Association of ACE I/D polymorphism with essential hypertension in South-Asian populations: Gender-bias in Indian populations—evidence from case-control and meta-analysis studies
Restricted accessResearch articleFirst published online 2025
Association of ACE I/D polymorphism with essential hypertension in South-Asian populations: Gender-bias in Indian populations—evidence from case-control and meta-analysis studies
The role of Angiotensin Converting Enzyme (ACE) intron-16 I/D polymorphism (rs4646994) in essential hypertension (EH) is contradictory in South Asian populations. The study objectives were to investigate correlation between rs4646994 polymorphism and EH in the North-Indian population of Jammu, and to perform a meta-analysis to validate its role in South-Asian populations.
Methodology
A total of 422-cases and 395-controls were genotyped in the original study. Meta-analysis was performed on 4987-cases and 5302-controls following the PRISMA and STREGA guidelines. SPSS-v25.0 and web-based tools were used for statistical analyses.
Results
Our original case-control study revealed a statistically significant association between the rs4646994 polymorphism and EH, with the D allele being the risk allele. The observed significance level was higher when the recessive genetic model was tested [OR = 1.68(95%CI:1.16–2.43), P=0.006]. Interestingly, only males carrying the DD-genotype were at significantly higher odds of developing EH [OR = 2.68(95%CI:1.58–4.53), P<0.0001]. The meta-analysis further corroborated an increased risk for EH in the presence of DD-genotype in the South-Asian populations [OR = 1.48(95%CI:1.35–1.62), P<0.0001] and largely supported the gender-wise differences in Indian populations, with males at relatively higher risk.
Conclusion
Our data provide strong evidence supporting the role of rs4646994 polymorphism in essential hypertension in the South-Asian populations, particularly Indians, and highlight the significance of considering gender as a biological variable in genetic studies related to hypertension risk.
Collaboration NCDRF. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet2021; 398: 957–980. 2021/08/28.
2.
GuptaSAgrawalBKGoelRK, et al.Angiotensin-converting enzyme gene polymorphism in hypertensive rural population of Haryana, India. J Emerg Trauma Shock2009; 2: 150–154. 2009/12/17.
3.
MillerJAScholeyJW. The impact of renin-angiotensin system polymorphisms on physiological and pathophysiological processes in humans. Curr Opin Nephrol Hypertens2004; 13: 101–106. 2004/04/20.
4.
WarrenHREvangelouECabreraCP, et al.Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet2017; 49: 403–415. 2017/01/31.
5.
DauchetLKesse-GuyotECzernichowS, et al.Dietary patterns and blood pressure change over 5-y follow-up in the SU.VI.MAX cohort. Am J Clin Nutr2007; 85: 1650–1656. 2007/06/09.
6.
SessoHDCookNRBuringJE, et al.Alcohol consumption and the risk of hypertension in women and men. Hypertension2008; 51: 1080–1087. 2008/02/09.
7.
FormanJPStampferMJCurhanGC. Diet and lifestyle risk factors associated with incident hypertension in women. JAMA2009; 302: 401–411. 2009/07/23.
8.
LiuMYiJTangW. Association between angiotensin converting enzyme gene polymorphism and essential hypertension: a systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst2021; 22: 1470320321995074. 2021/03/18.
9.
ManosroiWWilliamsGH. Genetics of human primary hypertension: focus on hormonal mechanisms. Endocr Rev2019; 40: 825–856. 2018/12/28.
10.
PatelRSMasiSTaddeiS. Understanding the role of genetics in hypertension. Eur Heart J2017; 38: 2309–2312. 2017/05/26.
11.
JanoskiJRAielloILundbergCW, et al.Circadian clock gene polymorphisms implicated in human pathologies. Trends Genet2024; 40: 834–852. 2024/06/14.
12.
EvangelouEWarrenHRMosen-AnsorenaD, et al.Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet2018; 50: 1412–1425. 2018/09/19.
13.
SoporiSKavinayKBhanS, et al.CLOCK Gene 3'UTR and exon 9 polymorphisms show a strong association with essential hypertension in a North Indian population. BMC Med Genomics2024; 17: 289. 2024/12/19.
14.
MondryALohMLiuP, et al.Polymorphisms of the insertion / deletion ACE and M235T AGT genes and hypertension: surprising new findings and meta-analysis of data. BMC Nephrol2005; 6: 1–11. 2005/01/12.
15.
JinJJNakuraJWuZ, et al.Association of angiotensin II type 2 receptor gene variant with hypertension. Hypertens Res2003; 26: 547–552. 2003/08/20.
16.
KikuyaMSugimotoKKatsuyaT, et al.A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res2003; 26: 141–145. 2003/03/12.
17.
OnoKMannamiTBabaS, et al.Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res2003; 26: 131–134. 2003/03/12.
18.
AbbasSRazaSTChandraA, et al.Association of ACE, FABP2 and GST genes polymorphism with essential hypertension risk among a North Indian population. Ann Hum Biol2015; 42: 461–469. 2014/10/31.
19.
MastanaSNunnJ. Angiotensin-converting enzyme deletion polymorphism is associated with hypertension in a Sikh population. Hum Hered1997; 47: 250–253. 1997/11/14.
20.
MannanADSLallSUpadhyayAK, et al.Hypertension and genetic polymorphism of ACE and ADD1 gene in North Indian population. Int J Sci Res2017; 73: 16–24.
21.
KrishnanRSekarDKarunanithyS, et al.Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population. Genes Dis2016; 3: 159–163. 2016/03/25.
22.
SriMBAnanthapriyaVS, et al.A study on insertion/deletion polymorphism of ACE gene in essential hypertensive adults in coastal area. NeuroQuantology2022; 20: 7396–7403. 2022.
ShanmuganathanRKumaresanRGiriP. Prevalence of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism in South Indian population with hypertension and chronic kidney disease. J Postgrad Med2015; 61: 230–234. 2015/10/07.
25.
AshavaidTFShaliaKKNairKG, et al.ACE And AT1R gene polymorphisms and hypertension in Indian population. J Clin Lab Anal2000; 14: 230–237. 2000/10/06.
26.
RazaqAKhanAShahST, et al.Association of insertion /deletion polymorphism of ace gene with essential hypertension in patients of khyber pakhtunkhwa. Pak J Med Sci2024; 40: 461–466. 2024/02/15.
27.
HussainMAbbasSBilalA, et al.Association of ACE I/D polymorphism with risk of diabetes in cardiovascular disease patients. Exp Clin Endocrinol Diabetes2020; 128: 82–88. 2019/01/15.
28.
HussainMAwanFRGujjarA, et al.A case control association study of ACE gene polymorphism (I/D) with hypertension in Punjabi population from Faisalabad, Pakistan. Clin Exp Hypertens2018; 40: 186–191. 2017/10/24.
29.
AlviFMHasnainS. ACE I/D and G2350A polymorphisms in Pakistani hypertensive population of Punjab. Clin Exp Hypertens2009; 31: 471–480. 2009/10/09.
30.
ChowdhuryAHZamanMMHaqueKM, et al.Association of angiotensin converting enzyme (ACE) gene polymorphism with hypertension in a Bangladeshi population. Bangladesh Med Res Counc Bull1998 Dec; 24: 55–59.
31.
SrivastavaKSundriyalRMeenaPC, et al.Association of angiotensin converting enzyme (insertion/deletion) gene polymorphism with essential hypertension in northern Indian subjects. Genet Test Mol Biomarkers2012; 16: 174–177. 2011/11/23.
32.
RandhawaNKKumarAMatharooK, et al.Association study of angiotensin-converting enzyme ins/Del polymorphism with hypertension in punjabi population. Int J Hum Genet2006; 6: 317–321.
33.
RahmanFESArumugamSBhandariA, et al.Impact of lifestyle modification practices a pharmacogenetics of ACE I/D gene polymorphism in grade 1 hypertensive patient. Res Sq2024; 1–14 DOI: 10.21203/rs.3.rs-5406915/v1.
34.
DasMPalSGhoshA. Angiotensin converting enzyme gene polymorphism (insertion/deletion) and hypertension in adult Asian Indians: a population-based study from Calcutta, India. Hum Biol2008; 80: 303–312. 2009/01/10.
35.
MorshedMKhanHAkhteruzzamanS. Association between angiotensin I-converting enzyme gene polymorphism and hypertension in selected individuals of the Bangladeshi population. J Biochem Mol Biol2002; 35: 251–254. 2002/09/26.
36.
RanaGYadavSJoshiS, et al.Association of DD genotype of angiotensin-converting enzyme gene (I/D) polymorphism with hypertension among a North Indian population. J Community Genet2018; 9: 51–55. 2017/08/05.
37.
ChoudhuryIJothimalarRPatraAK. Angiotensin converting enzyme gene polymorphism and its association with hypertension in South Indian population. Indian J Clin Biochem2012; 27: 265–269. 2012/07/01.
38.
SameerASSyeedNTakSA, et al.ACE I/D polymorphism in hypertensive patients of Kashmiri population. Cardiol Res2010; 1: 1–7. 2010/12/01.
39.
RigatBHubertCCorvolP, et al.PCR Detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res1992; 20: 1433. 1992/03/25.
40.
BadaruddozaSN. No evidence for association between ACE gene insertion (I)/ deletion (D) polymorphism and hypertension in North Indian Punjabi population. Int J Hum Genet2012; 12: 179–185.
41.
BorahPKShankarishanPHazarikaNC, et al.Hypertension subtypes and angiotensin converting enzyme (ACE) gene polymorphism in Indian population. J Assoc Physicians India2012; 60: 15–17. 2013/02/16.
42.
ChandelSBKumarD. Association of high altitude hypertension with angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism. Urol Nephrol Open Access J2017; 5: 1–7.
43.
BadaruddozaAJSBSawhneyRRandhawaNK, et al.A study of angiotensin converting enzyme (ACE) gene polymorphism in essential hypertension among a business community in Punjab. Int J Hum Genet2009; 9: 231–234.
44.
SarangarajanRWinnRKiebishMA, et al.Ethnic prevalence of angiotensin-converting enzyme deletion (D) polymorphism and COVID-19 risk: rationale for use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. J Racial Ethn Health Disparities2021; 8: 973–980. 2020/09/10.
45.
Sayed-TabatabaeiFAOostraBAIsaacsA, et al.ACE Polymorphisms. Circ Res2006; 98: 1123–1133. 2006/05/13.
46.
LiberatiAAltmanDGTetzlaffJ, et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med2009; 6: e1000100. 2009/07/22.
47.
LittleJHigginsJPIoannidisJP, et al.Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement. PLoS Med2009; 6: e22. 2009/02/06.
48.
PurcellSChernySSShamPC. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics2003; 19: 149–150. 2002/12/25.
49.
SinghMSinghAKSinghS, et al.Angiotensin-converting enzyme gene I/D polymorphism increases the susceptibility to hypertension and additive diseases: a study on North Indian patients. Clin Exp Hypertens2016; 38: 305–311. 2016/04/01.
50.
Dhanachandra SinghKJajodiaAKaurH, et al.Gender specific association of RAS gene polymorphism with essential hypertension: a case-control study. Biomed Res Int2014; 2014: 538053. 2014/05/27.
51.
PatnaikMPatiPSwainSN, et al.Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann Hum Biol2014; 41: 145–152. 2013/10/12.
52.
VamsiUMSwapnaNReddySS, et al.Risk of angiotensin - converting enzyme (ACE) gene I/D and g.2350G > A polymorphisms in causing susceptibility to essential hypertension. Asian Biomed (Res Rev News)2012; 6: 255–264.
53.
RamuPUGShewadeDGSwaminathanRP, et al.Candidate gene polymorphisms of renin angiotensin system and essential hypertension in a South Indian Tamilian population. Int J Hum Genet2011; 11: 31–40.
54.
ParamasivamRReangasamyNArumugamD, et al.Association of ACE DD genotype with hypertension among the tribal populations of South India. Int Lett Nat Sci2016; 52: 1–8.
55.
BhavaniBAPadmaTSastryBKS, et al.The insertion I/ deletion D polymorphism of angiotensin-converting enzyme (ACE) gene increase the susceptibility to hypertension and / or diabetes. Int J Hum Genet2005; 5: 247–252.
56.
Nirupama DeviVLKarunakaraPRashmitaP, et al.Angiotensin converting enzyme gene polymorphism and hypertension in north coastal Andhra Pradesh, India. Int J Med Health Sci 2013; 2: 1–12.
57.
BhavaniBAPadmaTSastryBKS, et al.Gender specific association of insertion/deletion polymorphism of the human angiotensin converting enzyme gene with essential hypertension. Int J Hum Genet2004; 4: 207–213.
KupperNGeDTreiberFA, et al.Emergence of novel genetic effects on blood pressure and hemodynamics in adolescence: the Georgia cardiovascular twin study. Hypertension2006; 47: 948–954. 2006/03/29.
60.
HollenbergNK. A genome-wide search for susceptibility loci to human essential hypertension. Curr Hypertens Rep2001; 3: 7–8. 2001/05/19.
61.
NiiranenTJMcCabeELLarsonMG, et al.Risk for hypertension crosses generations in the community: a multi-generational cohort study. Eur Heart J2017; 38: 2300–2308. 2017/04/22.
62.
Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature2007; 447: 661–678. 2007/06/08.
63.
NiiranenTJMcCabeELLarsonMG, et al.Heritability and risks associated with early onset hypertension: multigenerational, prospective analysis in the framingham heart study. Br Med J2017; 357: j1949. 2017/05/14.
64.
Ralapanawa U. RAG-SACA-2: epidemiology of hypertension in South Asia. J Hypertens2023; 41: e169.
65.
TranDCLeLHGThaiTT, et al.Association between ACE I/D genetic polymorphism and the severity of coronary artery disease in Vietnamese patients with acute myocardial infarction. Front Cardiovasc Med2023; 10: 1091612. 2023/05/19.
66.
MoorthyNSaligrama RamegowdaKJainS, et al.Role of angiotensin-converting enzyme (ACE) gene polymorphism and ACE activity in predicting outcome after acute myocardial infarction. Int J Cardiol Heart Vasc2021; 32: 100701. 2021/01/12.
67.
BoraeyNFBebarsMAWahbaAA, et al.Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents. Pediatr Res2024; 96: 1347–1354. 2024/01/05.
68.
ThakurSSharmaVKaurD, et al.Angiotensin-Converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a conjoint regulator of coagulation, fibrinolytic, and RAAS pathway in infertility and associated pregnancy complications. J Renin Angiotensin Aldosterone Syst2022; 2022: 1695769. 2022/12/20.
69.
ZhouJBYangJKLuJK, et al.Angiotensin-converting enzyme gene polymorphism is associated with type 2 diabetes: a meta-analysis. Mol Biol Rep2010; 37: 67–73. 2009/08/06.
70.
LarsenCS. Reading the bones of la Florida. Sci Am2000; 282: 80–85. 2000/06/22.
71.
PatelDDParchwaniDNDikshitN, et al.Analysis of the pattern, alliance and risk of rs1799752 (ACE I/D polymorphism) with essential hypertension. Indian J Clin Biochem2022; 37: 18–28. 2022/02/08.
72.
ConnellyPJCaseyHMontezanoAC, et al.Sex steroids receptors, hypertension, and vascular ageing. J Hum Hypertens2022; 36: 120–125. 2021/07/08.
73.
Mauvais-JarvisFBairey MerzNBarnesPJ, et al.Sex and gender: modifiers of health, disease, and medicine. Lancet2020; 396: 565–582. 2020/08/24.
74.
MedinaDMehayDArnoldAC. Sex differences in cardiovascular actions of the renin-angiotensin system. Clin Auton Res2020; 30: 393–408. 2020/08/30.
75.
van den MeirackerAHBoomsmaF. The angiotensin II-sympathetic nervous system connection. J Hypertens2003; 21: 1453–1454. 2003/07/23.
76.
SunMWuCLiuL, et al.Interplay between the renin angiotensin system and oxidative stress contributes to alcohol addiction by stimulating dopamine accumulation in the mesolimbic pathway. Biochem Pharmacol2023; 212: 115578. 2023/05/04.
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