|Year : 2009 | Volume
| Issue : 6 | Page : 1038-1046
|A study on the association between Angiotensin-I converting enzyme I/D dimorphism and type-2 diabetes mellitus
Hania Nakkash Chmaisse1, Manal Jammal1, Hana Fakhoury2, Rajaa Fakhoury3
1 Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon
2 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
3 Faculty of Science, Beirut Arab University, Beirut, Lebanon
Click here for correspondence address and email
|Date of Web Publication||27-Oct-2009|
| Abstract|| |
Type-2 diabetes mellitus (T2DM) is a chronic disorder characterized by a varying range of predominant insulin resistance with relative insulin deficiency, to predominant insulin secretory defect with or without insulin resistance. Familial clustering as well as epidemiological studies has shown that genetic factors play a role in the development and progression of the disease. Among the genetic factors found to be associated with development of T2DM is the angiotensin-I converting enzyme (ACE) gene, which is located on chromosome 17q23. This study was conducted to study the association between ACE gene insertion/deletion (I/D) polymorphism and T2DM in a Lebanese diabetic cohort. Fifty-one patients with T2DM and 40 control subjects from different parts of Lebanon underwent genotyping for the ACE I/D, which was performed by PCR using specific primers. Chi-square and analysis of variance (ANOVA) were used for association studies and to assess the differences in the values among the groups. The distribution of the genotypes in the patients was as follows: 15/51 (29.4%) were homozygous for deletion allele (DD genotype), 24/51 (47.1%) were heterozygous (ID genotype), and 12/51 (23.5%) were homozygous for insertion allele (II genotype). Among the control subjects, 16/40 (40%) were homozygous for deletion (DD genotype), 13/40 (32.5%) were heterozygous (ID genotype), and 11/40 (27.5%) were homozygous for insertion (II genotype). The prevalence of the D-allele in T2DM patients (52.9%) was not significantly different from that in the controls (56.3%). Thus, ACE I/D dimorphism cannot be considered a risk factor for T2DM in the Lebanese population.
|How to cite this article:|
Chmaisse HN, Jammal M, Fakhoury H, Fakhoury R. A study on the association between Angiotensin-I converting enzyme I/D dimorphism and type-2 diabetes mellitus. Saudi J Kidney Dis Transpl 2009;20:1038-46
|How to cite this URL:|
Chmaisse HN, Jammal M, Fakhoury H, Fakhoury R. A study on the association between Angiotensin-I converting enzyme I/D dimorphism and type-2 diabetes mellitus. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Jul 16];20:1038-46. Available from: http://www.sjkdt.org/text.asp?2009/20/6/1038/57260
| Introduction|| |
The angiotensin-I converting (ACE) enzyme, a key component of the renin-angiotensin system (RAS), catalyses the C-terminal dipeptide cleavage (His-Leu) from angiotensin-I (Ang I) and generates the vasoconstricotor angiotensinII (Ang-II).  Angiotensin is pro-inflammatory  and pro-oxidant,  thus causing cellular toxicity and apoptosis. Some studies have demonstrated that chronic low grade systemic inflammation can predict the future risk of impaired glucose tolerance (IGT) and type-2 diabetes mellitus (T2DM). 
Moreover, several pharmacogenetic studies have shown that ACE inhibitors ,, and Ang-II receptor blockers  reduce the risk of developing T2DM in addition to conferring a beneficial effect on diabetic complications. , These results thus suggest that the inflammatory effect of Ang-II may play a role in the development of T2DM.
The ACE gene has 26 exons; exons 1-12 encode for the amino domain and exons 13-26 encode for the carboxyl domain. A commonly occurring variant in the ACE gene is an insertion and deletion polymorphism (I/D) of a 287 bp Alu repetitive sequence in intron 16.  Therefore, three genotypes have been identified: DD, II homozygotes and ID heterozygotes.
The polymorphism is responsible for the large proportion of variability of serum and tissue ACE activity, where insertion is associated with lower ACE activity,  and deletion is associated with higher ACE activity.  Indeed, the polymorphism accounted for 47% of the variance in serum ACE levels. 
Therefore, ACE I/D dimorphism has been studied in reference to various conditions related to the renin angiotensin system (RAS). In particular, the D-allele demonstrated an association with diseases affected by RAS such as hypertension,  coronary artery disease, ,, arterial wall stiffness,  diabetes,  and diabetic complications such as nephropathy. ,,,
Tissue or local RAS in skeletal muscles  affects the substrate utilization where low ACE activity increases the glucose uptake during exercise.  ACE inhibitors also increased skeletal muscle uptake, insulin sensitivity, glycogen storage, glucose transporter GLUT-4 synthase activity, and hexokinase activity. 
On the other hand, the local endocrine system in adipose tissue  has been reported to modify substrate mobilization. Low ACE activity increased insulin stimulated hexone transport in adipocytes,  and insulin suppression of nonesterified fatty-acid flux.  As a result of these findings, high ACE activity, namely the ACE DD genotype, seems to increase the risk of impaired glucose metabolism or diabetes mellitus (DM).
The aim of the present study was to examine the association of the ACE I/D polymorphism in Lebanese diabetics and controls.
| Materials and Methods|| |
A cohort of 51 patients with T2DM was recruited from the Field Hospital located at the Beirut Arab University. The patients originated from different areas of Lebanon and different religious sects. All patients had diabetes according to the World Health Organization (WHO) criteria.  The control population consisted of 40 healthy unrelated individuals at the Beirut Arab University with no family history of T2DM or other conditions.
All participants went through a detailed interview about personal disease history and smoking history. All subjects gave written informed consent before recruitment. Smokers as well as those who admitted to alcohol intake were excluded from the study. Both smoking (through a direct effect of nicotine) and alcohol (to a lesser extent) tend to increase circulating ACE levels.  Patients on ACE-inhibitor therapy as well, were not considered for enrollment [Table 1].
Clinical Traits Examined
The following traits were measured: height, body weight, HbA 1 C (for diabetics only), body mass index (BMI), fasting plasma glucose, total plasma cholesterol and plasma triglycerides, as well as the plasma ACE levels [Table 1].
DNA isolation and determination of ACE genotypes
Genomic DNA was isolated from peripheral leukocytes by a salting-out technique from 5 mL EDTA blood samples. (FlexiGene DNA kit, Qiagen).
Genotyping for ACE I/D polymorphism was performed by polymerase chain reaction (PCR) using the following flanking primer pair: forward
5'-CTG GAG ACC ACT CCC ATC CTT TCT3', reverse 5'-GAT GTG GCC ATC TTC GTC AGAT-3'. 
The PCR reaction was performed in a final volume of 25 ΅L containing 0.22 ΅g genomic DNA, 6 pmoles of each primer, 5 mM of MgCl2, 50 mM of KCl, 0.5 mM of each dNTP, 10 mM tris-HCl buffer (pH=8.3), 0.75 U of Taq polymerase, and 5% dimethylsulfoxide (DMSO). PCR was with an initial denaturation at 95°C for two minutes. Then, the DNA was amplified for 30 cycles with denaturation at 94°C for 30 seconds, annealing at 59°C for 30 seconds, and extension at 72°C for 45 seconds followed by a final extension at 72°C for nine minutes.
The PCR products were separated on a 2% ethidium bromide stained agarose gel. The DNA product was a 190 bp fragment in case of deletion (D allele), and a 490 bp fragment in the presence of insertion (I allele). Thus, there were three genotypes after electrophoresis: a 490 bp band (II), a 190 bp band (DD), or both 490 and 190 bp bands (ID) [Figure 1].
The ID heterozygotes may be mistyped as DD homozygotes due to the suppressed amplification of the I-fragment in relation to the D-fragment, although the mechanism of this suppression remains unclear. 
Thus, each sample with a genotype was submitted to a second independent PCR amplification using the insertion-specific primer pair: forward 5'-TGG GAC CAC AGC GCC CGC CACTAC-3', and a reverse 5'-TCG CCA GCC CTC CCA TGC CCA TAA-3', with identical PCR conditions, except for a change of DMSO concentration to 2.5%, which was needed to reduce the appearance of non-specific bands.  The reaction yielded a 335-bp fragment in the presence of I allele and no product in case the sample was homozygote for DD [Figure 2]. Inclusion of DMSO in the PCR reaction mixture improved the accuracy of ACE genotyping both when using I/D flanking primers and when an insertion-specific primer was employed. 
Plasma ACE Measurement
Plasma ACE concentration was measured by a quantitative sandwich enzyme immunoassay technique (Quantikine; Human ACE Immunoassay, R&D Systems).
| Statistical Analysis|| |
Data are given as the mean (SD). All statistical analyses were performed using the SPSS for Windows™, version 16.0. Genotype and allele frequencies in patient and control groups were calculated by direct counting. The association of the DD genotype and D-allele with T2DM was assessed by calculating the odds ratio (OR) and 95% confidence interval (95% CI). The statistical difference in genotype distribution and allele frequencies among the groups was assessed by the chi-square and Fisher's exact tests [Table 2]. The statistical significance of the traits and values between genotypes (D/D vs I/D or I/D vs I/I) were compared using one-way ANOVA.
| Results|| |
The distribution of ACE I/D polymorphism in the study group are shown in [Table 2]. The frequencies of ACE DD, ID and II genotypes among T2DM patients were 29.4%, 47.1 %, and 23.5 % respectively. The percentage of the D-allele was 52.9 % and of the I-allele was 47.1% in T2DM patients. In control subjects, the distribution of the ACE DD, ID, and II genotypes was 40%, 32.5%, and 27.5% respectively. The allele frequencies was 56.3% and 43.8% for the D and I alleles, respectively.
The difference of the DD genotype frequency between patients and controls was not statistically significant; 29.4% for patients and 40% for controls (OR= 0.6, 95% CI= 0.3-1.5, P= 0.4) [Table 3]. Similarly, the difference of the D-allele frequencies between patients and controls was also not significant; 52.9% for patients and 56.3% for controls (OR= 0.9, 95% CI= 0.5-1.6, P= 0.7). The diabetic D-allele carriers tended to have a significantly higher fasting plasma glucose levels compared to II subjects. [II (94 (19.1) mg/dL vs. ID 260.5 mg/ dL (118.7), P= 0.000052; II (94 (19.1) mg/dL) vs DD 245.9 (109.4) mg/dL, P=0.00061)].
The clinical traits related to diabetes (fasting plasma glucose and HbA 1 C), obesity, and dyslipidemia were measured. Results are summarized in [Table 1]. None of these traits, namely obesity, HbA 1 C, and lipid profile were different among the groups. ACE activity was significantly higher in patients [177.3 (66.3) ng/dL] than in controls [128 (59.8) ng/dL] (P< 0.001). ACE activity was significantly higher in DD and ID diabetics (DD vs II, P= 0.0002; ID vs II, P= 0.01). In controls, the DD genotype showed a significantly higher ACE activity than both ID and II genotypes (DD vs ID, P= 0.04, DD vs II, P= 0.002).
| Discussion|| |
T2DM is a chronic condition with major complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases. Epidemiological, twin and family studies have suggested the importance of genetic susceptibility in the development and progression of T2DM. There is a high concordance rate of almost 100% in monozygotic twins,  twotimes risk of developing diabetes in case of positive history in a first degree relative, and 80% risk in case an individual is born to two diabetic parents. 
We examined ACE gene polymorphism, one of the important genes in the RAS, in diabetic patients and healthy control individuals in Lebanon. The frequency of the DD genotype was not significantly different among T2DM patients (P= 0.4). The frequency of the D-allele as well, showed no statistical difference between patients and controls (P= 0.7).
Since the I/D polymorphism is associated with overall plasma ACE concentration, ACE might be considered a risk factor for development of T2DM and its complications. ,, Although this polymorphism is in the intronic region of the gene, studies have shown that the DD genotype is strongly associated with increased plasma or serum ACE levels,  thus predisposing individuals to T2DM and its complications. 
The frequency of the ACE D-allele among the control group in our study was 56.25%, which is not different from reports from earlier studies in the Lebanese population.  Furthermore, previous reports have shown a strong association between the D-allele and T2DM itself, rather than just related complications. Findings in Caucasians suggest that the Dallele may cluster in families at risk of T2DM, where the odds ratio for a family history was approximately 50% in DD subjects than in its there subjects. 
A Japanese population-based cross-sectional study reported that more individuals with DD (8.7%, P= 0.008) and ID (4.1%, P= 0.032) were diabetic than those with II (2.8%), and that the D-allele is a risk factor for DM and impaired glucose tolerance (IGT). 
Reports from the Middle Eastern populations including Turkey  and Iran  also supported this association. Data from the Turkish study have shown that T2DM patients without diabetic nephropathy carried the DD-genotype 1.77 times more frequently than the control subjects (P< 0.05), suggesting increased susceptibility to the disorder in the study group.  Investigation of the association of the polymorphism with metabolic syndrome in Iranian patients with T2DM showed that the frequency of the DD genotype as well as the D-allele was significantly increased in diabetic patients in comparison to the control group (P< 0 . 001). 
In contrast to the numerous studies reporting positive disease association, results obtained from this study showed no significant association between the D-allele and T2DM in the Lebanese population. Thus, the D-allele cannot thus far, be considered a risk factor for development of T2DM. These results are in agreement with another study in ethnic South Asians, where neither the DD-genotype nor the variant alleles were consistently associated with the presence of DM. 
In a population-based cross-sectional study in south London, no significant association between I/D polymorphism and impaired glucose metabolism in three different ethnic groups was found: whites, subjects of African descent, and subjects of south Asian descent. 
Moreover, and in accordance with our results, large genome-wide scans have so far failed to implicate the ACE gene as a risk factor for DM.  It has been previously reported that an I/D polymorphism of the ACE gene contributes to the variation of the serum ACE level.  Genetic polymorphism accounts for 44% of the variance in circulating ACE activity in Caucasians. ,, Our results show that ACE DD and ID genotypes were significantly associated with higher plasma ACE levels in patients (DD vs II, P= 0.000187; ID vs II, P= 0.00939). In the control group, the DD subjects were associated with significantly higher plasma ACE activity (DD vs II, P= 0.0369; DD vs II, P= 0.0015). Several studies have repeatedly confirmed that ACE DD genotype is associated with higher circulating and cellular ACE activities. ,,
In conclusion, the presence of a relationship between ACE I/D polymorphism and the occurrence of T2DM in the population is, so far, unlikely, thus distinguishing the Lebanese type2 diabetics from Caucasians and other regional populations. It is recommended that further studies should be conducted on larger study populations collected from different geographical regions within Lebanon to further assess ACE I/D polymorphism as a risk factor for development of T2DM. In addition, the results of such studies should be compared with those obtained from studies conducted in other Middle Eastern countries.
| References|| |
|1.||Davis GK, Roberts DH. Molecular genetics of the reninangiotensin system: Implications for angiotensin II receptor blockage. Pharmacol Ther 1997;75:43-50. [PUBMED] [FULLTEXT] |
|2.||Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Invest Drugs 2002;3:569-77. |
|3.||Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK. Angiotensin II sti-mulation of NAD(P)H oxidase activity: Upstream mediators. Circ Res 2002;91:406-13. [PUBMED] [FULLTEXT] |
|4.||Freeman D, Norrie J, Caslake M, et al. Creactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002. |
|5.||Malik RA. Can diabetic neuropathy be prevented by angiotensin-converting enzyme inhibitors? Ann Med 2000;32:1-5. [PUBMED] |
|6.||Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353: 611-6. [PUBMED] [FULLTEXT] |
|7.||Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B. Ramipril and the development of diabetes. JAMA 2001; 286:1882-5. |
|8.||Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. |
|9.||Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibition in progressive renal insufficiency study group. N Engl J Med 1996;334:939-45. |
|10.||Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene. Nucleic Acids Res 1992;201433. |
|11.||Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, Schunkert H. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995;92:1387-8. |
|12.||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. [PUBMED] [FULLTEXT] |
|13.||Ruiz J, Blanche H, Cohen N, et al. Insertion/ deletion polymorphism of the angiotensinconverting enzyme gene is strongly associated with coronary heart disease in non-insulindependent diabetes mellitus. Proc Natl Acad Sci USA 1994;91:3662-5. |
|14.||Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene fpr angiotensinconverting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-4. [PUBMED] [FULLTEXT] |
|15.||Fujisawa T, Ikegami H, Shen GO, et al. Angiotensin-I converting enzyme polymorphism is associated with myocardial infarction, but not with retinopathy or nephropathy, in NIDDM. Diabetes Care 1995;18:983-5. |
|16.||Taniwaki H, Kawagishi T, Emoto M, et al. Association of ACE gene polymorphism with arterial stiffness in patients with type 2 diabetes. Diabetes Care 1999;22:1858-64. [PUBMED] [FULLTEXT] |
|17.||Daimon M, Oizumi T, Saitoh T, 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. [PUBMED] [FULLTEXT] |
|18.||Nakajima S, Baba T, Yajima Y, Is Ace gene polymorphism a useful marker for diabetic albuminuria in Japanese NIDDM patients? Diabetes Care 1996;19:1420-2. |
|19.||Marre M, Bernadet P, Gallois Y, et al. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes 1994;43:84-8. |
|20.||Dudley CR, Keavney B, Stratton IM, Turner RC, Ratcliffe PJ. UK prospective study XV: relationship of rennin-angiotensin system gene polymorphism with micralbuminuria in NIDDM. Kidney Int 1995;48:1907-11. |
|21.||Jeffers BW, Estacio RO, Raynolds MV, Schrier RW. Angiotensin-converting enzyme gene polymorphism in non-insulin-dependent diabetes mellitus and its relationship with diabetic nephropathy. Kidney Int 1997;52:473-7. [PUBMED] |
|22.||Dragovic T, Minshall R, Jackman HL, Wang LX, Erdos EG. Kininase II-type enzymes; their positive role in muscle energy metabolism. Diabetes 1996;45:S35-7. |
|23.||Dietze G, Wicklmayr M, Bottger I, Schifmann R, Geiger R, Fritz H, Mehenert H. The kallikreinkinin system and muscle metabolism: biochemical aspects. Agents Actions 1981;10:334-43. |
|24.||Henrisken EJ, Jacob S. Effect of captopril on glucose transport activity in skeletal muscle of obese Zuker rats. Metabolism 1995;44:267-72. |
|25.||Jonsson JR, Game PA, Head RJ, Frewin DB. The expression and localization of the angiotensin-converting enzyme mRNA in human adipose tissue. Blood Press 1994;3:72-5. [PUBMED] |
|26.||Goldman J, Pfister D, Vukmirovich R. Potentiation of insulin stimulation of hexose transport by kallikrein and bradykinin in isolated rat adipocytes. Mol Cell Endocrinol 1987;50:183-91. [PUBMED] [FULLTEXT] |
|27.||Hennes MM, O'Shaughnessy IM, Kelly TM, LaBelle P, Egan BM, Kissebah AH. Insulinresistant lipolysis in abdominally obese hypertensive individuals: role of the renin-angiotensin system. Hypertension 1996;28:120-6. [PUBMED] [FULLTEXT] |
|28.||Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF Consultation 2006. |
|29.||Frossard P, Lestingent G, Obineche E, Hill S. The Angiotensin-Converting Enzyme (ACE) Gene Insertion/ Deletion Dimorphism Tracks with Higher Serum ACE Activities in Both Younger and Older Subjects. Ann Saudi Med 1998;18(5):389-92. |
|30.||Shanmugam V, Sell KW, Saha BK. Mistyping of ACE heterozygotes. PCR Met Appl 1993; 3:120-1. |
|31.||Fogarty DG, Maxwell AP, Doherty CC, Hughes AE, Nevin NC. ACE gene typing. Lancet 1994;343:851. [PUBMED] [FULLTEXT] |
|32.||Odawara M, Matsunuma A, Yamashita K. Mistyping frequency of the angiotensin-converting enzyme gene polymorphism and an improved method for its avoidance. Hum Genet 1997;100:163-6. [PUBMED] [FULLTEXT] |
|33.||Hitman GA. McCarthy MI. Genetics of noninsulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab 1991;5:455-76. |
|34.||Hsieh MC, Lin SR, Hsieh TJ, et al. Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan. Nephrol Dial Transplant 2000;15: 1008-13. [PUBMED] [FULLTEXT] |
|35.||Reaven GM. Banting Lecture. Role of insulin resistance in human disease. Diabetes 1988; 37:1595-607. |
|36.||Zimmet PZ. Kelly West Lecture 1991. Challenges in diabetes epidemiology-from West to the rest. Diabetes Care 1992;15:232-52. |
|37.||Hansen BC. The metabolic syndrome X. Ann N Y Acad Sci 1999;18:1-24. |
|38.||Pasha MA, Khan AP, Kumar R, et al. Variations in angiotensin-converting enzyme gene insertion/deletion polymorphism in Indian populations of different ethnic origins. J Bioscience 2002;27:67-70. |
|39.||Stephens JW, Dhamrait SS, Cooper JA, et al. 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. [PUBMED] [FULLTEXT] |
|40.||Sabbagh A, Otrock Z, Mahfoud Z, Zaatari G, Mahfouz R. Angiotensin-converting enzyme gene polymorphism and allele frequencies in the lebanese population: prevalence and review of the literature. Mol Biol Rep 2007;34:47-52. |
|41.||Ergen H, Hatemi H, Agachan B, Camlica H, Isbir T. Angiotensin-I converting enzyme gene polymorphism in Turkish type 2 diabetic patients. Exp Mol Med 2004;36:345-50. [PUBMED] [FULLTEXT] |
|42.||Nikzamir A, Nakhjavani M, Golmohamadi T, Dibai L. Association of Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism with Metabolic Syndrome in Iranians with Type 2 Diabetes Mellitus. Arch Iranian Med 2008;11:3-9. |
|43.||Van Valkengoed I, Stronks K, Hahntow I, Hoekstra J, 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:e12-4. |
|44.||Sagnella GA, Rothwell MJ, Onipinla AL, Wicks PD, Cook DG, Cappuccio FP. A population study of ethnic variations in the angiotensinconverting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism. J Hypertens 1999; 17:657-64. |
|45.||Frayling TM, McCarthy MI. Genetic studies of diabetes following the advent of the genomewide association study: where do we go from here? Diabetologia 2007;50:2229-33. [PUBMED] [FULLTEXT] |
|46.||Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992;51:197-205. [PUBMED] [FULLTEXT] |
|47.||Chiang FT, Lai ZP, Chern TH, Tseng CD, Hsu KL, Lo HM. Lack of association of the angiotensin converting enzyme polymorphism with essential hypertension in a Chinese population. Am J Hypertens 1997;10:197-201. |
|48.||Engeli S, Gorzelniak K, Kreutz R, Runkel N, Distler A, Sharma AM. Coexpression of reninangiotensin system genes in human adipose tissue. J Hypertens 1999;17:555-60. [PUBMED] [FULLTEXT] |
|49.||Phillips M, Speakman E, Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin system. Regul Pept 1993; 434:1-20. |
|50.||Velasquez M, Bhathena S, Striffler J, Thibault N, Scalbert E. Role of angiotensin-converting enzyme inhibition in glucose metabolism and renal injury in diabetes. Metabolism 1998;47 (12 suppl 1):7-11. |
|51.||Gunes HV, Ata N, Degirmenci I, et al. Frequency of angiotensin-converting enzyme gene polymorphism in Turkish hypertensive patients. Int J Clin Pract 2004;58:838-43. [PUBMED] [FULLTEXT] |
Basic Sciences Department, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard - Health Affairs, Riyadh
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||ACE I/D and MTHFR C677T polymorphisms are significantly associated with type 2 diabetes in Arab ethnicity: A meta-analysis
| ||Al-Rubeaan, K. and Siddiqui, K. and Saeb, A.T.M. and Nazir, N. and Al-Naqeb, D. and Al-Qasim, S. |
| ||Gene. 2013; 520(2): 166-177 |
||Association of angiotensin converting enzyme gene (I/D) polymorphism with hypertension and type 2 diabetes
| ||Zarouk, W.A. and Hussein, I.R. and Esmaeil, N.N. and Raslan, H.M. and Reheim, H.A.A. and Moguib, O. and Emara, N.A. and Aly A.A. and Hamed, M. |
| ||Bratislava Medical Journal. 2012; 113(1): 14-18 |
||Chromosome 15q21-22-related polymorphisms and haplotypes are associated with susceptibility to type-2 diabetic nonproliferative retinopathy
| ||Hsieh, Y.-Y. and Huang, Y.-C. and Chang, C.-C. and Wang, Y.-K. and Lin, W.-H. and Tsai, F.-J. |
| ||Genetic Testing and Molecular Biomarkers. 2012; 16(5): 442-448 |
||The relationship of ACE and CETP gene polymorphisms with cardiovascular disease in a cohort of Asian Indian patients with and those without type 2 diabetes
| ||Ganesan, M. and Bhaskar, S. and Mani, R. and Idris, M.M. and Khaja, N. and Gulla, S. and Kumar, U. and Moova, S. and Vattam, K.K. and Eppa, K. and Hasan, Q. and Pulakurthy, U.R. |
| ||Journal of Diabetes and its Complications. 2011; 25(5): 303-308 |
||Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: A snapshot review
| ||Gard, P.R. |
| ||International Journal of Molecular Epidemiology and Genetics. 2010; 1(2): 145-157 |
||Angiotensin converting enzyme D allele is associated with an increased risk of type 2 diabetes: Evidence from a meta-analysis
| ||Niu, W. and Qi, Y. and Gao, P. and Zhu, D. |
| ||Endocrine Journal. 2010; 57(5): 431-438 |
| Article Access Statistics|
| Viewed||3703 |
| Printed||77 |
| Emailed||0 |
| PDF Downloaded||656 |
| Comments ||[Add] |
| Cited by others ||6 |