ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus

Pan, Yan-Hong; Wang, Min; Huang, Yan-Mei; Wang, Ying-Hui; Chen, Yin-Ling; Geng, Li-Jun; Zhang, Xiao-Xi; Zhao, Hai-Lu

doi:https://doi.org/10.1155/2016/7420540

Disease Markers

On this page

Abstract Introduction Methods Results Discussion Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2016 | Article ID 7420540 | https://doi.org/10.1155/2016/7420540

ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus

Yan-Hong Pan,^1,2,3Min Wang,^1,2Yan-Mei Huang,^1,2,3Ying-Hui Wang,^1,2,3Yin-Ling Chen,^1,2,3Li-Jun Geng,^1,2,3Xiao-Xi Zhang,^1,2and Hai-Lu Zhao^1,2,3

Academic Editor: Donald H. Chace

Received18 Aug 2016

Revised14 Nov 2016

Accepted04 Dec 2016

Published26 Dec 2016

Abstract

Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m² and subjects were classified into 4 groups (lean, normal, overweight, and obese). PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes (DD, ID, and II) were not significant among the 4 groups of BMI-defined patients () while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) (all ). Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.

1. Introduction

Angiotensin converting enzyme (ACE), a key enzyme in the renin angiotensin system (RAS), can convert angiotensin I (Ang I) into vasoconstrictor molecule angiotensin II (Ang II) [1]. Body fat and body weight could be raised and lowered accordingly by stimulating and inhibiting the production of Ang II, suggesting a possible link between ACE and obesity [2]. In 1990, Rigat B firstly described the polymorphism of ACE gene characterized by the presence (I) or absence (D) of a 287 bp Alu repeat sequence within intron 16 [3]. It was pointed out that ACE gene I/D polymorphism is involved in blood pressure (BP) and body fatness [4–6]. Thereafter, numerous studies focused on the association between ACE gene I/D polymorphism and hypertension [7, 8]. However, large samples of epidemiological studies that focus on the relationship of ACE gene I/D polymorphism and obesity are lacking. Body mass index (BMI) is recommended as a crucial indicator for obesity definition based on the WHO guidelines [9]. Thus, we have conducted a cross-sectional study to identify the association between obesity and ACE gene I/D polymorphism in Chinese patients with type 2 diabetes mellitus (T2DM).

2. Methods

2.1. Subjects and Ethics

All the subjects were newly diagnosed T2DM patients between January 2012 and June 2015 from the teaching hospitals of Guilin Medical University. A study’s power calculation using the ratio of obesity and hypertension was done separately at the beginning of our work. By applying the sample estimate formula, we found that a sample size between 90 and 140 indicates a proper evaluation of the validity of the findings; thus, our participants (1,574 patients) were validated. And none of the patients recruited in the study were under antidiabetes and antihypertensive medications. The patients signed informed consent and an ethical approval was obtained from the institutional clinical research review committee. The diagnosis of T2DM was based upon the American Diabetes Association (ADA) criteria [10].

2.2. Metabolic Measurements

The metabolic variables included the definition of obesity (BMI and waist-to-hip ratio (WHR)), blood glucose (fasting plasma glucose (FPG) and glycated hemoglobin ()), lipid profile (total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)), and blood pressure (systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP)).

2.3. Data Collection and Laboratory Tests

Clinical data including age, sex, body weight, height, waist and hip circumference, and BP were collected for analysis. BMI was calculated according to the following formula: BMI = body weight (in kilograms)/square of the height (in meters). Patients were divided into four groups following the standard of adults’ BMI of Asian populations [11, 12]. WHR was calculated with waist circumference and hip circumference: WHR = waist/hip circumference (cm). Clinical data (FPG, , TC, TG, LDL-C, and HDL-C) were obtained by laboratory tests. Clinical and biochemical data were acquired as described previously [13]: an automated ion-exchange chromatographic method was used to measure (reference range: 5.1–6.4%; Bio-Rad, Hercules, CA). Coefficient of variation (CV) between interassay and intra-assay cases for was ≤ 3.1% at values < 6.5%. Enzymatic methods were used to detect TC, TG, and HDL-C measurements on the Hitachi 911 automated analyzer. Friedewald’s formula for triglyceride levels < 4.5 mmol/L was used to calculate LDL-C [14]. Both proper procedures and recommendations were used to measure resting BP as standard. We used the means of three sitting blood pressure readings taken one minute apart after 5 to 10 minutes of rest, using a digital blood pressure monitor [15]. Hypertension was defined according to a report of the expert committee on the diagnosis and classification of T2DM [16], SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg. MAP = (SBP + 2 × DBP)/3 (mmHg), and PP = SBP − DBP (mmHg).

2.4. Genetic Analysis

Genotyping for the ACE gene I/D polymorphism was performed using a PCR method as previously described [17]. The presence of II genotype produces a 490 bp fragment while in DD genotype a 190 bp fragment was confirmed, and the presence of both 490 and 190 bp fragments implied ID genotype.

2.5. Statistical Analysis

All data were expressed as means ± standard deviation [SD], frequency, or percentage, as appropriate. Hardy-Weinberg equilibrium was calculated using the gene-counting method and difference was assessed by Chi square () test. For continuous variables in normal distribution, one-way ANOVA was used to evaluate the difference among groups. All data were assessed using the PASW Statistics software 18.0 (SPSS Inc., Chicago, IL, USA). A two-tailed was considered to be statistically significant.

3. Results

A total of 1,574 patients were enrolled in this research. Of these newly diagnosed patients, 40.53% were male, 35.13% were hypertensive, and 27.06% were obese. Frequencies of ACE gene I/D polymorphism were in Hardy-Weinberg equilibrium, indicating a homogeneous and representative sample population. Frequencies of I and D alleles were 67.25% and 32.75%, respectively. The genotype frequencies were 11.18% for ID, 43.14% for II, and 45.68% for DD accordingly.

3.1. The Distribution of ACE Gene Polymorphism according to BMI Multiclassification in T2DM Population

Table 1 shows genotypes and alleles distribution of ACE gene I/D polymorphism in T2DM patients according to BMI categories. Association between the ACE polymorphism and the BMI-defined overweight and obesity was insignificant based on our analysis.

3.2. The Distribution of Hypertension according to BMI Multiclassification in T2DM Population

An association between hypertension and BMI was identified in our study (Table 2). The patients with higher BMI occupied higher proportion of hypertension (15.52, 35.66, 40.86, and 41.25% for lean, normal, overweight, and obese, resp.).

3.3. The Distribution of Hypertension and ACE Gene Polymorphism in T2DM Population

The relationships between ACE genotypes and hypertension and between ACE gene alleles and hypertension were demonstrated in Tables 3 and 4 and negative outcomes were found. The proportion of I allele in hypertension was higher than the D allele though it has no statistical significance.

3.4. Clinical and Biochemical Characteristics of BMI Multiclassification and ACE Gene I/D Polymorphism

Tables 5 and 6 summarize the clinical and biochemical profiles of patients according to BMI categories and ACE genotypes. Compared with the normal BMI group, obesity and overweight patients tended to have higher WHR, FPG, , TC, TG, LDL-C, SBP, DBP, and MAP values, but lower HDL-C level. Interestingly, ACE gene II carriers showed higher SBP and PP compared to DD and ID carriers in these Chinese T2DM subjects.

4. Discussion

To the best of our knowledge, this is the first large-scale epidemiological study to explore the relationship of ACE gene I/D polymorphism with obesity in Chinese patients with T2DM. Additionally, associations between the ACE gene I/D polymorphism and hypertension were analyzed. We found that there was no statistical significance in the relationship of ACE gene I/D polymorphism with BMI-based obesity, whereas ACE II carriers showed higher SBP and PP than those of DD and ID carriers.

It is increasingly recognized that obesity has been identified as a key risk factor for hypertension [18], dyslipidemia [19], and T2DM [20, 21]. However, it is still unclear whether there are complex interactions between genetic predisposition and environmental factors in the development of obesity. BMI has been considered as the key indicator in the identification of overweight and obesity, and increasing evidence of body fat composition, especially abdominal adipose tissue and ectopic fat deposition, was set [5, 22]. So, we explored the relationship between ACE gene I/D polymorphism and obesity based on BMI multiclassification. According to our findings, the relationship of ACE gene I/D polymorphism with BMI-defined obesity is insignificant in Chinese patients with T2DM; the obese group obtained higher ratio of hypertension. Furthermore, we also strengthened the fact that BMI is associated with hyperglycemia, hypertension, and dyslipidemia in T2DM patients [23, 24].

In addition, our results indicated that the ACE II carriers had higher SBP and PP than those of DD and ID carriers; this was a novel finding which was not reported in adults. In accordance with our results, one prior research reported that children carrying the II genotype were demonstrated to have higher BP and greater early growth acceleration compared to those with the other ACE genotypes [25]. Conversely, another study identified significantly higher SBP and MAP among those overfat D allele carrier subjects, compared to the normal fat D allele carriers and normal fat II subjects [26]. Besides, they also pointed out DD carriers with heavier BMI than those II individuals [26]. Other perspectives hold that ACE genotypes were not linked to BMI and obesity [27–29]. The controversies may be attributed to clinical characteristics of enrolled subjects, such as patients’ age, racial difference, and sample size. Our large sample sizes gained a more credible result undoubtedly in Asians. Based on our results, there is a trend in favor of the insignificant relationship between BMI and ACE gene I/D polymorphism, and this equivocal outcome may account for the different BMI cut-off points adopted by researchers to define overweight and obesity. The polled results implied that the physiological environment and internal metabolism played a key role in the development of obesity and hypertension in T2DM [21].

Study Limitations. One limitation in our research was that we mainly focused on a polymorphism point. It is well known that obesity and T2DM are polygenic disorders and have a multifactorial influence, as evidenced by the various disease outcomes modulated by the gene-gene and gene-environment interactions, and thus a combination of other gene polymorphisms was considerable. It is also worth pointing out that our analysis was a transversal and monocenter research in the study design. Further longitudinal studies need to be performed to strengthen our result.

In conclusion, SBP and PP might be higher in the ACE II carriers than those in DD and ID carriers. The relationship of ACE gene I/D polymorphism with obesity was insignificant in Chinese patients with T2DM.

Competing Interests

The authors declare that no competing interests exist.

Authors’ Contributions

Dr. Hai-lu Zhao designed the study. Yan-hong Pan prepared the manuscript. Min Wang and Yan-mei Huang directed all the data analyses with assistance from coauthors. Ying-hui Wang and Yin-ling Chen performed all laboratory work at the Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University. Dr. Xiao-xi Zhang and Li-jun Geng provided endless support in recruiting volunteers at the Affiliated Hospital of Guilin Medical University.

Acknowledgments

This study is partly supported by grants from the National Natural Science Foundation of China (81270934). The authors gratefully acknowledge all the participants for their support. The authors gratefully acknowledge all the enrolled patients and other medical professionals who contributed substantially to this cooperative study. They would also like to thank Dr. Qiwen Liao for her English proofing.

References

Y. Okamoto, S. Kihara, N. Ouchi et al., “Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice,” Circulation, vol. 106, no. 22, pp. 2767–2770, 2002.
View at: Publisher Site | Google Scholar
B. H. Jones, M. K. Standridge, and N. Moustaid, “Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells,” Endocrinology, vol. 138, no. 4, pp. 1512–1519, 1997.
View at: Publisher Site | Google Scholar
B. Rigat, C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol, and F. Soubrier, “An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels,” Journal of Clinical Investigation, vol. 86, no. 4, pp. 1343–1346, 1990.
View at: Publisher Site | Google Scholar
P. S. Leung and P.-O. Carlsson, “Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus,” Pancreas, vol. 30, no. 4, pp. 293–298, 2005.
View at: Publisher Site | Google Scholar
M. L. Mathai, N. Chen, L. Cornall, and R. S. Weisinger, “The role of angiotensin in obesity and metabolic disease,” Endocrine, Metabolic and Immune Disorders—Drug Targets, vol. 11, no. 3, pp. 198–205, 2011.
View at: Publisher Site | Google Scholar
F. Massiera, J. Seydoux, A. Geloen et al., “Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity,” Endocrinology, vol. 142, no. 12, pp. 5220–5225, 2001.
View at: Publisher Site | Google Scholar
K. Kim, “Association of angiotensin-converting enzyme insertion/deletion polymorphism with obesity, cardiovascular risk factors and exercise-mediated changes in Korean women,” European Journal of Applied Physiology, vol. 105, no. 6, pp. 879–887, 2009.
View at: Publisher Site | Google Scholar
P. Fernández-Llama, E. Poch, J. Oriola et al., “Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis,” Kidney International, vol. 53, no. 6, pp. 1743–1747, 1998.
View at: Publisher Site | Google Scholar
E. Anuurad, K. Shiwaku, A. Nogi et al., “The new BMI criteria for asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder japanese workers,” Journal of Occupational Health, vol. 45, no. 6, pp. 335–343, 2003.
View at: Publisher Site | Google Scholar
American Diabetes Association, “Standards of Medical Care in Diabetes—2010,” Diabetes Care, vol. 33, S1, pp. S11–S61, 2010.
View at: Publisher Site | Google Scholar
“Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies,” The Lancet, vol. 363, no. 9403, pp. 157–163, 2004.
View at: Publisher Site | Google Scholar
R. G. Kathrotia, S. J. Paralikar, P. V. Rao, and E. R. Oommen, “Impact of different grades of body mass index on left ventricular structure and function,” Indian Journal of Physiology and Pharmacology, vol. 54, no. 2, pp. 149–156, 2010.
View at: Google Scholar
G. N. Thomas, B. Tomlinson, J. C. N. Chan, J. E. Sanderson, C. S. Cockram, and J. A. J. H. Critchley, “Renin-angiotensin system gene polymorphisms, blood pressure, dyslipidemia, and diabetes in Hong Kong Chinese: a significant association of the ACE insertion/deletion polymorphism with type 2 diabetes,” Diabetes Care, vol. 24, no. 2, pp. 356–361, 2001.
View at: Publisher Site | Google Scholar
P. W. Wilson, R. D. Abbott, R. J. Garrison, and W. P. Castelli, “Estimation of very-low-density lipoprotein cholesterol from data on triglyceride concentration in plasma,” Clinical Chemistry, vol. 27, no. 12, pp. 2008–2010, 1981.
View at: Google Scholar
E. J. Roccella, “Update on the 1987 task force report on high blood pressure in children and adolescents: a working group report from the national high blood pressure education program,” Pediatrics, vol. 98, no. 4, pp. 649–658, 1996.
View at: Google Scholar
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, “Report of the expert committee on the diagnosis and classification of diabetes mellitus,” Diabetes Care, vol. 26, supplement 1, pp. S5–S20, 2003.
View at: Publisher Site | Google Scholar
F. Cambien, O. Poirier, L. Lecerf et al., “Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction,” Nature, vol. 359, no. 6396, pp. 641–644, 1992.
View at: Publisher Site | Google Scholar
G. de Simone, R. B. Devereux, M. Chinali et al., “Risk factors for arterial hypertension in adults with initial optimal blood pressure: the Strong Heart Study,” Hypertension, vol. 47, no. 2, pp. 162–167, 2006.
View at: Publisher Site | Google Scholar
B. V. Howard, G. Ruotolo, and D. C. Robbins, “Obesity and dyslipidemia,” Endocrinology and Metabolism Clinics of North America, vol. 32, no. 4, pp. 855–867, 2003.
View at: Publisher Site | Google Scholar
C. Lorenzo, M. Okoloise, K. Williams, M. P. Stern, and S. M. Haffner, “The metabolic syndrome as predictor of type 2 diabetes: the san antonio heart study,” Diabetes Care, vol. 26, no. 11, pp. 3153–3159, 2003.
View at: Publisher Site | Google Scholar
R.-N. Feng, C. Zhao, C. Wang et al., “BMI is strongly associated with hypertension, and waist circumference is strongly associated with type 2 diabetes and dyslipidemia, in Northern Chinese adults,” Journal of Epidemiology, vol. 22, no. 4, pp. 317–323, 2012.
View at: Publisher Site | Google Scholar
J. E. Hall, A. A. Da Silva, J. M. Do Carmo et al., “Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins,” Journal of Biological Chemistry, vol. 285, no. 23, pp. 17271–17276, 2010.
View at: Publisher Site | Google Scholar
K. Narkiewicz, “Diagnosis and management of hypertension in obesity,” Obesity Reviews, vol. 7, no. 2, pp. 155–162, 2006.
View at: Publisher Site | Google Scholar
S. Mehri, S. Mahjoub, S. Hammami et al., “Renin-Angiotensin system polymorphisms in relation to hypertension status and obesity in a Tunisian population,” Molecular Biology Reports, vol. 39, no. 4, pp. 4059–4065, 2012.
View at: Publisher Site | Google Scholar
J. Min, Y. J. Kim, H. Lee et al., “Is the association between ACE genes and blood pressure mediated by postnatal growth during the first 3 years?” Early Human Development, vol. 88, no. 6, pp. 425–429, 2012.
View at: Publisher Site | Google Scholar
J. C. Eisenmann, M. A. Sarzynski, K. Glenn, M. Rothschild, and K. A. Heelan, “ACE I/D genotype, adiposity, and blood pressure in children,” Cardiovascular Diabetology, vol. 8, article 14, 2009.
View at: Publisher Site | Google Scholar
R. Cooper, N. McFarlane-Anderson, F. I. Bennett et al., “ACE, angiotensinogen and obesity: a potential pathway leading to hypertension,” Journal of Human Hypertension, vol. 11, no. 2, pp. 107–111, 1997.
View at: Publisher Site | Google Scholar
A. Passaro, E. Dalla Nora, C. Marcello et al., “PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome,” Cardiovascular Diabetology, vol. 10, article 112, 2011.
View at: Publisher Site | Google Scholar
H. Alsafar, A. Hassoun, S. Almazrouei et al., “Association of angiotensin converting enzyme insertion-deletion polymorphism with hypertension in emiratis with type 2 diabetes mellitus and its interaction with obesity status,” Disease Markers, vol. 2015, Article ID 536041, 7 pages, 2015.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2016 Yan-Hong Pan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

2554

Downloads

1119

Citations