rs5186 — AGTR1 A1166C

3' UTR variant in angiotensin II type 1 receptor affecting blood pressure regulation and ARB drug response

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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 .

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.

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 .

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 brain health66 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.

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, and cerebrovascular changes, C allele carriers may benefit from closer monitoring of metabolic health 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.

Drug Interactions

losartan dose_adjustment literature
valsartan dose_adjustment literature
candesartan altered_metabolism literature
irbesartan dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal Receptor Normal

Standard angiotensin receptor expression and typical ARB response

You have two copies of the common A allele at this position in the AGTR1 gene. This is the most common genotype, found in approximately 64% of people of European descent and even more frequently in East Asian (93%) and African (94%) populations. Your AT1 receptor expression follows the typical pattern, and you're likely to respond normally to angiotensin receptor blocker medications if prescribed for blood pressure management.

AC Intermediate Response Intermediate

Potentially enhanced response to ARB medications with some compensatory effects

Research suggests complex effects of the AC genotype. Your body may mount stronger compensatory renin-angiotensin system activation over time. The variant has also been associated with modest increases in risk for metabolic syndrome, NAFLD with hypertension, and cerebrovascular changes in aging. However, the overall clinical significance remains uncertain given heterogeneous study findings.

CC Reduced Expression Reduced

Significantly altered receptor expression with variable cardiovascular and metabolic effects

The CC genotype has been linked to larger white matter hyperintensities in brain imaging even in healthy older adults. However, the literature shows substantial heterogeneity, and effects may vary by ethnicity, sex, and other factors. Some studies find no association with cardiovascular outcomes.