|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
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|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 2019 Dec 5];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.
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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]
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