Genetic determinants of angiotensin-converting enzyme: functionality of loci as a basis for associative links

Background. One of the most important regulators of blood pressure is angiotensin-converting enzyme (ACE). High levels of ACE cause an increased risk of arterial hypertension (HTN) and other diseases. GWAS data on genetic determinants of ACE were obtained, but only some of them are located in the gene (near the gene) ACE, and a significant part is located in other regions of the genome. Understanding the mechanisms underlying the association of GWAS-significant polymorphisms with the level/activity of ACE will significantly expand the use of these loci, both in scientific research in the study of genetic determinants of pathological conditions associated with elevated blood pressure, and will create the prerequisites for their introduction into practical medicine as genetic markers of the risk of HTN and other diseases.
Objective. To study the functional effects of single nucleotide polymorphisms (SNPs) associated with the level/activity of ACE according to GWAS data.
Design and methods. We assessed the functional effects of GWAS-significant polymorphisms associated with ACE level/activity based on the analysis of their epigenetic effects (HaploReg v.4.2 database), association with expression (eQTL), alternative gene splicing (sQTL) (GTEx Portal database, — V10 was used), alternative mRNA polyadenylation (aQTL) (3'aQTL-atlas database was used), biological pathways and protein interactions (STRING, V12.0).
Results. Among 14 GWAS-significant for ACE level/activity polymorphic loci, some SNPs (n = 8, rs116112765, rs4968782, rs3730025, rs4308, rs4343, rs4353, rs4362, rs4363) are localized in the ACE gene region, they are functionally associated with 16 genes (ACE, TANC2, FTSJ3, PSMC5, KCNH6, DCAF7, CSH2, ACE3P, TCAM1P, SMARCD2, CYB561, PPIAP55, STRADA, EEF1DP7, TEX2, LIMD2) and can have direct epigenetic, eQTL, sQTL, aQTL influence on the ACE gene. Another part of GWAS-significant for ACE level/activity SNPs (n = 6, rs7626301, rs8176746, rs507666, rs115478735, rs495828, rs11603123) is located outside the ACE gene region and exhibits its functional effects in relation to other 16 genes (HRG-AS1, HRG, LCN1P1, Y_RNA, ABO, ST3GAL4, KIRREL3, OBP2B, SURF6, SURF1, REXO4, DBH-AS1, MED22, DBH, MYMK, SLC2A6). Apparently, these loci modulate the level/activity of ACE through protein products encoded by these genes, which participate in biological pathways significant for the level/activity of ACE as following: the formation of ACE in endothelial cells of the lungs and blood cells (through the activating effect of thyroid hormones and calcium); the formation of endothelial cells in which ACE is synthesized, in the process of angiogenesis and endothelial regeneration; maintaining the viability of ACE-producing cells, due to the regulation of their mitotic cycle; ensuring the stability of ACE, through sialylation of circulating ACE in plasma; deactivation of ACE, due to the regulation of the level of albumin, which inactivates ACE.
Conclusion. The putative medical and biological basis determining the associations of GWAS-significant polymorphic loci for the level/activity of ACE may be both their direct epigenetic, eQTL, sQTL, aQTL influence on this gene (for SNPs located in the ACE gene region), and biological pathways involving protein products functionally associated with these loci (for SNPs located outside the ACE gene region).

1. Rudnicki M, Mayer G. Significance of genetic polymorphisms of the renin–angiotensin–aldosterone system in cardiovascular and renal disease. Pharmacogenomics. 2009;10:463–476. https://doi.org/10.2217/14622416.10.3.463

2. Jordan J, Kurschat C, Reuter H. Arterial hypertension: diagnosis and treatment. Dtsch. ÄrzteblattInt. 2018;115:557–568. https://doi.org/10.3238/arztebl.2018.0557

3. Ivanova TA. Polymorphic loci of AC026703.1 and HFE genes are associated with severe hypertension. Research Results in Biomedicine. 2023;9(1):22–38. (In Russ.) https://doi.org/10.18413/2658-6533-2023-9-1-0-2

4. Sultan RH, Elesawy BH, Ali TM, Abdallah M, Assal HH, Ahmed AE, et al. Correlations between kidney and heart function bioindicators and the expressions of Toll-Like, ACE2, and NRP-1 receptors in COVID-19. Vaccines. 2022;10(7):1106. https://doi.org/10.3390/vaccines10071106

5. Ivanova TA. Sex-specific features of interlocus interactions determining susceptibility to hypertension. Research Results in Biomedicine. 2024;10(1):53–68. (In Russ.) https://doi.org/10.18413/2658-6533-2024-10-1-0-3

6. Giani JF, Veiras LC, Shen JZY, Bernstein EA, Cao D, Okwan-Duodu D, et al. Novel roles of the renal angiotensin-converting enzyme. Mol Cell Endocrinol. 2021;529:111257. https://doi.org/10.1016/j.mce.2021.111257

7. Ribeiro-Oliveira A, Nogueira A.I, Pereira RM, Boas WWV, dos Santos RAS, Silva ACS. The renin–angiotensin system and diabetes: an update. Vasc Health Risk Manag. 2008;4:787–803.

8. Chung CM, Wang RY, Chen JW, Fann CS, Leu HB, Ho HY, et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharmacogenomics J. 2010;10(6):537–544. https://doi.org/10.1038/tpj.2009.70

9. Pietzner M, Wheeler E, Carrasco-Zanini J, Cortes A, Koprulu M, Wörheide MA, et al. Mapping the proteo-genomic convergence of human diseases. Science. 2021;374(6569):eabj1541. https://doi.org/10.1126/science.abj1541

10. Kamyshnikova LA, Efremova OA, Fentisov VV, Bolkhovitina OA, Churnosov MI. Genetic determinants of angiotensin-converting enzyme levels (data from genome-wide studies). Arterial’naya Gipertenziya=Arterial Hypertension. 2024;30(6):537–552. (In Russ.) https://doi.org/10.18705/1607-419X-2024-2446

11. HaploReg v4.2 [cited 2024 December 4]. Available from: https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php

12. Genotype-Tissue Expression (GTEx Portal V8) [cited 2024 December 4]. Available from: https://www.gtexportal.org/home/

13. 3′aQTL-atlas: an atlas of 3′UTR alternative polyadenylation quantitative trait loci across human normal tissues [cited 2024 December 4]. Available from: https://wlcb.oit.uci.edu/3aQTLatlas/

14. STRING V12.0 [cited 2024 December 4]. Available from: https://string-db.org/

15. Nalesnik EO. Angiotensin-converting enzyme: a well-known stranger. Part II. Arterial’naya Gipertenziya = Arterial Hypertension. 2023;29(6):548–556. (In Russ.) https://doi.org/10.18705/1607-419X-2023-29-6-543-556

16. Martyniak A, Tomasik PJ. A new perspective on the reninangiotensin system. Diagnostics (Basel). 2023;13(1):16. https://doi.org/10.3390/diagnostics13010016

17. Nalesnik EO. Angiotensin-converting enzyme: a well-known stranger. Part I. Arterial’naya Gipertenziya = Arterial Hypertension. 2023;29(4):353–370. (In Russ.) https://doi.org/10.18705/1607-419X-2023-29-4-353-370

18. Bull HG, Thornberry NA, Cordes EH. Purification of angiotensin-converting enzyme from rabbit lung and human plasma by affinity chromatography. J Biol Chem. 1985;260(5):2963–2972.

19. Baudin B, Alves N, Pilon A, Bénéteau-Burnat B, Giboudeau J. Structural and biological roles of glycosylations in pulmonary angiotensin I-converting enzyme. Glycobiology. 1997;7(4):565–570. https://doi.org/10.1093/glycob/7.4.565

20. Danilov SM. Conformational fingerprinting using monoclonal antibodies (on the example of angiotensin-converting enzyme – ACE). Mol Biol. 2017;51(6):1046–1061. (In Russ.) https://doi.org/10.7868/S0026898417060155

21. Nehme A, Cerutti C, Dhaouadi N, Gustin MP, Courand P-Y, Zibara K, et al. Atlas of tissue renin-angiotensin-aldosterone system in human: a transcriptomic meta-analysis. Sci Rep.2015;5:10035. https://doi.org/10.1038/srep10035

22. Fagyas M, Úri K, Siket IM, Fülöp GÁ, Csató V, Daragó A, et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) II: albumin suppresses angiotensin converting enzyme (ACE) activity in human. PLoS One. 2014;9(4):e87844. https://doi.org/10.1371/journal.pone.0087844

23. Kwok-Shing Wong M. Subchapter 42D — angiotensin converting enzyme. Editor(s): Ando H, Ukena K, Nagata S. Handbook of Hormones (Second Edition), Academic Press, 2021:505–508. https://doi.org/10.1016/B978-0-12-820649-2.00128-5

24. Mamedov VN, Danilov SM, Samokhodskaya LM, Okhobotov DA, Kamalov DM, Melnikov NА, et al. Phenotyping of angiotensin-converting enzyme in the prostate in patients with prostate cancer and benign prostatic hyperplasia. Urology. 2020;5:20–27. (In Russ.) https://doi.org/10.18565/urology.2020.5.20-27

25. Caron B, Patin E, Rotival M, Charbit B, Albert ML, Quintana-Murci L, et al. Milieu Intérieur Consortium. Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes. Genome Med. 2022;14(1):28. https://doi.org/10.1186/s13073-022-01032-y

26. Gudjonsson A, Gudmundsdottir V, Axelsson GT, Gudmundsson EF, Jonsson BG, Launer LJ, et al. A genome-wide association study of serum proteins reveals shared loci with common diseases. Nat Commun. 2022;13(1):480. https://doi.org/10.1038/s41467-021-27850-z

27. Kauwe JS, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL, et al. Genome-wide association study of CSF levels of 59 Alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet. 2014;10(10):e1004758. https://doi.org/10.1371/journal.pgen.1004758

28. Bone WP, Siewert KM, Jha A, Klarin D, Damrauer SM, The VA Million Veteran Program, et al. Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther. 2021;13(1):34. https://doi.org/10.1186/s13195-021-00773-z

29. Surapaneni A, Schlosser P, Zhou L, Liu C, Chatterjee N, Arking DE, et al. Identification of 969 protein quantitative trait loci in an African American population with kidney disease attributed to hypertension. Kidney Int. 2022;102(5):1167–1177. https://doi.org/10.1016/j.kint.2022.07.005

30. Kitano M, Kizuka Y, Sobajima T, Nakano M, Nakajima K, Misaki R, et al. Rab11-mediated post-Golgi transport of the sialyltransferase ST3GAL4 suggests a new mechanism for regulating glycosylation. J Biol Chem. 2021;296:100354. https://doi.org/10.1016/j.jbc.2021.100354

31. Folkersen L, Gustafsson S, Wang Q, Hansen DH, Hedman ÅK, Schork A, et al. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab. 2020;2(10):1135–1148. https://doi.org/10.1038/s42255-020-00287-2

32. Barondes SH, Cooper DN, Gitt MA, Leffler H. Galectins. Structure and function of a large family of animal lectins. J Biol Chem. 1994;269(33):20807–20810.

33. Young WJ, Warren HR, Mook-Kanamori DO, Ramírez J, van Duijvenboden S, Orini M, et al. Determined serum calcium levels and markers of ventricular repolarization: a mendelian randomization study in the UK Biobank. Circ Genom Precis Med. 2021;14(3):e003231. https://doi.org/10.1161/CIRCGEN.120.003231

34. Mondal N, Buffone A Jr, Stolfa G, Antonopoulos A, Lau JT, Haslam SM, et al. ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes. Blood. 2015;125(4):687–696. https://doi.org/10.1182/blood-2014-07-588590

35. Clutario KM, Abdusamad M, Ramirez I, Rich KJ, Gholkar AA, Zaragoza J, et al. Human REXO4 is required for cell cycle progression [preprint]. bioRxiv. 2025;9:2025.01.08.631954. https://doi.org/10.1101/2025.01.08.631954

36. Rodriguez PQ, Unnersjö-Jess D, Zambrano SS, Guo J, Möller-Hackbarth K, Blom H, et al. Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death. Sci Rep. 2020;10(1):20037. https://doi.org/10.1038/s41598-020-76870-0

37. Elenis E, Skalkidou A, Skoog-Svanberg A, Sydsjö G, Stavreus-Evers A, Åkerud H. HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study. BMC Med Genet. 2018;19(1):44. https://doi.org/10.1186/s12881-018-0550-8

38. Sinnott-Armstrong N, Tanigawa Y, Amar D, Mars N, Benner C, Aguirre M, еt al. Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat Genet. 2021;53(2):185–194. https://doi.org/10.1038/s41588-020-00757-z

39. Chen MH, Raffield LM, Mousas A, Sakaue S, Huffman JE, Moscati A, et al. Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations. Cell. 2020;182(5):1198–1213. https://doi.org/10.1016/j.cell.2020.06.045

40. Katz DH, Tahir UA, Bick AG, Pampana A, Ngo D, Benson MD, et al. National Heart, Lung, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†. Whole genome sequence analysis of the plasma proteome in black adults provides novel insights into cardiovascular disease. Circulation. 2022;145(5):357–370. https://doi.org/10.1161/CIRCULATIONAHA.121.055117

41. Gavard J. Endothelial permeability and VE-cadherin: a wacky comradeship. Cell Adh Migr. 2014;8(2):158–64. https://doi.org/10.4161/cam.29026

42. Thareja G, Belkadi A, Arnold M, Albagha OME, Graumann J, Schmidt F, et al. Consortium TQGPR, Suhre K. Differences and commonalities in the genetic architecture of protein quantita tive trait loci in European and Arab populations. Hum Mol Genet. 2023;32(6):907–916. https://doi.org/10.1093/hmg/ddac243

43. Kovářová N, Cížková Vrbacká A, Pecina P, Stránecký V, Pronicka E, Kmoch S, et al. Adaptation of respiratory chain biogenesis to cytochrome c oxidase deficiency caused by SURF1 gene mutations. Biochim Biophys Acta. 2012;1822(7):1114–1124. https://doi.org/10.1016/j.bbadis.2012.03.007

44. Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–1424. https://doi.org/10.1038/s41588-021-00931-x

45. Williams AT, Chen J, Coley K, Batini C, Izquierdo A, Packer R, et al. Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease. Nat Commun. 2023;14(1):6713. https://doi.org/10.1038/s41467-023-42284-5

46. Png G, Gerlini R, Hatzikotoulas K, Barysenka A, Rayner NW, Klarić L, et al. Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing. Hum Mol Genet. 2023;32(8):1266–1275. https://doi.org/10.1093/hmg/ddac275

47. Valkov N, Das SY. RNAs: biogenesis, function and implications for the cardiovascular system. Adv Exp Med Biol. 2020;1229:327–342. https://doi.org/10.1007/978-981-15-1671-9_20

48. Maedera S, Mizuno T, Ishiguro H, Ito T, Soga T, Kusuhara H. GLUT6 is a lysosomal transporter that is regulated by inflammatory stimuli and modulates glycolysis in macrophages. FEBS Lett. 2019;593(2):195–208. https://doi.org/10.1002/1873-3468.13298