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NDT Advance Access originally published online on May 3, 2007
Nephrology Dialysis Transplantation 2007 22(9):2549-2553; doi:10.1093/ndt/gfm252
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The relationship between the insertion/deletion polymorphism of the ACE gene and hypertension in Iranian patients with type 2 diabetes

Manouchehr Nakhjavani1, Fatemeh Esfahanian1, Alireza Jahanshahi1, Alireza Esteghamati1, Abdol Rahim Nikzamir2, Armin Rashidi1 and Mahin Zahraei2

1Endocrine and Metabolism Research Center, Vali-Asr Hospital and 2Department of Biochemistry, School of Medicine, Medical Sciences, University of Tehran, Tehran, Iran

Correspondence and offprint requests to: Armin Rashidi, No 12, Aramesh Alley, Mellat Park, Tehran, Iran. Email: rasidiarmin{at}yahoo.com



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Observations on the association between the ACE gene polymorphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. Moreover, the relationship between insertion/deletion (I/D) polymorphism and hypertension in the diabetic population has not been sufficiently studied. The aim of this study was to evaluate for the first time the possible association between I/D polymorphism and hypertension in an Iranian diabetic adult population.

Methods. A total of 82 consecutive patients with type 2 diabetes and hypertension (Group A) and 87 patients with type 2 diabetes but without hypertension (Group B) were included. Patients who had a history of hypertension before the onset of diabetes and those with findings suggesting secondary hypertension were excluded. The following variables were determined for each patient: age, sex, body mass index (BMI), diabetes duration and the drugs used, history of coronary artery disease and its complications, blood pressure (systolic and diastolic), fasting blood sugar (FBS), haemoglobin A1c (HbA1c), total cholesterol (Chol), low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides (TG), plasma creatinine (Crt) and 24 h urine albumin excretion. Polymerase chain reaction (PCR) was used to detect the I/D alleles. Univariate (chi-squared and t-test) and multivariate (multivariate binary logistic regression with adjusted odds ratios) analyses were applied to determine the association between I/D polymorphism (with genotype II as reference) and hypertension. P < 0.05 was considered statistically significant.

Results. In univariate analysis, the groups were statistically similar in all variables except for diabetes duration (156.05 ± 73.54 months in Group A vs 121.74 ± 65.53 months in Group B; P = 0.002), Crt (1.04 ± 0.25 mg/dl in Group A vs 0.93 ± 0.23 mg/dl in Group B; P = 0.003), albuminuria (486.25 ± 484.60 mg/d in Group A vs 316.50 ± 459.56 mg/d in Group B; P = 0.021) and the frequency of DD genotype (27 cases in Group A vs 11 cases in Group B; P = 0.026). Multivariate logistic regression (using age, sex and BMI as clinically significant variables and diabetes duration, Crt, albuminuria and genotype as statistically significant variables) was then used to determine independent associations and adjusted odds ratios (OR). The DD genotype was the strongest independent predictor of hypertension [P = 0.029, OR = 3.122, 95% confidence interval (CI) = 1.127–8.647], followed by log (albuminuria) (P = 0.042, OR = 1.183, 95% CI = 1.006–1.391). Considering albuminuria as a categorical variable did not change the results significantly.

Conclusion. The DD polymorphism in the ACE gene is independently associated with hypertension in the diabetic population.

Keywords: albuminuria; ACE; diabetes; hypertension; polymorphism



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The pathophysiology of the association between essential hypertension and type 2 diabetes is poorly understood. Both conditions are thought to result from an interplay between multiple genetic and environmental factors [1,2]. One possible genetic determinant is the angiotensin-converting enzyme gene polymorphism, which gives three different genotypes II, ID and DD, where I and D stand for insertion and deletion, respectively [3].

Most (but not all) studies on the association of ACE gene polymorphism with type 2 diabetes have shown that the DD genotype is associated with increased risk of developing type 2 diabetes [4,5]. On the other hand, the association between I/D polymorphism and hypertension is still controversial. Some studies have proposed that the DD genotype increases the incidence of essential hypertension [6–8], while others have not found a significant association [9–12].

The authors are aware of only two case-control studies, in Swedish [13] and Turkish populations [14], that have evaluated whether I/D polymorphism alters the risk of developing hypertension in diabetic patients. However, caution should be exercised in extrapolating an association found in one population to others. The presence or absence of an observed association in any ethnic, racial or geographic population may be related to a number of other factors including gene-gene and gene-environmental interactions.

We therefore opted for the first time to elucidate the possible association between the I/D polymorphism and hypertension in an Iranian diabetic adult population. Studies of this type can confirm whether the observed associations are consistent over different ethnicities and populations.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study population
A total of 82 consecutive patients with type 2 diabetes and hypertension (Group A) and 87 patients with type 2 diabetes but without hypertension (Group B) who referred to our diabetes clinic between March 2005 and March 2006 were enrolled into the study. Patients who had a history of hypertension before the onset of diabetes and those with findings suggesting secondary hypertension such as renovascular, renal parenchymal, thyroid or adrenal diseases were excluded. All patients gave their written informed consent and the local ethics committee at Tehran University of Medical Sciences approved the study protocol.

The following variables were determined for each patient: age, sex, body mass index (BMI) according to Quetelet equation by using BMI = weight in kilograms/height in metres squared, diabetes duration and the drugs used (oral agents, insulin or both), history of coronary artery disease and its complications, blood pressure (systolic and diastolic), fasting blood sugar (FBS), haemoglobin A1c (HbA1c), total cholesterol (Chol), low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides (TG), plasma creatinine (Crt) and 24h urine albumin excretion with albuminuria defined as an albumin excretion of ≥30 mg per day. The diagnosis of diabetes was based upon the WHO criteria [15]. Blood pressure was recorded by an electronic device on the right arm in the sitting position after 5 min rest. Systolic and diastolic blood pressures were calculated from two recordings with a minimal interval of 10 min. Hypertension was defined as a mean systolic blood pressure of ≥140 mmHg, mean diastolic blood pressure of ≥90 mmHg or taking antihypertensive medications. Patients with a plasma creatinine ≥1.5 mg/dl were excluded.

ACE gene I/D polymorphism
Genomic DNA was isolated from peripheral blood leukocytes according to a standard salting out method [16]. For amplification, a flanking primer pair was used and when it was necessary, a primer pair that recognizes the insertion specific sequence was also employed for confirmation of the specificity of the amplification reactions [17–19]. PCR was performed with 20 pm of each primer (sense primer: 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3' and anti-sense primer: 5'-GAT GTG GCC ATC ACA TTC GTC AGAT-3') in a final volume of 25 µl, containing 0.5 µg genomic DNA, 2 mM MgCl2, 10 mM Tris-HCl (pH = 8.3), 0.2 mM of each dNTP and 0.5 unit of Taq polymerase. PCR was done with an initial denaturation at 94°C for l min. Then the DNA was amplified for 30 cycles with denaturation at 94°C for 30 s, annealing at 58°C for 30 s, and extension at 72°C for l min followed by final extension at 72°C for 8 min. After electrophoresis in a 2% ethidium bromide-stained agarose gel, the PCR products were visualized under UV light. In the case of the deletion (D allele) and insertion (I allele), a 190 bp fragment and a 490 bp fragment were obtained, respectively. Therefore, there will be three genotypes after electrophoresis: A 490 bp band (genotype II), a 190 bp band (genotype DD) and both 490 bp and 190 bp band (ID genotype). Mistyping of ID heterozygote as D homozygotes may occur. Thus, each sample which had the DD genotype was submitted to PCR amplification using the forward 5'-TCG GAC CAC AGC GCC CGC CAC TAC-3' and the reverse 5'-TCG CCA GCC CTC CCA TGC CCA TAA-3' primers with identical PCR conditions except for an annealing temperature of 67°C. The reaction yielded a 335 bp amplicon only in the presence of an I allele and no product when the samples were homozygous for DD.

Statistical analysis
Data were analysed with SPSS statistical program (SPSS Inc., SPSS/PC+, Chicago: Illinois, USA). Results are presented as mean ± SD. All tests were two-sided and P < 0.05 was considered statistically significant. Significance of differences between group means was tested by the Student's t-test and differences in proportions were assessed by the chi-square test. Multivariate binary logistic regression was used to determine the independent association between genotype (with the II genotype considered as reference) and hypertension. Age, sex and BMI as clinically significant variables as well as the statistically significant variables extracted from the univariate analysis were included in regression and the adjusted odds ratios were calculated. Variables with non-normal distributions were log-transformed in multivariate analysis. Associations were expressed as adjusted odds ratio (OR) with 95% confidence interval (95% CI).



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Among 169 individuals included in the study, there were 86 (50.9%) men and 83 (49.1%) women. The mean age of patients was 56.90 ± 6.50 years (range: 43–76 years) and the mean BMI was 26.50 ± 4.93 (range: 16.05–43.70). Systolic/Diastolic blood pressures were 150.19 ± 12.81/90.02 ± 9.08 and 121.55 ± 9.66/77.49 ± 5.09 mmHg in groups A and B respectively (P < 0.001). There was no significant difference between the two groups regarding age (P = 0.419), sex (P = 0.646), BMI (P = 0.421), history of coronary artery disease (P = 0.233) or CCU admission (P = 0.330), hypoglycaemic drugs used (P = 0.052), FBS (P = 0.493), HbA1c (P = 0.445), TG (P = 0.519), Chol (P = 0.614), LDL (P = 0.599) and HDL (P = 0.308) (Table 1). However, Group A suffered from diabetes significantly longer (P = 0.002, OR = 1.007, 95% CI = 1.003–1.012) and had a significantly higher Crt (P = 0.003, OR = 7.176, 95% CI = 1.865–27.603) as well as a higher degree of albuminuria (P = 0.021, OR = 1.001, 95% CI = 1.000–1.001 with albuminuria considered as a numerical variable and P = 0.003, OR = 2.591, 95% CI = 1.387–4.831 when it was considered as a categorical variable) compared with Group B.


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  		Table 1. Characteristics of the two groups

 
The DD:ID:II ratio in the whole study population, Groups A and B was 50:127:83,

27:33:22 and 11:51:25, respectively indicating that the gene is in Hardy–Weinberg equilibrium in all groups (Table 1). The distribution of genotypes among the two groups was significantly different (P = 0.005). In univariate analysis (with genotype II as reference), the DD genotype was associated with a significantly increased risk of hypertension (P = 0.026, OR = 2.789, 95% CI = 1.128–6.898), but the ID genotype did not show a significant association (P = 0.403).

Age, sex and BMI (as clinically significant variables) as well as diabetes duration, Crt, albuminuria and genotype (all according to the results of univariate analysis) were selected for multivariate analysis. Diabetes duration and albuminuria (when considered as a quantitative variable) were log-transformed to make normal distributions. In multivariate binary logistic regression (R2 = 0.220), the DD genotype was a significant and the strongest independent predictor of hypertension (P = 0.029, OR = 3.122, 95% CI = 1.127–8.647 with albuminuria considered as a numerical variable and P = 0.028, OR = 3.133, 95% CI = 1.131–8.677 when it was considered as a categorical variable). The only other variable with significant (although marginal) independent association was albuminuria (P = 0.042, OR = 1.183, 95% CI = 1.006–1.391 when considered as a numerical variable and P = 0.042, OR = 1.468, 95% CI = 1.014–2.126 when considered as a categorical variable) (Tables 2 and 3).


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  		Table 2. Comparison between the groups by regression while albuminuria is considered as a numerical variable

 

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  		Table 3. Comparison between the groups by regression while albuminuria is considered as a categorical variable

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The results of our study showed that the DD genotype is strongly associated with increased risk of hypertension in the diabetic population. The DD genotype (vs the II genotype) independently increased the risk of hypertension in diabetes 3.1-fold, while the ID genotype did not alter the risk significantly. This pattern suggests a recessive mode of inheritance in allele D of the ACE gene polymorphism, as also suggested in other studies [8].

By excluding patients with features suggesting secondary hypertension and those who had hypertension before their diabetes was diagnosed, we confined our study to diabetes-related (and possibly essential) hypertension. The pathogenesis of hypertension in diabetes is complex and involves several interrelated factors that collectively increase the propensity to develop hypertension. Multiple maladaptive pathways that involve renal sodium retention, increased sympathetic nervous system activity, vascular dysfunction and increased rennin–angiotensin–aldosterone system activity play roles in this process [20]. In our series, the diabetes-related component of hypertension was partly reflected in the independent association between albuminuria, as a measure of glomerular insult and hypertension. However, it could not explain all of the odds of developing hypertension in diabetes. A major part was actually due to the presence of the DD genotype.

Results about the association between ACE gene polymorphism and essential hypertension have been inconsistent. Some studies have proposed that the DD genotype increases the incidence of essential hypertension [6–8], while others have not found a significant association [9–12]. Ethnic as well as geographic differences might be responsible for the observed controversies. For example, a study on Caucasian and Afro-Caribbean peoples showed that ACE gene polymorphism is associated with hypertension in Afro-Caribbean but not in European descent [21].

The association between I/D polymorphism and the combination of diabetes and hypertension has not been sufficiently studied yet. A previous study on hypertensive patients showed that those with the DD genotype had a higher risk for insulin resistance than those with the long allele I of the ACE gene polymorphism [22]. The reverse approach, comparing the risk of hypertension in diabetics with the DD genotype and those with the II or ID genotypes, has been taken in two previous studies. The first study in Turkey did not show a significant association between ACE gene polymorphism and hypertension in diabetics [14]. The other study was performed in Sweden [13] and suggested that the DD genotype increases the risk of hypertension in diabetic patients.

Both diabetes and hypertension are multifactorial diseases, with many different interacting parameters existing in their pathophysiology. The only way to assess the independent role of any potential determinant in these conditions is by eliminating the potentially confounding effects of other involved parameters. One appropriate analytical method is multivariate regression. Of the two studies mentioned above, regression analysis was used only in the latter. We repeated that study with the same method in an Iranian population, inspired by the fact that an association found in one population might not be true in others. In contrast to the mentioned study, which analysed obese and non-obese patients separately, we included BMI (along with age and sex as clinically significant variables) in the covariate list of regression analysis. Although the two groups in our study were similar in sex, age and BMI, we considered these variables as potential confounders in multivariate analysis to prevent missing any significant, although subtle, confounding effects. We also included in the regression model the variables with significant associations in univariate analysis (Crt, diabetes duration, albuminuria). Our results support those obtained by Bengtsson et al. [13].

In conclusion, we showed for the first time in an Iranian diabetic population that the DD polymorphism in the ACE gene is independently associated with hypertension. Clustering of risk factors associated with insulin resistance in hypertensive diabetic patients (compared to patients with diabetes alone) has been previously suggested [23]. The results of the present study along with those obtained by Bengtsson et al. [13] support the hypothesis that patients with both hypertension and type 2 diabetes are different from those with type 2 diabetes alone. Diabetic patients with the DD genotype seem to be more prone to hypertension based on these results.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 1.10.06
Accepted in revised form: 2. 4.07


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 Journal of Renin-Angiotensin-Aldosterone SystemHome page
A. Nikzamir, A. Esteghamati, M. Feghhi, M. Nakhjavani, A. Rashidi, and Javad Zavar Reza
The insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with progression, but not development, of albuminuria in Iranian patients with type 2 diabetes
Journal of Renin-Angiotensin-Aldosterone System, June 1, 2009; 10(2): 109 - 114.
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