Association Of Single Nucleotide Polymorphism With Insertion/Deletion ACE Gene Detected Using RhAmp Platform In COVID-19 And Hypertension Patients
The high activity of Angiotensin Converting Enzyme (ACE) in patients with hypertension is thought to affect the risk and severity of COVID-19. Insertion/deletion (I/D) and SNP polymorphisms of the ACE gene can affect ACE activity in the Renin-Angiotensin System (RAS). This study aims to identify linkage disequilibrium SNPs rs4331 (A/G), rs4341 (G/C), and rs4343 (G/A) with I/D polymorphisms reported in previous studies and their associations with the severity of COVID-19 with hypertension comorbid. A cross-sectional study in 2021 recruited 95 samples of COVID-19 patients from two regions representing the eastern and western parts of Indonesia. Detection of polymorphisms using rhAmp SNP showed the percentage of genotypes GG, AG, and AA at rs4331 according to genotype II, DI, and DD in polymorphism I/D (57%, 32%, and 11%). In contrast, rs4341 only showed one type of genotype (GG), and 37% of the samples were undetermined at rs4343. Based on the linkage disequilibrium, it is known that rs4331, rs1799752, and rs4343 are in strong LD (D'= 0.97 and 0.99), and rs4331 and rs1799752 can be markers of genes to replace one with another (R2= 0.957). The haplotype analysis showed a significant difference between the residents of western and eastern Indonesia (p = 0.005), whereas this was not the case with hypertension comorbidities and the severity of COVID-19. Seventeen percent of the G-I-G-G haplotypes showed moderate-severe severity, while 15% of the A-D-G-G haplotypes showed mild severity. Therefore, it can be concluded that the high I/D, rs4331, and rs4343 polymorphisms are likely co-inherited and that the G-I-G-G haplotype is associated with moderate-to-severe severity in COVID-19.
Aung, A. K., Aitken, T., Teh, B. M., Yu, C., & Ofori-asenso, R. (2020). Angiotensin converting enzyme genotypes and mortality from COVID-19: An ecological study. Journal of Infection, 81(January), 961–965. https://doi.org/10.1016/j.jinf.2020.11.012
Ayalew, H., Tsang, P. W., Chu, C., Wang, J., Liu, S., Chen, C., & Ma, X. F. (2019). Comparison of TaqMan, KASP and rhAmp SNP genotyping platforms in hexaploid wheat. PLoS ONE, 14(5), 1–9. https://doi.org/10.1371/journal.pone.0217222
Bánhegyi, V., Enyedi, A., Fülöp, G. Á., Oláh, A., Siket, I. M., Váradi, C., … Tóth, A. (2021). Human tissue angiotensin converting enzyme (ACE) activity is regulated by genetic polymorphisms, posttranslational modifications, endogenous inhibitors and secretion in the serum, lungs and heart. Cells, 10(7). https://doi.org/10.3390/cells10071708
Bartakova, J., Deissova, T., Slezakova, S., Bartova, J., Petanova, J., Kuklinek, P., … Izakovicova Holla, L. (2022). Association of the angiotensin I converting enzyme (ACE) gene polymorphisms with recurrent aphthous stomatitis in the Czech population: case–control study. BMC Oral Health, 22(1), 1–9. https://doi.org/10.1186/s12903-022-02115-3
Bellone, M., & Calvisi, S. L. (2020). ACE polymorphisms and COVID-19-related mortality in Europe. Journal of Molecular Medicine, 98(11), 1505–1509. https://doi.org/10.1007/s00109-020-01981-0
Beltz, K., Tsang, D., Wang, J., Rose, S., Bao, Y., Wang, Y., … Chen, C. (2018). A High-Performing and Cost-Effective SNP Genotyping Method Using rhPCR and Universal Reporters. Advances in Bioscience and Biotechnology, 09(09), 497–512. https://doi.org/10.4236/abb.2018.99034
Braz, G. T., He, L., Zhao, H., Zhang, T., Semrau, K., Rouillard, J. M., … others. (2021). Comparative analysis of tandem repeats from hundreds of species reveals unique insights into centromere evolution. Genome Biology, 14(1), 1–20. http://dx.doi.org/10.1038/s41467-021-22738-4
Calabrese, C., Annunziata, A., Coppola, A., Pafundi, P. C., Guarino, S., Di Spirito, V., … Fiorentino, G. (2021). ACE Gene I/D Polymorphism and Acute Pulmonary Embolism in COVID19 Pneumonia: A Potential Predisposing Role. Frontiers in Medicine, 7(January), 1–6. https://doi.org/10.3389/fmed.2020.631148
Chandra, V. A., Siregar, Y., & Arina, C. A. (2020). Correlation of ACE Gene Polymorphism and Hypertension in Stroke Ischemic Patients. Sumatera Medical Journal, 3(1), 41–47. https://doi.org/10.32734/sumej.v3i1.3310
Chung, C. M., Wang, R. Y., Fann, C. S. J., Chen, J. W., Jong, Y. S., Jou, Y. S., … Pan, W. H. (2013). Fine-Mapping Angiotensin-Converting Enzyme Gene: Separate QTLs Identified for Hypertension and for ACE Activity. PLoS ONE, 8(3), e56119. https://doi.org/10.1371/journal.pone.0056119
Devaux, C. A., Rolain, J. M., & Raoult, D. (2020). ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. Journal of Microbiology, Immunology and Infection, 53(3), 425–435. https://doi.org/10.1016/j.jmii.2020.04.015
Faustine, I. et al. (n.d.). Distribution of ACE gene InDel genotypes and clinical characteristics of patients with hypertension and COVID-19 in Palu City and Lahat District, Indonesia.
Faustine, I., Malik, A., Andrajati, R., & Wanandi, S. I. (2021). Clinical Characteristics and Severity Profile of COVID-19 Patient with Hypertension in Palu , Central Sulawesi. 32(4), 563–572. https://doi.org/10.22146/ijp.2729
Glenn, K. L., Du, Z. Q., Eisenmann, J. C., & Rothschild, M. F. (2009). An alternative method for genotyping of the ACE I/D polymorphism. Molecular Biology Reports, 36(6), 1305–1310. https://doi.org/10.1007/s11033-008-9313-5
Han, C., Han, X., Liu, F., & Huang, J. (2017). Ethnic differences in the association between angiotensin‐converting enzyme gene insertion/deletion polymorphism and peripheral vascular disease: A meta‐analysis. Chronic Diseases and Translational Medicine, 3(4), 230–241. https://doi.org/10.1016/j.cdtm.2017.07.002
Heidari, M. M., Hadadzadeh, M., & Fallahzadeh, H. (2019). Development of one-step tetra-primer ARMS-PCR for simultaneous detection of the angiotensin converting enzyme (ACE) I/d and rs4343 gene polymorphisms and the correlation with CAD patients. Avicenna Journal of Medical Biotechnology, 11(1), 118–123.
Integrated DNA Technologies Inc. (2017). Rhamp-Snp-Genotyping. Idt_Protocol. https://www.idtdna.com/pages/products/qpcr-and-pcr/genotyping/rhamp-snp-genotyping/rhamp-snp-assays
Jacobs, M., Lahousse, L., Van Eeckhoutte, H. P., Wijnant, S. R. A., Delanghe, J. R., Brusselle, G. G., & Bracke, K. R. (2021). Effect of ACE1 polymorphism rs1799752 on protein levels of ACE2, the SARS-CoV-2 entry receptor, in alveolar lung epithelium. ERJ Open Research, 7(2), 1–4. https://doi.org/10.1183/23120541.00940-2020
Kang, H. J., Kim, C. H., Park, D. S., Choi, S. Y., Lee, D. H., Nam, H. S., … Woo, J. H. (2012). The Impacts of ACE activity according to ACE I/D polymorphisms on muscular functions of people aged 65. Annals of Rehabilitation Medicine, 36(4), 433–446. https://doi.org/10.5535/arm.2012.36.4.433
Kankanit Rattanathanawan, Polphet Thongket, Benjaporn Panichareon, W. S. (2018). Studies of single nucleotide polymorphism (SNP) of angiotensin-converting enzyme (ACE) gene and serum ACE protein level in association with hypertension in Thai patient. 25(2), 56–66.
Krishnan, R., Sekar, D., karunanithy, S., & Subramanium, S. (2016). Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population. Genes and Diseases, 3(2), 159–163. https://doi.org/10.1016/j.gendis.2016.03.001
Peplonska, B., Adamczyk, J. G., Siewierski, M., Safranow, K., Maruszak, A., Sozanski, H., … Zekanowski, C. (2017). Genetic variants associated with physical and mental characteristics of the elite athletes in the Polish population. Scandinavian Journal of Medicine and Science in Sports, 27(8), 788–800. https://doi.org/10.1111/sms.12687
Peta Sebaran | Covid19.go.id. (n.d.). Retrieved March 24, 2022, from https://covid19.go.id/peta-sebaran
Sabater Molina, M., Nicolás Rocamora, E., Bendicho, A. I., Vázquez, E. G., Zorio, E., Rodriguez, F. D., … Gimeno Blanes, J. R. (2022). Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease. PloS One, 17(2), e0263140. https://doi.org/10.1371/journal.pone.0263140
WHO Coronavirus (COVID-19) Dashboard. (n.d.). Retrieved March 6, 2022, from https://covid19.who.int/table
Yamamoto, N., Ariumi, Y., Nishida, N., Yamamoto, R., Bauer, G., Gojobori, T., … Mizokami, M. (2020). SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. Gene, 758(June), 144944. https://doi.org/10.1016/j.gene.2020.144944
Zeng, W., Yang, S., Song, N., & Chu, F. (2021). The impact of angiotensin converting enzyme insertion/deletion gene polymorphism on diabetic kidney disease: A debatable issue. Nefrología, 933(x x), 17. https://doi.org/10.1016/j.nefro.2021.07.00