ACE Gene

Angiotensin-converting enzyme (ACE) is an essential component of the renin-angiotensin system, a critical regulator of blood pressure and fluid balance within the body.  ACE catalyzes the transformation of angiotensin I into angiotensin II. 

This potent vasoconstrictor not only elevates blood pressure but also prompts the adrenal cortex to secrete aldosterone, further influencing blood pressure and fluid balance.  Moreover, ACE deactivates the vasodilator peptide bradykinin, adding another layer to its role in increasing blood pressure.

ACE’s activity is particularly significant in cardiovascular and renal functions.  Angiotensin II, produced by ACE, contributes to cardiovascular challenges like cardiac remodeling, vascular inflammation, and endothelial dysfunction, which play roles in hypertension, atherosclerosis, and heart failure. 

In the kidneys, ACE is crucial for regulating both the glomerular filtration rate and renal blood flow.

Laboratory testing for ACE levels provides insights into its activity and implications in clinical settings, helping monitor conditions like sarcoidosis and assess genetic variations linked to diverse diseases, including cardiovascular and renal disorders.  

The role of ACE gene polymorphisms, particularly the well-studied insertion/deletion polymorphism, underscores their significance in disease risk and treatment response, emphasizing their relevance in personalized medicine.

Biological Role of ACE: What is ACE?  [5., 6., 11., 17.] 

Angiotensin-converting enzyme (ACE) is a vital enzyme in the renin-angiotensin system (RAS), which plays a pivotal role in regulating blood pressure and fluid balance within the body.  Specifically, ACE’s primary role is to increase blood pressure.

ACE is a zinc metalloprotease that catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor that increases blood pressure.  Angiotensin II also stimulates the adrenal cortex to produce the mineralocorticoid aldosterone, which increases blood pressure and affects fluid balance. 

ACE also inactivates bradykinin, a vasodilator peptide, thereby further contributing to increased blood pressure.  

ACE is primarily expressed in the vascular endothelial cells of the lungs, but it is also found in other tissues such as the endothelial and kidney epithelial cells, the brain, and the male reproductive system. 

Interestingly, the ACE gene encodes two isozymes: somatic ACE, expressed in various tissues including the lung, including vascular endothelial cells, epithelial kidney cells, and testicular Leydig cells.  The other isoenzyme is germinal ACE, which is expressed only in sperm.  

The activity of ACE is targeted by ACE inhibitors such as captopril, which are widely used as pharmaceutical drugs to treat hypertension, heart failure, and diabetic nephropathy by inhibiting the conversion of angiotensin I to angiotensin II.  

Influence on Cardiovascular and Renal Function  [9., 13.]

Beyond its effects on blood pressure and fluid balance, ACE has significant implications for cardiovascular and renal function.  

Angiotensin II, generated by ACE activity, exerts various cardiovascular effects including cardiac remodeling, vascular inflammation, and endothelial dysfunction.  [13.] 

These actions contribute to the pathophysiology of conditions such as hypertension, atherosclerosis, and heart failure. 

In the kidneys, ACE activity plays a crucial role in the regulation of glomerular filtration rate and renal blood flow, making it relevant in the context of kidney diseases and renal function.

Involvement in Inflammatory and Fibrotic Processes  [2., 10.]

ACE's actions extend beyond cardiovascular and renal function to include modulation of inflammatory and fibrotic processes. 

Angiotensin II, generated by ACE, promotes inflammation and fibrosis through activation of various signaling pathways, including transforming growth factor-beta (TGF-β). 

These pro-inflammatory and pro-fibrotic effects contribute to tissue remodeling and organ damage in conditions such as sarcoidosis and fibrotic lung diseases. 

ACE's role in bradykinin metabolism can also influence inflammatory responses and tissue injury, further implicating ACE in the pathogenesis of inflammatory disorders.

Laboratory Testing Options for ACE

The assessment of Angiotensin-Converting Enzyme (ACE) levels through laboratory testing provides valuable insights into its activity and its potential implications in clinical practice. Various methodologies are available for measuring ACE levels, each offering unique advantages and applications. 

ACE levels may be tested in the blood, commonly to assess and monitor conditions such as sarcoidosis, leprosy, and Gaucher disease.  [4.] 

Genetic testing may also be performed to assess for alterations in the ACE gene.  Variations in this gene, including a specific 287 bp Alu repeat element, have been linked to various conditions such as cardiovascular diseases, psoriasis, renal disorders, stroke, and Alzheimer's disease. 

The gene's relevance extends to infectious diseases, as its counterpart, ACE2, plays a role in the progression of diseases caused by coronaviruses including SARS-CoV and SARS-CoV-2. 

The ACE gene produces multiple protein variants through alternative splicing, including forms specific to general bodily and testicular functions. 

Genetic Alterations in the ACE Gene

The gene for the ACE protein may contain alterations or mutations that cause alterations of function of the ACE protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Role of ACE Gene Polymorphisms in Disease Risk  [2., 8., 12., 14.] 

The insertion/deletion (I/D) polymorphism of the ACE gene has been extensively studied in the context of cardiovascular diseases, hypertension, and renal disorders. 

The D allele, associated with higher ACE activity, has been linked to an increased risk of cardiovascular events, including myocardial infarction, stroke, and heart failure. 

Conversely, the I allele, associated with lower ACE activity, has been associated with reduced cardiovascular risk and improved prognosis in some populations.  

ACE gene polymorphisms have also been implicated in the pathogenesis of hypertension and renal diseases, with certain genotypes predisposing individuals to elevated blood pressure and renal dysfunction. 

ACE gene variants may influence treatment responses to ACE inhibitors and other medications targeting the renin-angiotensin-aldosterone system (RAAS), highlighting their importance in personalized medicine approaches.

Laboratory Testing Procedure for ACE

The blood test for Angiotensin-Converting Enzyme (ACE) involves a blood draw via venipuncture.  

Genetic testing for single nucleotide polymorphisms (SNPs) in the ACE gene typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Interpretation of ACE Testing 

The reference range for blood testing of the ACE enzyme is: [7.] 

<40 units/L

Genetic test results should be reviewed with a medical professional who can guide appropriate treatment and management.  In some situations, genetic counseling may be advised.  

Related Biomarkers to Test

Renin  [3., 16.] 

Renin, an enzyme produced by the juxtaglomerular cells of the kidney, initiates the RAAS cascade by catalyzing the conversion of angiotensinogen to angiotensin I. 

As the primary regulator of RAAS activity, renin plays a central role in blood pressure regulation and fluid balance.  Measurement of plasma renin activity (PRA) or renin concentration provides valuable information about RAAS activation and may aid in the diagnosis and management of hypertension, heart failure, and renal disorders. 

Elevated renin levels are often observed in conditions characterized by hypovolemia, while decreased renin levels may indicate RAAS suppression or volume expansion.

Aldosterone  [15.] 

Aldosterone, a mineralocorticoid hormone secreted by the adrenal cortex, acts on the distal nephron to promote sodium retention and potassium excretion, thereby regulating electrolyte balance and blood pressure.  Aldosterone synthesis and release are tightly regulated by RAAS components, including angiotensin II and ACE. 

Measurement of plasma aldosterone concentration (PAC) or aldosterone-to-renin ratio (ARR) can provide insights into aldosterone production and RAAS activity. 

Elevated aldosterone levels are associated with conditions such as primary aldosteronism, hypertension, and heart failure, while decreased aldosterone levels may occur in conditions such as adrenal insufficiency or hypoaldosteronism.

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