rs5186 — AGTR1 A1166C

AGTR1 A1166C — Blood Pressure Regulation and Drug Response Variant

The AGTR1 gene¹¹ AGTR1 gene
encodes the angiotensin II type 1 receptor, a critical component of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure, fluid balance, and cardiovascular function. The A1166C variant (rs5186) is the most well-studied AGTR1 SNP, located in the 3′ untranslated region . While it doesn't change the protein sequence directly, it may affect mRNA stability and transcription, or be in linkage disequilibrium with another polymorphism of regulatory significance .

The Mechanism

This variant sits in the 3' UTR²² 3' UTR
the untranslated region after the protein-coding sequence where regulatory elements control gene expression.

The AGTR1 A1166C polymorphism may influence the stability of mRNA expression and might be involved in cellular signaling mediated by the angiotensin II receptor . Some studies have found that the C allele is associated with reduced AGTR1 mRNA levels — 0.8-fold lower in heterozygotes and 0.27-fold lower in homozygotes compared to AA carriers , though findings are inconsistent across studies.

The AT1 receptor mediates the effects of angiotensin II, causing vasoconstriction, sodium retention, increased blood pressure, and activation of inflammatory pathways. The receptor is the target of ARBs³³ ARBs
angiotensin receptor blockers, a class of blood pressure medications including losartan, valsartan, candesartan, and irbesartan.

The Evidence

The relationship between rs5186 and hypertension has been extensively studied but remains controversial.

A systematic review and meta-analysis of AGTR1 polymorphisms and hypertension found that the literature is too heterogeneous to draw meaningful conclusions , with insufficient evidence that polymorphisms in the AGTR1 gene are risk factors for hypertension . However, specific populations and conditions show clearer associations.

For cardiovascular outcomes⁴⁴ For cardiovascular outcomes, a meta-analysis of 53 studies with 20,435 CHD cases and 23,674 controls found only a weak association between A1166C and coronary heart disease, likely due to publication bias and heterogeneity . In contrast, the rs5186 polymorphism significantly increases the risk of restenosis after percutaneous coronary intervention (PCI) in Asian populations .

For metabolic conditions⁵⁵ For metabolic conditions, the gain-of-function rs5186 A1166C variant has been linked to hypertension, cardiovascular disease, and metabolic syndrome .

The variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion .

For kidney health⁶⁶ For kidney health, the C allele shows an odds ratio of 1.84 for diabetic nephropathy in Iranian patients , and shows a likelihood ratio of 1.89-2.01 for GFR depletion in type 2 diabetes patients .

For brain health⁷⁷ For brain health,

C1166 variant carriers show significantly larger subcortical hyperintensity volume compared to AA genotype carriers in healthy older adults , suggesting the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity prior to changes in cognition .

Practical Implications

The primary clinical relevance of rs5186 is in predicting response to ARB medications.

Individuals with the AC genotype show significant reduction in systolic blood pressure after candesartan medication in Chinese populations .

The percentage of systolic BP reduction with candesartan-based treatment was greater in patients with AC genotypes compared to AA homozygotes .

However, carrying the 1166C allele is associated with greater compensatory increase in renin activity and more modest effect on aldosterone after candesartan treatment , suggesting long-term RAAS activation that may affect clinical outcomes.

The variant also has implications beyond blood pressure. Given its associations with metabolic syndrome, NAFLD, diabetic nephropathy, and cerebrovascular changes, C allele carriers may benefit from closer monitoring of metabolic health, kidney function, and cardiovascular risk factors — particularly if they have diabetes or metabolic syndrome.

Interactions

AGTR1 rs5186 functions as part of the renin-angiotensin-aldosterone system pathway. It may interact with other RAAS-related SNPs including ACE I/D (rs4340), which affects angiotensin-converting enzyme activity and modifies response to ACE inhibitors, and AGT M235T (rs699), which influences angiotensinogen levels and blood pressure. Studies suggest that individuals with multiple RAAS pathway variants show cumulative effects on hypertension risk and treatment response. The variant's effects may also be modified by CYP2C9 polymorphisms, particularly for ARBs metabolized by this enzyme like losartan and irbesartan.