Single Nucleotide Variants in the Angiotensin II Receptor Type 2 and its Association With Arterial Hypertension: A Systematic Review

Totomoch-Serra, Armando; Brito-Carreón, César A.; Muñoz, María de Lourdes; García-Méndez, Nayely

doi:10.36660/ijcs.20230163

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International Journal of Cardiovascular Sciences

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Original Article • Int J Cardiovasc Sci 37 • 2024 • https://doi.org/10.36660/ijcs.20230163 copy

Single Nucleotide Variants in the Angiotensin II Receptor Type 2 and its Association With Arterial Hypertension: A Systematic Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Arterial hypertension (AH) is a chronic disease distributed worldwide, and the Angiotensin II receptor type 2 (AGTR2) gene variants are potential DNA markers to study in association with this disease.

Objective:

This systematic review (SR) aimed to identify single nucleotide variants in the AGTR2 gene as genetic markers associated with AH.

Methods:

The electronic databases MEDLINE, Web of Science, SCOPUS, Cochrane Central Register, EMBASE, SciELO, and TripDatabase were searched for research up to September 2023. Case-control studies with DNA variants in the AGTR2 gene associated with AH as the outcome were included in the review. Boolean connectors and keywords were used according to each database.

Results:

After diverse rounds of scrutiny, a final number of eight articles were included for 8911 participants, comprising 5451 cases and 3460 controls. A significant proportion of the selected studies were performed in Asian populations and were heterogeneous. Although 238 variants were shown in the gnomAD v2.1.1 database for September 2023, only six variants were identified in all the analyzed studies.

Conclusions:

The results obtained were not conclusive that a specific variant located in the AGTR2 gene has a strong association with AH. The study of this gene re-emerged last year as an essential target to investigate due to its participation in the development of agonist therapy to treat mild COVID-19 cases. Future studies with better statistical power are desirable to replicate the primary findings.

Keywords:
Genetic Association Studies; Hypertension; Angiotensin II Type 2 Receptor

Author	Cases with HAS	Controls	Total	Variant as reported in the primary article	Location and reference	HWE	Initial screening	HAT association	Other association or observation
Zivković et al., (2007)¹¹	114	190	304	-1332 A/G	Intron 1 NC_000023.11:g.116170939G>A	Not informed	Not performed	Hemizygosity for “G” allele in variant −1332 A/G was susceptible for hypertension in males [OR=1.6; CI 95%=1.0-2.6; P=0.04]	It is suggested a higher association with the variant in older hypertensive Serbians [OR=2.4; CI=1.2-5.0; P=0.02]
Jin et al., (2003)¹²	2262	1007	3269	1.- A1675G 2.- A1818T 3.-G4303A 4.- C4599A	1.- Intron 1 NC_000023.11:g.116170939G>A 2.-Intron 2 NC_000023.11:g.116171082A>T 3.- 3'UTR G4303A (NC_000023.11:g.116173577A>G) 4.- 3'UTR NC_000023.11:g.116173873A>C	Tested	30 unrelated healthy men were included for screening AGTR2 variant frequencies	C4599A was associated with AH in women. [OR=0.46; CI 95%=0.26-0.81; P-value=0.0058] conferring a protective role of the genotypes AC or CC.	Significant association remained after adjustment to age in women. It is informed that women with the AA genotype in variant C4599A have higher odds of developing AH.
Zhang et al., (2003)¹⁵	250	250	500	SNP03 (new variant [1334T/C])	Promoter NC_000023.11:g.116170599T>C	Not informed	19 persons, sequencing 2938 kb region	Association of variant 1334T/C in male hypertensive subjects [X2= 5.63;P=<0.05]	Substitution T to C was not found with different distribution in women,
Zhang et al., (2006)¹⁶	262	75	337	1.- G/T rs5193 2.- G/A rs5194 (G2274A)	1.- 3’ UTR NC_000023.11:g.116173571G>T 2.-3’ UTR NC_000023.11:g.116173577A>G	Tested	16 persons to amplify the whole length of AGTR2	Negative	T-A haplotype carriers with AH indicated lower levels of left ventricular mass and left ventricular hypertrophy index
Kabadou et al., (2012)¹⁷	382	403	785	C3123A	3’ UTR NC_000023.11:g.116173873A>C	Tested	Not performed	Negative	Based on their results, suppose BMI must be studied for association with the variant
Kotani et al., (2013)¹⁸	82	79	161	(A/C) 3124	3’ UTR NC_000023.11:g.116173873A>C	Tested	Not informed	Negative	“A” allele carriers had lower HDL-C levels among non-hypertensive women
Wang et al., (2014)¹⁹	1090	700	1790	1.- rs5193 2.- rs5194	1.- 3’ UTR NC_000023.11:g.116173571G>T 2.-3’ UTR NC_000023.11:g.116173577A>G	Tested only in women	Not informed	In women, rs5193 and rs5194 were nearly associated under the allelic model, but the association disappeared under posterior analysis [P-value X² test=0.002; P-value logistic regression=0.229; OR=0.729; IC 97%=0.485-1.19]	It was found an association for ADRB3 rs4994 and CYP11B2 rs1799998 with AH
Li et al., (2015)²⁰	1009	756	1765	1.- rs1403543 (G1675A) 2.- rs5194 (G2274A)	1.- Intron 1 NC_000023.11:g.116170939G>A 2.-3’ UTR NC_000023.11:g.116173577A>G	Tested	Not performed	Variant rs1403543 was associated with AH in males [allelic model; OR=1.72; CI 95%= 1.15-2.58; P=0.008] and females [additive model; OR=1.8; CI 95%=1.4-2.31; P=<0.001]; [dominant model; OR=1.87; CI 95%=1.4-2.51; P=<0.001]; [recessive model; OR= 3.06; CI 95%=1.43-6.53;P=0.004]	Haplotype G-T-G-G-A was over-represented, including other genes in the X chromosome (rs1978124, rs2106809, rs1403543, rs5194, rs 56204867)

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[1] Mailing Address: Armando Totomoch-Serra Instituto Nacional de Cardiologia Ignacio Chavez, Electrocardiology. Juan Badiano 1, Belisario Domínguez Secc 16, Tlalpan. Postal code: 14080, Ciudad de Mexico – Mexico. E-mail: totomoch@gmail.com