Syed Kashif Nawaz [1] Shahida Hasnain [*] [1]

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Angiotensin converting enzyme

Angiotensin converting enzyme (ACE) is a chloride and zinc dependent carboxypeptidase enzyme present on the surface of epithelial and endothelial cells. In humans, two isoforms exist. One is larger protein, composed of 1300 amino acids (150–180 kDa) and is called somatic ACE (sACE), due to its presence in somatic tissues. sACE can be anchored in plasma membrane through transmembrane domain, or be present in plasma in the soluble form (1). The other isoform is a smaller protein composed of 730 amino acids (100–110 kDa), present only in testicles and called germinal form or testicular form (tACE). Its function is not clear, but it appears to be involved in male fertility (2). These isoforms differ in active sites: sACE has two active sites, whereas tACE has only one active site (3).
Major functions of ACE are as follows:
- conversion of decapeptide angiotensin I (inactive) to octapeptide angiotensin II (active compound). Angiotensin II causes vasoconstriction, release of aldosterone, mediation of cell growth, and proliferation and induction of endothelial dysfunction (4-7);
- inactivation of bradykinin (a vasodilating neurokinin) allowing for vasoconstriction (3);
- signal transduction pathway (8);
- in vitro degradation of amyloid beta peptide (9); and
- GPI-ase activity which allows for the release of membrane glycosylphosphatidylinositol (GPI) – anchored protein (10).

Genetics of angiotensin converting enzyme

A single gene is responsible for the expression of both sACE and tACE. It is located at locus 17q23. ACE gene is 21 kb long and composed of 26 exons and 25 introns. Alternative promoters are responsible for the expression of each isoform. The promoter for sACE lies in the 5’ flanking region of the first exon and transcribes exon 1-12 and 14-26, whereas the promoter for tACE lies within intron 12 and transcribes exon 13-26 (11,12). The initiation sites for the transcription of two mRNAs encoding these isoforms are 5.7 kb apart and polyadenylation sites are 628 bp apart (13).

Insertion/deletion (I/D) polymorphism in ACE gene

In 1990, Rigat et al. observed a polymorphism involving insertion of 287 bp sequence (NCBI ref. SNP ID: rs1799752) resulting in insertion (I) allele, whereas deletion (D) allele is present in the absence of insertion (14). This polymorphism is responsible for the ACE activity level, which increases 2-fold in homozygous deletion carriers (D/D), as compared to homozygous insertion carriers (I/I). I/D carriers show intermediate ACE activity. This codominance was observed both, in plasma and tissue ACE levels (15).

Detection of I/D polymorphism

Rigat et al. (1990)used a set of primers flanking the insertion region for the detection of I/D polymorphism through polymerase chain reaction (PCR) (14). In this method, there was a problem of 5%-10% of mistyping, causing preferred amplification of the D allele depicting I/D heterozygotes as D/D carriers (16). For accurate genotyping, this mistyping had to be eliminated. Different strategies were adopted by different scientists. Shanguman et al. (1993) used 5% dimethyl sulfoxide (DMSO) and sense primer from the 5 end of the insertion sequence, along with the standard antisense primer (17). Later on, step down PCR modification in this method improved the accuracy of the method (18).
Multiplex PCR method and use of real time PCR were also devised for the detection of I/D polymorphism,but both methods failed to replace Shangumans method, due to problems related to post PCR handling, such as agarose diagonal gel electrophoresis in case of multiplex PCR and expensive nature of real time PCR (19,20). Recently, Koyama et al. (2008) have described a quick and easy technique involving DHPLC (denaturing high performance liquid chromatography) in non denaturing conditions to analyze the PCR product for screening for I/D polymorphisms in genetic epidemiological studies (21). This method removes the chances of mistyping and yields 100% accuracy in I/D heterozygotes, but expenses of chromatography do not prove it to be cost effective.

Effects of I/D polymorphism on human health

The influence of I/D polymorphism on pathophysiological conditions mediated through ACE activity has generated a lot of data showing its association with several diseases (Table 1). In the present review, its role in deciding on the health status is discussed in the light of previous studies on several health indicators.
Table 1. Diseases in association with ACE polymorphism

Growth and ACE polymorphism

Intrauterine environment have obvious effects on the gene expression of ACE, which ultimately influences the period of gestation and birth weight of the newborn. Kajantie et al. (2004) noticed the association of I/I genotype with shorter gestation duration and higher birth weight, which indirectly means less chances for development of coronary heart diseases, type 2 diabetes, insulin resistance and metabolic syndrome in adults (22-24). So, a concept was developed on I allele to be responsible for higher birth weight. This concept remained acceptable until Hindmarsh et al. (2007) have claimed that there is no association of ACE genotype of the newborn or his/her parents with birth weight (25). However, I/I genotype exhibited advantageous role in the early growth of babies, showing more gain in weight, body mass index and midarm circumference in one fiscal year as compared to the babies with D/D genotype, the majority of which showed no change or catch-down. I/D genotype was distributed equally across all the categories. These effects were more prominent in males. So, I/I genotype has positive effects on the early growth after birth.

Diabetes and ACE polymorphism

There are many association studies showing influence of ACE I/D polymorphism on the onset of diabetic mellitus (26-29).However, recent findings do not support this statement. For example, a large follow up of 10.2 years in 24,309 Caucasian women free from diabetes at baseline failed to show any association of ACE genotype with diabetes (30). This result was replicated in many other studies in different ethnic groups, both in patients with and without nephropathy (31-33).So, ACE polymorphism cannot be supposed as an independent factor responsible for diabetes. Anyhow, further research can investigate other effective genetic factors and environmental factors to find out the possible role of ACE in the onset of diabetes.

Diabetic nephropathy and ACE polymorphism

Diabetic nephropathy is a major cause of mortality in chronic diabetic patients. The clinical course of the disease is variable among patients. A meta-analysis by Ng et al. (2005) comprising 14,727 subjects showed a significantly higher risk of diabetic nephropathy in the carriers of D allele as compared with the I/I genotype group (OR = 1.28; 95% CI = 1.14-1.45) (34). Findings of Movva et al. (2007) also demonstrated D allele carriers with type 2 diabetes to be more vulnerable to the development of diabetic nephropathy (35).

Diabetic retinopathy and ACE polymorphism

Diabetic retinopathy is blindness due to retinal damage as a complication of diabetes mellitus. The ACE gene has been the main probable candidate gene predisposing the development of diabetic retinopathy. Findings reported by Globocnik-Petrovic et al. (2003) show no association of ACE genotype with diabetic retinopathy, non-proliferative, proliferative or severe proliferative type (36). However, Matsumoto et al. (2000) and Feghhi et al. (2008) observed frequent occurrence of D/D allele in patients with proliferative diabetic retinopathy in Japanese and Iranian population, respectively (37,38). Contradictory results reported by Wiwanitkit (2008) also reject involvement of ACE polymorphism in the development of diabetic retinopathy (39). So, because of contradictory findings, it is difficult to define the role of ACE polymorphism in the expression of diabetic retinopathy.

Atherosclerosis and ACE polymorphism

Atherosclerosis can be diagnosed by measuring intima media thickness (IMT), on autopsy and by determining coronary calcification. Sayed-Tabatabaei et al. (2003) conducted a meta-analysis of 23 articles published until October 2002, including 9,833 subjects to study the association of ACE polymorphism with atherosclerosis based on IMT measurement (40). Data suggested strong relation between D allele and common carotid IMT. This association was more prominent in subjects with cerebrovascular disease, diabetes or hypertension. Similar results have been reported by Pawel et al. (2008) and Kretowski et al. (2007) (41,42). It is noteworthy that experiments involving autopsy measurements and coronary calcification for the detection of atherosclerosis showed no association of ACE polymorphism with atherosclerosis (43,44). Discordant findings due to different diagnostic methods pose the need of more reliable diagnostic methods to confirm the presence of disease, which will help identify the role of ACE polymorphism in atherosclerosis.

Hypertension and ACE polymorphism

D/D genotype is predicted to be associated with hypertension, because of the increased level of ACE activity. Different ACE variants showed different chances to develop hypertension, due to aging and abnormality in nocturnal blood pressure (45,46).The first meta-analysis based on 23 studies consisting of 28 case-control groups with 6,923 subjects showed a 10% increased, but statistically non-significant risk, of hypertension in D/D versus I/I genotype. Anyhow, there was a significant correlation between D genotype and hypertension in women and in Asians (47). Another meta-analysis restricted to Caucasians, also failed to show any association between ACE genotype and hypertension (48). Findings by Miyama et al. (2007) and Glavnik and Petrovic (2007) also showed no influence of ACE genotype on hypertension (49,50). These contradictory results indicate the complex interaction of ACE polymorphism with the environmental and other genetic factors for the expression of hypertension. Recently, Bautista et al.(2008) have reported on D/D genotype as an independent factor for developing hypertension among Hispanics. Similar findings have been reported for the Chinese population and male population of Bangladesh, Japan and Argentina (51-55).However, Napoles et al.(2007) found no association of ACE genotype and hypertension in Cuban population (56). It is also noteworthy that the effects of ACE polymorphism in different ethnic groups are different. It predicts the effects of different lifestyles and environmental factors causing hypertension in different ethnic groups.

Coronary heart disease and ACE polymorphism

The role of D/D genotype in myocardial infarction observed by Cambien et al. (1992) generated huge scientific interest, but contradictory results make its role controversial (57). A meta-analysis involving 1,918 white subjects (1,196 cases and 722 controls) showed no difference in ACE genotype (P > 0.05) or allele frequency (P > 0.05) between cases and controls. The overall OR for D allele as an independent risk factor in ischemic stroke was 1.31 under a recessive model, and 1.14 under a dominant model. This result indicates that D allele, acting recessively, is a modest but independent risk factor for ischemic stroke onset (58). These results, however, were not confirmed by a large meta-analysis of 46 studies including a total of 32,715 white individuals (48). Results showed an association of ACE polymorphism with plasma activity level, but not with cardiovascular diseases. Meta-analysis studies in Asian population also showed the absence of any role of ACE polymorphism in disease occurrence (59). Later on, similar results were replicated in the next years (60,61). It can be concluded that ACE genotyping has no prominent association with myocardial infarction.

Alzheimer’s disease and ACE polymorphism

In vitro degradation of amyloid beta-peptide by ACE predicted its possible protective role against Alzheimer’s disease (AD). First of all, Kehoe et al. (1999) observed positive association between I allele and AD (62). Later on, they found that SNPrs 4343 was more associated with AD in spite of SNPrs 4291, which was previously thought to be a strong genetic variation responsible for AD (63). Effects of ACE polymorphism on AD were further verified by a meta-analysis by Lehmann et al. (2005) (64). The meta-analysis included 39 studies comprising 6,037 AD cases and 12,099 controls. Findings suggested that D/D carriers were at a reduced risk (OR = 0.81; 95% CI = 0.72-0.90; P < 0.001); I/I homozygotes exhibited no association with AD, while heterozygotes were more vulnerable to AD. Similar results were seen among North Europeans, South Caucasians, and East Asians. Anyhow, in North Europeans, both association and Hardy-Weinberg analysis indicated partial heterogeneity, due to unknown reason. These results were also replicated in other studies (65,66). Some discordant results have also been reported, thus opening way to further investigations to confirm the role of ACE in disease manifestation (67-69). The greater body of data confirming association as compared to those denying association appears to suggest the influence of several factors on deciding about ACE polymorphism as a candidate gene variation responsible for AD.

Parkinson’s disease

Little work has been done to find out any relation of ACE polymorphism with Parkinson’s disease (PD). Lin et al. (2003) conducted a case-control study comprising of 127 sporadic PD patients and 198 healthy controls, and observed the presence of homozygote D/D genotype to be more frequent in patients with PD than in controls (P = 0.048), although there was no significant difference in the allelic frequency (P = 0.133) (70). A stepwise logistic regression analysis verified the independent role of D/D genotype as a risk factor for PD (OR = 1.32; 95% CI = 1.12-2.16).
Lin et al. (2007) also observed that ACE I/D polymorphism was primary predictor for the occurrence of psychosis in L-dopa patients (71). So, ACE genotyping is recommended in PD patients for identification of subjects at risk and for minimizing the chances of L-dopa induced psychosis. These studies are not sufficient for conclusive role of ACE polymorphism but seek confirmation through a cohort followed until the late phase of PD.

Cancer and ACE polymorphism

ACE polymorphism involvement in the occurrence of several malignancies, tumor cell proliferation, tumor cell migration, angiogenesis and metastatic behavior is mediated by angiotensin I/I which has been proven to be an angiogenic and growth factor (72). This information has become a basis for many association studies related to different types of cancer. We shall discuss the outcomes of some of them.
Breast cancer
In 2003, Koh et al. analyzed 189 incident breast cancer cases and 671 female cohort control subjects for sorting out any impact of ACE polymorphism on breast cancer in Singapore (73). It was observed that I allele carriers were at a low risk as compared to D allele carriers, suggesting that the renin-angiotensin system may serve as a therapeutic target for breast cancer treatment and prevention. This finding was also supported by many other studies (74-76).
Oral cancer
Vairaktaris et al. (2007) recorded a three-fold risk in I/I homozygotes for developing oral cancer, regardless of smoking habit or alcohol consumption, early or advanced stage of cancer, and presence or absence of a family history of cancer or thrombophilia (77). For confirmation of the above mentioned results, additional analyses with a larger sample size are required.
Gastric cancer
No relation of ACE polymorphism with gastric cancer was observed by Röcken et al. (2005) but in the same year, discordant results were obtained by Goto et al. (72,78). Their results were based on a study including 454 Japanese subjects undergoing health checkup and 202 gastric cancer patients. There was no effect of the polymorphism on Helicobacter pylori seropositivity or gastric atrophy. However, I/D carriers were at an increased risk of gastric cancer (OR = 1.59; 95% CI = 1.02-2.48).
Colorectal carcinoma
Röcken et al. (2007) conducted experiments to assess local expression of ACE by using quantitative reverse transcription-polymerase chain reaction and by immunohistochemistry in colorectal carcinomas and adenomas (79). Results showed greater production of ACE protein in adenomas (17 Š81%Ć) and cancer epithelial cells (22 Š100%Ć) than in the corresponding non-neoplastic crypt and surface epithelium (2 Š10%Ć and 2 Š9%Ć, respectively). Moreover, I/D polymorphism was found to be associated with gender specific differences in primary tumor size and patient survival. Female colorectal carcinoma patients were found to more frequently have I/D genotype and less frequently I/I and D/D genotypes as compared to male patients. Tumors of I/D and D/D male carriers were larger than those of I/I genotype. In the same year, the findings reported by Nikiteas et al. negated the above results suggesting controversial predisposition of ACE polymorphism for colorectal cancers (80).

Muscle performance and ACE polymorphism

Endothelium-dependent vasodilation can be increased with aerobic exercise in healthy individuals due to the increase in nitric oxide (NO) production and decreased NO inactivation, leading to an increase in NO bioavailability. Improvement of vasodilation by regular isotonic exercise varies with different alleles of ACE carriers. ACE I/I carriers can better improve this vasodilation as compared to I/D and D/D carriers (81). So, I/I genotype promotes the chances for improvement of vasodilation during aerobic exercise.
Frequency distribution of ACE genotype indicates that I/I and I/D genotypes are frequent in endurance athletes, long distance runners, rowers and mountaineers, whereas D/D genotype is found mostly among top level professional French cyclists (82,83).Moran et al. (2006) observed a relation of I allele with phenotypes related more to strength than to endurance in 1,027 teenage Greeks (84). It suggests a more complicated role for the ACE gene in human physical performance than previously described. This finding apparently opposes the results of previous experiments. However, those studies are not comparable due to high selection and relatively small population. So, a modest influence of ACE gene on physical performance is clear in general population. Now, the only challenge is to trace out the mechanism of ACE influence on performance related phenotypes.

Immunity and ACE polymorphism

Effects of ACE genotype on immunity and immune disorders have also been a topic of interest during the previous decade. We shall precisely discuss a few of them pointing out the importance of ACE polymorphism.
The role of ACE I/D polymorphism in defense against sepsis in children was studied in detail by Cogulu et al. (2008) (85). They noted that I allele carriers (I/I or I/D genotype) were at an increased risk as compared to D/D carriers. This finding speculates the protective role of D/D genotype against sepsis. As this finding is based on the experiment with a small number of subjects (N = 287), it is needed to repeat the experiment in a large population to make a doubt free conclusion.
Asthma and allergic rhinitis
Development of symptoms of asthma in some patients and of allergic rhinitis in other patients conjectures the involvement of genetic factors. Lue et al. (2006) tried to find out the genetic reason for the two different phenotypes and speculated the ACE polymorphism for it (86). They performed genotyping for ACE in 106 children with allergic rhinitis but no asthma, 105 age- and gender-matched children with allergic rhinitis and asthma, and 102 healthy children. Serum level of total immunoglobulin E (IgE), allergen-specific IgE sensitivity, and eosinophil count were also measured for each sample. A more frequent occurrence of D/D genotype in children with both allergic rhinitis and asthma than in children with allergic rhinitis but no asthma showed the protective role of D/D genotype in the development of asthma phenotype in children with allergic rhinitis.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) manifestation due to ACE polymorphism was confirmed by Lee et al. (2006) in a meta-analysis study of 13 comparison studies including 1,411 patients with SLE and 1,551 controls (87). No effect of ACE I/D polymorphism was observed on SLE either in total sample or according to ethnic groups. A trend for association of D/D genotype (OR = 1.212; 95% CI = 0.966-1.520; P = 0.097) and D allele with SLE was observed in Caucasian patients (OR = 1.157; 95% CI = 0.991-1.349; P = 0.064); however, it was not statistically significant. So, it is obvious that there is no relation of ACE polymorphism with SLE.

Bones and ACE polymorphism

Osteoporosis, a bone disease, is a multifactorial problem reported in elderly subjects of both sexes. Scarce data are available showing the role of ACE I/D polymorphism in the manifestation of osteoporosis and its treatment. There is evidence showing an association of ACE polymorphism with osteoporosis (88). Findings suggest that low ACE activity associated with ACE I/I genotype has a beneficial role in its treatment. In a cross-sectional study of 3,887 Chinese men (N = 1958) and women (N = 1,929), Lynn et al. (2006) observed that I/I carriers showed better results with ACE inhibitor therapy as compared to I/D or D/D carriers (89,90). Similar advantageous effects of ACE I/I genotype have been reported by Woods et al. (2001) for hormone replacement therapy (91). So, ACE I/D polymorphism is also important in relation to bones.

Longevity and ACE polymorphism

The status of several diseases in association with ACE polymrophism (Table 1) predicts it as a marker of longevity. For confirmation of this hypothesis, Schachter et al. (1994) genotyped 338 centenarians and 164 control individuals aged 20 to 70 years, from a cohort ascertained by the Centre d’Etude du Polymorphisme Humain (CEPH) in Paris, France (92). Their findings were unexpected showing frequent occurrence of D/D genotype in the centenarian group compared with the control group (40%vs. 26%, P = 0.01). In 2000, the experiment was repeated with 560 additional French centenarians, each paired with a younger individual of the same sex and geographic origin. However, the results now failed to reveal a difference between the centenarian and control populations (93). A similar conclusion has been reported by Nacmias et al. (2007) (67).
In a population based study, Arias-Vasquez et al. (2003) genotyped 6,968 elderly individuals and found no relation of ACE polymorphism with longevity but with early mortality, which was common in smokers with D/D genotype, whereas frequency distribution was not significantly different in non smokers (94). So, ACE polymorphism has significant relation with mortality at early age due to cardiovascular and non-cardiovascular diseases in the presence of other physical and environmental factors.


Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. ACE polymorphism was thought to be responsible for longevity because of its role in the expression of many diseases. In the beginning, I/I genotype was thought to be associated with high birth weight, which is a sign of healthy future in old ages. But later on, it was found that there is no relation between birth weight of the newborn but that early growth after birth is influenced by I/I or I/D genotype. The protective effects of I/I allele against cardiovascular diseases and diabetic complications are not obvious and are still controversial. These facts show that ACE polymorphism has a low-level role in determining longevity.


Potential conflict of interest
None declared.


1.   Zhao Y, Xu C. Structure and function of angiotensin converting enzyme and its inhibitors. Chin J Biotech 2008;24:171-6.
 2.   Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 2002;23: 177-83.
 3.   Jaspard E, Wei L, Alhenc-Gelas F. Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J Biol Chem 1993;268:9496-503.
 4.   Erdos EG, Skidgel RA.The angiotensin I-converting enzyme. Lab Invest 1987;56:345-8.
 5.   Brewster UC, Perazella MA The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med 2004;116:263-72.
 6.   Carluccio M, Soccio M, De Caterina R. Aspects of gene polymorphisms in cardiovascular disease: the renin-angiotensin system. Eur J Clin Invest 2001;31:476-88.
 7.   Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996;97:1916-23.
 8.   Fleming I. Signaling by the angiotensin-converting enzyme. Circ Res 2006;14:98:887-96.
 9.   Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 2001;276:47863-8.
10.   Kondoh G, Tojo H, Nakatani Y, Komazawa N, Murata C, Yamagata K, et al. Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization. Nat Med 2005;11:160-6.
11.   Hubert C, Houot AM, Corvol P, Soubrier F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 1991;266: 15377-83.
12.   Howard TE, Shai SY, Langford KG, Martin BM, Bernstein KE. Transcription of testicular angiotensin-converting enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene. Mol Cell Biol 1990;10: 4294-302.
13.   Thekkumkara TJ, Livingston W3rd, Kumar RS, Sen GC. Use of alternative polyadenylation sites for tissue-specific transcription of two angiotensin-converting enzyme mRNAs. Nucleic Acids Res 1992;20:683-7.
14.   Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
15.   Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JCM. ACE polymorphisms. Circ Res 2006;98:1123-33.
16.   Odawara M, Matsunuma A, Yamshita K. Mistyping frequency of the angiotensin converting enzyme gene polymorphism and an improved method for its avoidance. Hum Gen 1997;100:163-6.
17.   Shanguman V, Sell KW, Saha BK. Mistyping ACE heterozygotes. Genome Res 1993;3:120-1.
18.   Chiang FT, Hsu KL, Chen WM, Tseng CD, Tseng YZ. Determination of angiotensin converting enzyme gene polymorphisms: step down PCR increases detection of heterozygotes. Clin Chem 1998;44:1353-6.
19.   Evans AE, Poirier O, Kee F, Lecerf L, McCrum E, Falconer T, et al. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. QJM 1994;87:211-4.
20.   Lin MH, Tseng CH, Tseng CC, Huang CH, Chong CK, Tseng CP. Real time PCR for rapid genotyping of angiotensin converting enzyme insertion/deletion polymorphism. Clin Biochem 2001;34:661-6.
21.   Koyama RG, Castro RMRPS, De Mello MT, Tufik S, Pedrazzoli M. Simple detection of large InDeLS by DHPLC: the ACE gene as a model. J Biomed Biotech 2008;568183.
22.   Kajantie E, Rautanen A, Kere J, Andersson S, Yliharsila H, Osmond C, et al. The effects of the ACE gene insertion/deletion polymorphism on glucose tolerance and insulin secretion in elderly people are modified by birth weight. J Clin Endocrinol Metab 2004;89:5738-41.
23.   Barker DJP, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005;353:1802-9.
24.   Rotteveel J, van Weissenbruch MM, Twisk JWR, de Waal HAD. Infant and childhood growth patterns, insulin sensitivity, and blood pressure in prematurely born young adults. Pediatrics 2008;122:313-21.
25.   Hindmarsh PC, Rodeck CH, Humphries SE. Polymorphisms in the angiotensin converting enzyme gene and growth in the first year of life. Ann Hum Gen 2007;71:176-84.
26.   Feng Y, Niu T, Xu X, Chen C, Li Q, Qian R, et al. Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes. Diabetes 2002;51:1986-8.
27.   Daimon M, Oizumi T, Saitoh T, Kameda W, Hirata A, Yamaguchi H, et al. The D allele of the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism is a risk factor for type 2 diabetes in a population-based Japanese sample. Endocr J 2003;50:393-8.
28.   Stephens JW, Dhamrait SS, Cooper JA, Acharya J, Miller GJ, Hurel SJ, Humphries SE. The D allele of the ACE I/D common gene variant is associated with type 2 diabetes mellitus in Caucasian subjects. Mol Genet Metab 2005;84:83-9.
29.   Singh PP, Naz I, Gilmour A, Singh M, Mastana S. Association of APOE (Hha1) and ACE (I/D) gene polymorphisms with type 2 diabetes mellitus in North West India. Diabetes Res Clin Pract2006;74:95-102.
30.   Conen D, Glynn RJ, Buring JE, Ridker PM, Zee RY. Renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms are not associated with the risk of incident type 2 diabetes mellitus: a prospective cohort study. J Intern Med 2007;263:376-85.
31.   van-Valkengoed IGM, Stronks K, Hahntow IN, Hoekstra JBL, Holleman F. The angiotensin converting enzyme insertion/deletion polymorphism and differences in fasting plasma glucose in Hindustani Surinamese, African Surinamese and ethnic Dutch: the population-based SUNSET-study. Diabetes Res Clin Pract 2008;81:e12-e14.
32.   Arfa I, Abid A, Nouira S, Elloumi-Zghal H, Malouche D, Mannai I, et al. Lack of association between the angiotensin-converting enzyme gene (I/D) polymorphism and diabetic nephropathy in Tunisian type 2 diabetic patients. JRAAS 2008;9:32-6.
33.   Eroglu Z, Cetinkalp S, Erdogan M, Kosova B, Karadeniz M, Kutukculer A, et al. Association of the angiotensinogen M235T and angiotensin-converting enzyme insertion/deletion gene polymorphisms in Turkish type 2 diabetic patients with and without nephropathy. J Diabetes Complications 2008;22:186-90.
34.   Ng DP, Tai BC, Koh D, Tan KW, Chia KS. Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy: a meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects. Diabetologia 2005;48: 1008-16.
35.   Movva S, Alluri RV, Komandur S, Vattam K, Eppa K, Mukkavali KK, et al. Relationship of angiotensin-converting enzyme gene polymorphism with nephropathy associated with type 2 diabetes mellitus in Asian Indians. J Diabetes Complications 2007;21:237-41.
36.   Globocnik-Petrovic M, Hawlina M, Peterlin B, Petrovic D. Insertion/deletion plasminogen activator inhibitor 1 and insertion/deletion angiotensin-converting enzyme gene polymorphisms in diabetic retinopathy in type 2 diabetes. Ophthalmologica 2003;217:219-24.
37.   Matsumoto A, Iwashima Y, Abiko A, Morikawa A, Sekiguchi M, Eto M, Makino I. Detection of the association between a deletion polymorphism in the gene encoding angiotensin I-converting enzyme and advanced diabetic retinopathy. Diabetes Res Clin Pract 2000;50:195-202.
38.   Feghhi M, Nikzamir A, Esteghamati A, Farahi F, Nakhjavani M, Rashidi A. The relationship between angiotensin-converting enzyme insertion/deletion polymorphism and proliferative retinopathy in type 2 diabetes. Diabetes Res Clin Pract 2008; 81:e1-e4.
39.   Wiwanitkit V. Angiotensin-converting enzyme gene polymorphism is correlated to diabetic retinopathy: a meta-analysis. J Diabetes Complications 2008;22:144-6.
40.   Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM, Witteman JC. Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis. Stroke 2003;34:1634-9.
41.   Pawel N, Iwona Z, Krystian W. The D allele of angiotensin I-converting enzyme gene insertion/deletion polymorphism is associated with the severity of atherosclerosis. Clin Chem Lab Med 2008;46:446-52.
42.   Kretowski A, McFann K, Hokanson JE, Maahs D, Kinney G, Snell-Bergeon JK, et al. Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis. Diabetes 2007;56:863-71.
43.   Scheer WD, Boudreau DA, Hixson JE, McGill HC, Newman WP 3rd, Tracy RE, et al. ACE insert/delete polymorphism and atherosclerosis. Atherosclerosis 2005;178:241-7.
44.   Oei HH, Sayed-Tabatabaei FA, Hofman A, Oudkerk M, van Duijn CM, Witteman JC. The association between angiotensin-converting enzyme gene polymorphism and coronary calcification. The Rotterdam Coronary Calcification Study. Atherosclerosis 2005;182:169-73.
45.   Szadkowska A, Pietrzak I, Klich I, Młynarski W, Bodalska-Lipińska J, Bodalski J. Polymorphism I/D of the angiotensin-converting enzyme gene and disturbance of blood pressure in type 1 diabetic children and adolescents. Przegl Lek 2006;63:32-6.
46.   Freitas SRS, Cabello PH, Moura-Neto RS, Dolinsky LC, Bóia MN. Combined Analysis of genetic and environmental factors on essential hypertension in a Brazilian rural population in the Amazon Region. Arq Bras Cardiol 2007;88:393-7.
47.   Staessen JA, Wang JG, Ginocchio G, Petrov V, Saavedra AP, Soubrier F, et al. The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. J Hypertens 1997;15:1579-92.
48.   Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A. ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol 2000;20:484-92.
49.   Miyama N, Hasegawa Y, Suzuki M, Hida W, Kazama I, Hatano R, et al. Investigation of major genetic polymorphisms in the renin-angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university. Clin Exp Hypertens 2007;29:61-7.
50.   Glavnik N, Petrovič D. M235T polymorphism of the angiotensinogen gene and insertion/deletion polymorphism of the angiotensin-1 converting enzyme gene in essential arterial hypertension in Caucasians. Folia Biol (Praha) 2007;53:69-70.
51.   Bautista LE, Vargas CI, Oróstegui M, Gamarra G. Population-based case-control study of renin-angiotensin system genes polymorphisms and hypertension among Hispanics. Hypertens Res 2008;31:401-8.
52.   Zhang YL, Zhou SX, Lei J, Zhang JM. Association of angiotensin I-converting enzyme gene polymorphism with ACE and PAI-1 levels in Guangdong Chinese Han patients with essential hypertension. Nan Fang Yi Ke Da Xue Xue Bao 2007;27:1681-4.
53.   Morshed M, Khan H, Akhteruzzaman S. Association between angiotensin I-converting enzyme gene polymorphism and hypertension in selected individuals of the Bangladeshi population. J Biochem Mol Biol 2002;35:251-4.
54.   Higaki J, Baba S, Katsuya T, Sato N, Ishikawa K, Mannami T, et al. Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men: the Suita Study. Circulation 2000;101:2060-5.
55.   Jiménez PM, Conde C, Casanegra A, Romero C, Tabares AH, Orías M. Association of ACE genotype and predominantly diastolic hypertension: a preliminary study. JRAAS 2007;8:42-4.
56.   Nápoles OC, Castellanos MS, Leal L, Casalvilla R, Camacho H, Ferrer A, et al. ACE I/D polymorphism study in a Cuban hypertensive population. Clin Chim Acta 2007;378:112-6.
57.   Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-4.
58.   Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998;64:227-30.
59.   Banerjee I, Gupta V, Ganesh S. Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis 2007. J Hum Genet 2007;52:205-19.
60.   Xu X, Li J, Sheng W, Liu L. Meta-analysis of genetic studies from journals published in China of ischemic stroke in the Han Chinese population. Cerebrovasc Dis 2008;26:48-62.
61.   Dikmen M, Günes HV, Degirmenci I, Ozdemir G, Basaran A. Are the angiotensin-converting enzyme gene and activity risk factors for stroke? Arq Neuropsiquiatr 2006;64:211-6.
62.   Kehoe PG, Russ C, McIlory S, Williams H, Holmans P, Holmes C, et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat Genet 1999;21:71-2.
63.   Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B, et al. Haplotypes extending across ACE are associated with Alzheimer’s disease. Hum Mol Genet 2003;12:859-67.
64.   Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol 2005;162:305-17.
65.   Kölsch H, Jessen F, Freymann N, Kreis M, Hentschel F, Maier W, Heun R. ACE I/D polymorphism is a risk factor of Alzheimer’s disease but not of vascular dementia. Neurosci Lett 2005;377:37-9.
66.   Sleegers K, den Heijer T, van Dijk EJ, Hofman A, Bertoli-Avella AM, Koudstaal PJ, et al. ACE gene is associated with Alzheimer’s disease and atrophy of hippocampus and amygdale. Neurobiol Aging 2005;26:1153-9.
67.   Nacmias B, Bagnoli S, Tedde A, Cellini E, Bessi V, Guarnieri B, et al. Angiotensin converting enzyme insertion/deletion polymorphism in sporadic and familial Alzheimer’s disease and longevity. Arch Gerontol Geriatr 2007;45:201-6.
68.   Camelo D, Arboleda G, Yunis JJ, Pardo R, Arango G, Solano E, et al. Angiotensin-converting enzyme and alpha-2-macroglobulin gene polymorphisms are not associated with Alzheimer’s disease in Colombian patients. J Neurol Sci 2004;218:47-51.
69.   Bowirrat A, Cui J, Waraska K, Friedland RP, Oscar-Berman M, Farrer LA, et al. Lack of association between angiotensin-converting enzyme and dementia of the Alzheimer’s type in an elderly Arab population in Wadi Ara, Israel. Neuropsychiatr Dis Treat 2005;1:73-6.
70.   Lin JJ, Yueh KC, Chang DC, Lin SZ. Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson’s disease. J Neurol Sci 2003;199:25-9.
71.   Lin JJ, Yueh KC, Lin SZ, Harn HJ, Liu JT. Genetic polymorphism of the angiotensin converting enzyme and L-dopa-induced adverse effects in Parkinson’s disease. J Neurol Sci 2007;252:130-4.
72.   Röcken C, Lendeckel U, Dierkes J, Westphal S, Carl-McGrath S, Peters B, et al. The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. Clin Cancer Res2005;11:2526-30.
73.   Koh WP, Yuan JM, Sun CL, van den Berg D, Seow A, Lee HP, Yu MC. Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore. Cancer Res 2003;63:573-8.
74.   González-Zuloeta Ladd AM, Arias-Vásquez A, Sayed-Tabatabaei FA, Coebergh JW, Hofman A, Njajou O, et al. Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2005;14:2143-6.
75.   Yaren A, Turgut S, Kursunluoglu R, Oztop I, Turgut G, Kelten C, Erdem E. Association between the polymorphism of the angiotensin-converting enzyme gene and tumor size of breast cancer in premenopausal patients. Tohoku J Exp Med 2006;210:109-16.
76.   Van der Knaap R, Siemes C, Coebergh JW, van Duijn CM, Hofman A, Stricker BH. Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: the Rotterdam Study. Cancer 2008;112:748-57.
77.   Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, et al. Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with increased risk for oral cancer. Acta Oncol 2007;46:1097-102.
78.   Goto Y, Ando T, Nishio K, Ishida Y, Kawai S, Goto H, Hamajima N. The ACE gene polymorphism is associated with the incidence of gastric cancer among H. pylori seropositive subjects with atrophic gastritis. Asian Pac J Cancer Prev. 2005;6:464-7.
79.   Röcken C, Neumann K, Carl-McGrath S, Lage H, Ebert MP, Dierkes J, et al. The gene polymorphism of the angiotensin I-converting enzyme correlates with tumor size and patient survival in colorectal cancer patients. Neoplasia 2007;9:716-22.
80.   Nikiteas N, Tsigris, C, Chatzitheofylaktou A, Yannopoulos A. No association with risk for colorectal cancer of the insertion/deletion polymorphism which affects levels of angiotensin-converting enzyme. In Vivo 2007;21:1065-8.
81.   Tanriverdi H, Evrengul H, Tanriverdi S, Turgut S, Akdag B, Kaftan HA, Semiz E. Improved endothelium dependent vasodilation in endurance athletes and its relation with ACE I/D polymorphism. Circ J 2005;69:1105-10.
82.   Lucía A, Gómez-Gallego F, Chicharro JL, Hoyos J, Celaya K, Córdova A, et al. Is there an association between ACE and CKMM polymorphisms and cycling performance status during 3-week races? Int J Sports Med 2005;26:442-7.
83.   Hruskovicová H, Dzurenková D, Selingerová M, Bohus B, Timkanicová B, Kovács L. The angiotensin converting enzyme I/D polymorphism in long distance runners. J Sports Med Phys Fitness 2006;46:509-13.
84.   Moran CN, Vassilopoulos C, Tsiokanos A, Jamurtas AZ, Bailey ME, Montgomery HE, et al. The associations of ACE polymorphisms with physical, physiological and skill parameters in adolescents. Eur J Hum Genet 2006;14:332-9.
85.   Cogulu O, Onay H, Uzunkaya D, Gunduz C, Pehlivan S, Vardar F, et al. Role of angiotensin-converting enzyme gene polymorphisms in children with sepsis and septic shock. Pediatr Int 2008;50:477-80.
86.   Lue KH, Ku MS, Li C, Sun HL, Lee HS, Chou MC. ACE gene polymorphism might disclose why some Taiwanese children with allergic rhinitis develop asthma symptoms but others do not. Pediatr Allergy Immunol 2006;17:508-13.
87.   Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. Angiotensin-converting enzyme insertion/deletion polymorphism and systemic lupus erythematosus: a meta-analysis. J Rheumatol 2006;33:698-702.
88.   Pérez-Castrillón JLJusto ISilva JSanz AMartín-Escudero JCIgea R, et al. Relationship between bone mineral density and angiotensin converting enzyme polymorphism in hypertensive postmenopausal women. Am J Hypertens2003;16:233-5.
89.   Lynn HKwok TWong SYWoo JLeung PC. Angiotensin converting enzyme inhibitor use is associated with higher bone mineral density in elderly Chinese. Bone 2006;38:584-8.
90.   Pérez-Castrillón JLSilva JJusto ISanz AMartín-Luquero MIgea R, et al. Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms. Am J Hypertens 2003;16:453-9.
91.   Woods DOnambele GWoledge RSkelton DBruce SHumphries SE, Montgomery H. Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density. J Clin Endocrinol Metab 2001;86:2200-4.
92.   Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994;6:29-32.
93.   Blanche H, Cabanne L, Sahbatou M, Thomas G. A study of French centenarians: are ACE and APOE associated with longevity? C R Acad Sci III 2001;324:129-35.
94.   Arias-Vasquez A, Sayed-Tabatabaei FA, Schut AF, Hofman A, Bertolli-Avella AM, Vergeer JM, et al. Angiotensin converting enzyme gene, smoking and mortality in a population-based study. Eur J Clin Invest 2005;35:444-9.