Original ArticleRelationship 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
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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