid: 9091502
Wrobel AG (2023) Mechanism and evolution of human ACE2 binding by SARS-CoV-2 spike. Curr Opin Struct Biol 81:102619. https://doi.org/10.1016/j.sbi.2023.102619
doi: 10.1016/j.sbi.2023.102619
pubmed: 37285618
pmcid: 10183628
Zabiegala A, Kim Y, Chang KO (2023) Roles of host proteases in the entry of SARS-CoV-2. Anim Dis 3(1):12. https://doi.org/10.1186/s44149-023-00075-x
doi: 10.1186/s44149-023-00075-x
pubmed: 37128508
pmcid: 10125864