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The renin-angiotensin-aldosterone system (RAAS) is central to the control of blood pressure
and the target of several types of anti-hypertensive drugs. This pathway depicts a simplified
representation of the pharmacodynamics (PD) of RAAS-acting drugs including candidate genes for
the pharmacogenomics (PGx) of ACE inhibitors, angiotensin receptor blockers (ARBs), renin
inhibitor aliskiren and aldosterone receptor antagonists.
The core of this pathway was elucidated over a century ago and involves the conversion of
angiotensinogen to angiotensin I (Ang I) by renin, its subsequent conversion to angiotensin II
(Ang II) by angiotensin converting enzyme. Ang II activates the angiotensin II receptor type 1
to induce aldosterone synthesis, increasing water and salt resorption and potassium excretion
in the kidney and increasing blood pressure [PMID: 18035185]. The key candidate genes involved
in the core pathway are angiotensiogen, AGT; renin, REN; angiotensin converting enzyme, ACE;
and angiotensin II receptor type 1, AGTR1.
Although depicted in the center of the pathway in this graphic, the ACE gene product, angiotensin
converting enzyme, is predominantly found attached to the plasma membrane (tissue bound ACE).
ACE can be released into plasma (soluble ACE); however this form is not considered to catalyze
the cleavage of Ang I to Ang II [PMIDs: 9153279; 1510141] ace inhibitor class of drugs on candidate
genes in the renin-angiotensin-aldosterone pathway (RAAS). ACE inhibitors target the ACE gene product
resulting in downstream reduction of Ang II, decreasing aldosterone secretion and reducing blood
pressure. ARBs target AGTR1 blocking its activation, also resulting in lower levels of aldosterone
and lower blood pressure. The decrease in aldosterone decreases sodium and water resorption,
decreases potassium excretion and decreases blood pressure. Angiotensin signaling downstream of
AGTR1 can occur through several different pathways, including modulation of intracellular calcium,
but also via 12-lipoxygenase, PKC and src kinase family routes (not depicted in detail) [PMID: 15134803].
The type 2 angiotensin receptor, AGTR2, is considered to act in opposition to AGTR1, inducing
vasodilation, growth inhibition and apoptosis [PMID: 18035185]. ARBs are selective for
AGTR1 and do not bind to AGTR2. The story with both angiotensin receptors is good deal
more complex than pictured as recently several GPCR interacting proteins have been identified
that modulate both receptor actions as well as receptor dimerization and activation without
ligands by mechanical forces [PMID: 17717300]. Activation of AGTR1 and downstream signaling
including release of calcium, leads to transcriptional upregulation of CYP11B2, aldosterone
synthase, and synthesis of aldosterone from cholesterol [PMID: 15134803]. The mineralocorticoid
receptor, NR3C2, to which aldosterone binds, is the target for spironolactone and eplerenone
[PMIDs:15134803; 18729003].
The suppression of aldosterone by ACE inhibitors is incomplete since alternative pathways
can still generate Ang II via chymase (CMA1) or cathepsin G (CTSG) degradation of Ang I
[PMID: 18035185]. This is known as aldosterone escape or breakthrough. It has also been
observed with ARBs [PMID: 17376010]. Aliskiren, acting upstream of ACE is thought to avoid
this, however the discovery of the Pro-renin and renin receptor ((P)RR, coded for by ATP6AP2)
is very recent and its role in the pathway not yet understood [PMID:18417113]. In order
to achieve sufficient decrease in blood pressure patients often receive multiple drugs,
and poly-therapy is the norm in secondary cardiovascular event prevention, heart failure
and diabetes. Through their action on the bradykinin pathway, ACE inhibitors also increase
production of nitric oxide and induce vasodilation through this route [PMIDs: 18182246; 9207629].
ACE2, its products and their receptor MAS1 represent relatively recent additions to the
candidate genes for this pathway [PMID: 18449520]. Thus the RAAS is not the simple endocrine
system as was initially thought.
There is considerable inter-individual variation in response to antihypertensive treatments.
PGx offers the potential to achieve better blood pressure control in hypertensive patients,
prevent organ damage in cardiovascular and renal diseases and reduce side effects. Adverse
drug responses (ADRs) to ACE inhibitors include mild side effects such as cough and serious
side effects such as angioedema [PMID: 16679330]. ARBs have fewer reported side effects
however the long term benefits are still not as clear as those of ACE inhibitors [PMID:
11459211]. Aliskiren is also reported to have a favorable side effect profile [PMID: 17956203]
although recently a case of drug-induced long QT syndrome and torsades de pointes was
reported [PMID: 19279548]. Side effects of spironolactone and eplerenone are hyperkalemia
(both) gynecomastia (spironolactone only) [PMID: 18729003]
PGx studies of antihypertensive PD have examined genes in the RAAS pathway with the insertion/deletion
(I/D) polymorphism in ACE (variously reported as rs4340, rs1799752, rs13447447, rs4646994) being
the most commonly studied variant [PMID: 15174896] and ACE inhibitors the most studied drugs.
More details including mapping information can be found in the ACE VIP
annotation. In the majority of PGx studies of ACE
inhibitors the D allele has tended to be associated with greater lowering of blood pressure
but the results are inconclusive [PMIDs: 19074621; 19497121]. PGx studies of ACE I/D and other
RAAS-acting drugs also have had mixed results [PMID: 15174896]. Since coughing is not a side
effect of ARBs or renin inhibitors it is considered to be related to the bradykinin pathway actions
of ACE inhibition [PMID: 8583482] and a BDKR2 polymorphism has been associated with ACE
inhibitor-induced cough [PMIDs: 12522467; 10904024].
Polymorphisms in AGT (AGT:Met235Thr, rs699)
and AGTR1 (AGTR1:1166A>C, rs5186) have also been
examined in studies of RAAS-acting drugs but with conflicting results (see variant annotations).
A recent study identified a variant in NOS3 (NOS3(-786)T>C,
rs2070744) as associated with
treatment-resistant hypertension, where treatment was up to three antihypertensive drugs and
included ACE inhibitors and ARBs as well as diuretics, beta and alpha blockers and calcium
channel blockers [PMID: 19650939]. To date, there are no reports catalogued in PubMed that looked
at pharmacogenomics of aliskiren.
Although currently there are no treatment guidelines for RAAS-acting drugs based on genomics, large
multi-gene haplotype and Genome Wide PGx studies such as PERGENE may provide clearer evidence to
improve therapeutic choices, reduce side effects, improve blood pressure control and prevent organ damage.
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