Annotated PGx Gene Information for ACE

Citation: PharmGKB summary: very important pharmacogene information for angiotensin-converting enzyme.
Thorn CF, Klein TE, Altman RB. Pharmacogenet Genomics. 20(2):143-146, February 2010. PMID: 19898265

PharmGKB VIP Submitted by: Caroline F. Thorn (PharmGKB)
PharmGKB VIP Reviewed by: Marisa Wong Medina (PARC)
PharmGKB VIP Submission date: August 7, 2006
PharmGKB VIP Updated: October 19, 2009

Gene HGNC Name:	ACE
Introductory Information:	Angiotensin Converting Enzyme, ACE, plays an important role in two pathways which contribute to the regulation of blood pressure, the renin-angiotensin-aldosterone system (RAAS) and the kinin-kallikrien cascade. ACE converts the inactive angiotensin I peptide (also known as Ang I or Ang 1-10) to the active angiotensin II (Ang II or Ang 1-8) (see the RAAS-acting drug Pathways). Angiotensin II has a variety of functions including vasoconstriction and stimulating release of aldosterone, that in turn causes resorption of sodium and water from urine and increases blood pressure. [reviewed in PMID: 11931993]. ACE also inactivates the vasodilator bradykinin, a component of the kinin-kallikrien cascade, preventing it from stimulating its receptor (BDKRB2) and the subsequent downstream release of nitric oxide, which relaxes vascular smooth muscle and lower blood pressure PMID: 12676166. In addition ACE has also been shown to have a variety of other interesting substrates and interactions including Amyloid Precursor protein, APP, a major component of plaques in Alzheimer's disease (AD) [PMIDs:17504229; 15733091]. ACE is the target of the ACE inhibitor family of drugs making it a potential PD pharmacogene. However, most evidence to date on polymorphisms in ACE have been with respect to their impact on disease and clinical outcomes rather than drug response (described extensively in OMIM 106180 and various reviews including PMIDs:17504229; 16690893; 19497121; 19290794). More than 300 studies have examined over 100 different conditions including cardiovascular disease, renal disease diabetes and AD but only about half of the studies found significant association PMID:17504229. ACE inhibitors are standard treatment for hypertension, heart failure, and renal disease PMID: 19074621 but there is also discussion about potential use for treatment of AD PMID: 17362841. The ACE gene has been resequenced in African-American and European-American individuals from the Coriell DNA repository and 78 variants and 13 haplotypes were identified PMID: 10319862. The most well known variant in the ACE gene is the insertion/deletion in intron 16, ACE:I/D described in more detail later [PMIDs: 1976655, 16690893]. Other SNPs in ACE have been significantly associated with AD, including rs1800764, rs4267385 and rs4291, and are catalogued in an online repository at http://www.alzgene.org PMID: 17192785 (Accessed on 9/9/09). Variants rs4290 and rs7213516 in the ACE promoter have been shown to reduce transcription and have been associated with adverse cardiovascular outcomes PMID: 18946466. The ACE gene comprises 26 exons that are alternately spliced to give two isoforms. The predominant isoform contains exons 1-12 and 14-26 and when translated results in a 1306 amino acid protein with two zinc binding catalytic domains (N and C terminal sites). It is expressed in many tissues including kidney, intestine and lung in endothelial, epithelial and neuroepithelial cell types [PMIDs: 11931993; 18449520]. This is referred to as somatic ACE or sACE. There is a truncated isoform expressed only in testis, tACE or gACE/germinal ACE, which contains only the C-terminal catalytic site comprised of exons 13-26 [PMIDs: 10319862; 11931993]. One report mentions a third splice variant, that starts at the same place as tACE but extends through several additional exons, however no additional data was found to support this PMID: 17504229. 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 is an M2 zinc metalloprotease and the active sites have the zinc binding motif HEXXH PMID:18449520. ACE inhibitor drugs were designed using a rational approach but at that time a structure was not available and they were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. A 3d structure for tACE (1o8a) was elucidated in 2003 and also with the ACE inhibitor lisinopril bound (1o86) PMID:12540854. These structures showed than rather than resembling carboxypeptidase A it looked more similar to neurolysin and may allow for structure-based design of more efficient ACE inhibitors with fewer side effects. Many other crystal structures currently are available in the pdb, several co-crystallized with inhibitors (including 1uze, 1uzf, 2iux). Adverse drug responses (ADRs) to ACE inhibitors include mild side effects such as cough and serious side effects such as angioedema. These ADRs occur at different frequencies in different racial and ethnic groups, with an increased risk for cough in Asians and women and an increased risk for angioedema in black individuals PMID: 16679330. ACE inhibition is also associated with birth defects, particularly cardiovascular and renal abnormalities, and ACE inhibitors are contraindicated for women who are or may become pregnant [PMIDs: 19198819; 16689556].
Key PubMed IDs:	1976655, 16679330
Reviews:	1976655, 16690893, 16614314
Key Pathways:	ACE Inhibitor Pathway
Drugs/Substrates:	ace inhibitors, captopril, enalapril, fosinopril, imidapril, lisinopril
Phenotypes/Diseases:	Phenotypes: Genetic Epidemiology of Responses to Antihypertensives (GERA) Diseases: Hypertension, Cough, Angioneurotic Edema
Important Variants	ACE: I/D

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