Angiotensin-Converting Enzyme Genetic Polymorphism rs4343 as Risk of Diabetic Nephropathy in Jambi-Malay Population

Elfiani Elfiani, Anggelia Puspasari, Cut Wulan Arif, Citra Maharani, Zulkhair Ali, Novadian Suhaimi, Ian Effendi, Suprapti Suprapti, Nyimas Natasha Ayu Shafira


Background: Diabetic nephropathy (DN) is one of the frequent complications of type II diabetes mellitus (T2DM) in Jambi province. Controlling blood glucose and blood pressure does not guarantee DN prevention, since genetic factors may also contribute to this disease. Multi-ethnic studies showed that one of the strongest genetic factors associated with DN was single nucleotide polymorphism rs4343 of angiotensin-converting enzyme (ACE) gene. Study regarding phenotype-genotype association of ACE rs4343 and DN has not yet been performed in Jambi Province, which is dominated by Malay ethnicity. This study was conducted to reveal the association between ACE rs4343 and the risk of DN in the Jambi-Malay population.

Materials and methods: This was a cross-sectional study involving 75 subjects (44 with DN and 31 without DN) who suffered from T2DM and hypertension. DN was defined as albumin to creatinine ratio (ACR) ≥30 mg/g. Genotyping was performed with one-step tetra amplification refractory mutation system-polymerase chain reaction (PCR) using specific primer for ACE rs4343. Bivariate and multivariate analyses were performed to analyze the genetic risk for DN.

Results: The bivariate analysis showed the proportion of DN subjects was higher than non-DN within the AG genotype (11:1) than within the AA (33:30) genotype. This difference was statistically significant (p=0.012; OR (95% CI): 10.00 (1.22-82.15)). Multivariate analysis showed that AG genotype (p=0.047; OR (95% CI): 10.04 (1.03-97.31)) and uncontrolled blood pressure (p=0.001; OR (95% CI): 6.72 (2.08-21.71)) were the risk factors of DN in the Jambi-Malay population.

Conclusion: Polymorphism of ACE rs4343 is a risk factor of DN in the Jambi-Malay Population.

Keywords: rs4343, angiotensin-converting enzyme gene, diabetic nephropathy, Malay, Jambi

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Kementerian Kesehatan Republik Indonesia. Laporan Nasional RISKESDAS 2018. Jakarta: Badan Penelitian dan Pengembangan Kesehatan; 2019, article.

Mihardja L, Delima D, Massie RGA, Karyana M, Nugroho P, Yunir E. Prevalence of kidney dysfunction in diabetes mellitus and associated risk factors among productive age Indonesian. J Diabetes Metab Disord. 2018; 17(1): 53-61, CrossRef.

Kusdiyah E, Makmur MJ, Aras RBP. Karakteristik faktor-faktor risiko terjadinya komplikasi kronik nefropati diabetik dan atau penyakit pembuluh darah perifer pada penderita diabetes mellitus di RSUD Raden Mattaher tahun 2018. Electron J Sci Environ Health Dis. 2020; 1(1): 19-32, CrossRef.

Kirtaniya AAIK, Lestarini A, Permatananda PANK, Aryastuti AASA. Association of ELMO1 genetic polymorphism (rs741301) with the progression of diabetic kidney disease in Balinese patients with type 2 diabetes mellitus. Mol Cell Biomed Sci. 2023; 7(1): 47-51, CrossRef.

Menambath DT, Yella DR, Khandige AP, Kuthethur S, Mangalore N. Assessment of sdLDL-C by three different formula and its correlation with clinical variables among diabetes individuals with and without nephropathy. Indones Biomed J. 2021; 13(2): 140-6, CrossRef.

Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017; 12(12): 2032-45, CrossRef.

Persson F, Rossing P. Diagnosis of diabetic kidney disease: State of the art and future perspective. Kidney Int Suppl (2011). 2018; 8(1): 2-7, CrossRef.

Wei L, Xiao Y, Li L, Xiong X, Han Y, Zhu X, et al. The susceptibility genes in diabetic nephropathy. Kidney Dis. 2018; 4(4): 226-237, CrossRef.

van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, et al. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes. 2018; 67(7): 1414-27, CrossRef.

Regele F, Jelencsics K, Shiffman D, Paré G, McQueen MJ, Mann JF, et al. Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes. Nephrol Dial Transplant. 2015; 30 Suppl 4: iv26-34, CrossRef.

Tziastoudi M, Stefanidis I, Zintzaras E. The genetic map of diabetic nephropathy: Evidence from a systematic review and meta-analysis of genetic association studies. Clin Kidney J. 2020; 13(5): 768-81, CrossRef.

Rahimi Z. The role of renin angiotensin aldosterone system genes in diabetic nephropathy. Can J Diabetes. 2016; 40(2): 178-83, CrossRef.

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): 537-44, CrossRef.

Firouzabadi N, Shafiei M, Bahramali E, Ebrahimi SA, Bakhshandeh H, Tajik N. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population. Psychiatry Res. 2012; 200(2-3): 336-42, CrossRef.

Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010; 6(6): 319-30, CrossRef.

Chawla T, Sharma D, Singh A. Role of the renin angiotensin system in diabetic nephropathy. World J Diabetes. 2010; 1(5): 141-5, CrossRef.

Puspasari A, Enis RN, Herlambang. Genetic variant of vascular endothelial growth factor (VEGF)-A rs699947 is associated with preeclampsia. Mol Cell Biomed Sci. 2022; 6(2): 70-6, CrossRef.

Huo P, Zhang D, Guan X, Mei Y, Zheng H, Feng X. Association between genetic polymorphisms of ACE & eNOS and diabetic nephropathy. Mol Biol Rep. 2015; 42(1): 27-33, CrossRef.

Su SL, Yang HY, Wu CC, Lee HS, Lin YF, Hsu CA, et al. Gene-gene interactions in renin-angiotensin-aldosterone system contributes to end-stage renal disease susceptibility in a Han Chinese population. ScientificWorldJournal. 2014; 2014: 169798, CrossRef.

Babi Heera S, Mahwish UN, Rahman F, Sayeeduddin S , Raju SB, Jahan P. Synonymous variant of ACE gene (rs4343) is coupled with early age at onset and diminished diabetic duration in south indian diabetic nephropathy patients. Genet Mol Res. 2019; 18(2): gmr16039954, article.

Ahluwalia TS, Ahuja M, Rai TS, Kohli HS, Bhansali A, Sud K, et al. ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy. DNA Cell Biol. 2009; 28(3): 141-50, CrossRef.

Perkumpulan Endrokrinologi Indonesia (PERKENI). Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia 2021. Jakarta: PB PERKENI; 2021, article.

National Kidney Foundation [Internet]. CKD-EPI Creatinine Equation (2021) [updated 2021 Jan 1; cited 2023 Dec 15]. Available from:

Abedin-Do A, Pouriamanesh S, Kamaliyan Z, Mirfakhraie R. Angiotensin-converting enzyme gene rs4343 polymorphism increases susceptibility to migraine. CNS Neurosci Ther. 2017; 23(8): 698-9, CrossRef.

Wagnew F, Eshetie S, Kibret GD, Zegeye A, Dessie G, Mulugeta H, et al. Diabetic nephropathy and hypertension in diabetes patients of sub-Saharan countries: A systematic review and meta-analysis. BMC Res Notes. 2018; 11(1): 565, CrossRef.

Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, et al. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care. 2013; 36(8): 2301-10, CrossRef.

Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, et al. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet. 2004; 12(5): 395-9, CrossRef.

Chen J, Chatterjee N. Exploiting Hardy-Weinberg equilibrium for efficient screening of single SNP associations from case-control studies. Hum Hered. 2007; 63(3-4): 196-204, CrossRef.

National Center for Biotechnology Information [Internet]. Reference SNP (rs) Report rs4343 [updated 2022 Sep 1; cited 2023 Dec 15]. Available from:

Ehnert S, Linnemann C, Braun B, Botsch J, Leibiger K, Hemmann P, et al. One-step ARMS-PCR for the detection of SNPs-using the example of the PADI4 gene. Methods Protoc. 2019; 2(3): 63, CrossRef.

Medrano RF, de Oliveira CA. Guidelines for the tetra-primer ARMS-PCR technique development. Mol Biotechnol. 2014; 56(7): 599-608, CrossRef.


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