Original Article
Relationship between insertion/deletion (I/D) polymorphism of angiotensin converting enzyme (ACE) gene and susceptibility to type 2 diabetes mellitus in the Middle East and North Africa Region: A meta-analysis

https://doi.org/10.1016/j.dsx.2021.102386Get rights and content

Highlights

  • Susceptibility to T2DM strongly results from the interaction between environmental and genetic factors.

  • Single nucleotide polymorphism plays an important role in the susceptibility to genetic diseases.

  • Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with T2DM susceptibility in MENA region.

Abstract

Background and aims

The association between insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and the risk of type 2 diabetes mellitus (T2DM) remains controversial. This study aimed to assess the effect of the ACE I/D gene polymorphism on T2DM in the Middle East and North Africa region (MENA region).

Material and methods

Our data was extracted from PubMed, Science Direct, and the Web of Science. The predefined inclusion criteria included only the human case-control studies of English Peer-reviewed papers containing the data on genotype distributions of ACE I/D polymorphism and the T2DM risk. Review articles, meeting abstracts, editorials, animal studies, and studies not providing genotype distribution data or without sufficient data were excluded from this work. Results of this meta-analysis were expressed using odds ratios (OR) and 95% confidence intervals (CI). Indeed, the potential sources of heterogeneity and bias were examined by the Egger regression.

Results

Of 2755 identified articles, 10 studies were selected, including 2710 patients with T2DM and 2504 control subjects. Overall, we found a significant increased risk of T2DM susceptibility and the D allele of ACE I/D gene polymorphism (OR = 1.97; 95% CI = 1.33–2.93, p = 0.0007), recessive (OR = 2.16; 95% CI = 1.27–3.67; p = 0.004), dominant (OR = 2.45; 95% CI = 1.54–3.91; p = 0.0001), homozygote (OR = 3.35; 95% CI = 1.78–6.29; p = 0.0001) and heterozygote comparisons (OR = 1.76; 95% CI = 1.07–2.88; p = 0.024).

Conclusion

Our result suggests that this polymorphism may contribute to the development of T2DM in the MENA Region. This result needs to be confirmed by future well-designed studies with larger sample sizes in diverse populations and ethnicities.

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, mainly resulting from insulin resistance in combination with impaired insulin secretion, and is one of the most common multifactorial chronic metabolic diseases not only in developed countries but also in developing countries [[1], [2], [3]].

Diabetes is considered one of the leading global risk factors for death, accounting for approximately 418,900 deaths in the Middle East and North Africa Region (MENA Region) in 2019 [4]. The International Diabetes Federation estimates about 55 million adults with diabetes in MENA, 45% of whom are undiagnosed. This number is expected to increase to 108 million by 2045 [4]. In addition to enhancing the risk of premature death, diabetes is a major cause of various chronic complications, including hypertension, cardiovascular disease, nephropathy, neuropathy, retinopathy, lower limb amputations, and other metabolic disorders [5]. Moreover, the determination of the genetic factors predisposing to T2DM will permit the identification of individuals genetically predisposed to T2DM and perfect the current therapy and prevention strategies.

The number of patients with diabetes mellitus has reached more than 451 million worldwide in 2017, and this number is predicted to increase to 693 million by 2045 [6]. This increased prevalence is well known to be related to modern lifestyle factors such as unhealthy diet, overweight and obesity, sedentary lifestyle, stress, smoking, intestinal microbiota dysbiosis, and chemical exposure. In addition, there are genetic and epigenetic factors that favor the disease [[7], [8], [9]].

Various genetic polymorphisms, especially the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, have been reported to be associated with T2DM. Angiotensin-converting-enzyme not only is a key component of the renin-angiotensin system but also plays an essential function in blood pressure homeostasis by hydrolyzing angiotensin I to the vasoconstrictor peptide angiotensin II [10]. Otherwise, it has been suggested that high levels of Ang II may play a critical role in glucose and insulin regulation, and may increase the risk of diabetes [11,12]. Studying the ACE gene is supported by clinical and experimental studies showing that treatment with ACE-inhibitors prevents and reduces the progression of diabetic nephropathy and suppresses hepatic glucose production in type 2 diabetic patients [13,14].

The ACE gene is located on the long arm of the 17th chromosome in humans (17q23.3) [15]. The I/D polymorphism of the ACE gene is defined by the presence or absence of an Alu-repeat sequence of 287 base pairs in intron 16 [16]. Although the (I/D) polymorphism is in the intronic region of the ACE gene, this polymorphism is of functional significance as the ACE levels have been shown to be genetically controlled. Patients with the II genotype have the lowest ACE levels, whilst patients homozygous for the D allele (DD) have the highest levels resulting in increased activity of angiotensin II, which may predispose the individual to a variety of disorders, including T2DM [17,18].

The MENA region is made up of 20 countries located in Western Asia and stretching as far as Africa. With more than 570 million inhabitants, the region represents 20% of the world's population and it comprises more than ten different ethnic groups, the most important being the Arabs, the Turks, the Persians, and the Kurds. It shares a number of cultural, traditional, economic and environmental similarities across countries; for example, some of the most extreme impacts of climate change will be felt in the region [19].

The MENA region has undergone rapid epidemiological and demographic changes in recent decades, driven by economic development, improved sanitation, infrastructure, and urbanization, which have had a significant impact on lifestyle as well as the nutritional and health status of the populations of the region [19].

The prevalence of diabetes in this region is 12.8%, the second highest after North America and the Caribbean among all IDF regions [20]. Proprietary single nucleotide polymorphism (SNP) patterns for T2DM have been identified among Arab ethnicities. Therefore, genetics may be an important contributing factor in the MENA region [21].

Previous studies have reported that the D allele of the ACE gene is associated with an increased risk of T2DM in various populations [[22], [23], [24]]. These conflicting results could be due to differences related to ethnicity and gender. Although a great number of association studies have shown the correlation between ACE gene polymorphism and T2DM, the results still required additional support. Here we performed a meta-analysis on previous reports on ACE gene polymorphism and its association with T2DM in the Mena-region.

Section snippets

Identification of studies

In the present meta-analysis, we include publications on the association of I/D polymorphism of the ACE gene to T2DM susceptibility published up to July 2020 in the MENA region. These relevant studies were found based by searching in PubMed, Science Direct, and Web of Science using the combination of the following keywords: « Angiotensin-converting enzyme or ACE » and « polymorphism or genotype » and « Type 2 diabetes mellitus or type 2 diabetes or T2DM » and « MENA countries (Algeria, Bahrain,

Characteristics of studies

A total of 2755 references were extracted from PubMed, Science Direct, and Web of Science (Fig. 1). Ten qualifying case-control articles were included in this meta-analysis with a total of 2710 T2DM patients, including 637 males and 2073 females (mean age varied between 42.9 ± 12.5 and 59.3 ± 7.9 years) and 2504 control subjects including, 655 males and 1849 females (mean age varied between 32.2 ± 10.9 and 57.12 ± 10 years). Table 1 provide a detailed screening process. Among these studies, two

Discussion

Susceptibility to T2DM is strongly influenced by genetic factors. Many investigations have confirmed that genetic factors appear to play a critical role in the development of T2DM [37]. This study represents the first application of meta-analysis to assess the risk of T2DM in relation to the I/D polymorphism of the ACE gene in the MENA region from Bahrain, Egypt, Tunis, Iran, and Lebanon.

The present meta-analysis includes 10 studies including a total of 2710 patients with T2DM and 2504 control.

Conclusion

In summary, our meta-analysis suggests that the I/D polymorphism of the ACE gene is associated with an increased risk of T2DM in the MENA population. However, for a more in-depth assessment of the association between this polymorphism and the T2DM risk, further research is needed with larger sample sizes, performed in various ethnic populations, and exploiting also the effect of the gene-gene and gene-environment interactions.

Authors’ contributions

Houda El Alami: Conceptualization the study, designed the study, collected and analyzed data, interpreted data, prepared and reviewed manuscript for the final submission.

Lahcen Wakrim, Omar Abidi and Hassan Ghazal, Naima Khlil and Abderrahim Naamane: Reviewed the manuscript for the final submission.

Salsabil Hamdi: Conceptualization the study, designed the study, revision and validation manuscript for the final submission.

Funding

This research received no specific grant from any funding agency, commercial or not-for- profit sectors.

Availability of data materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of competing interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

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