Association of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism with the Risk of Atherosclerosis
Introduction
Atherosclerosis (AS) is one of the most common leading causes of morbidity and mortality among cardiovascular disease around the world.1 AS is deemed as a series of vascular alterations ranging from endothelial dysfunction to overt carotid, coronary, cerebral, or peripheral arterial disease, eventually leading to myocardial ischemia and infarction.2 As a complex multifactorial disease, the pathophysiological process of AS involves a large number of biological pathways such as lipid metabolism, endothelial dysfunction, and inflammation.3, 4 Although the precise etiology of AS remains unclear, this complex disease has been generally recognized to correlate significantly with genetic factors.5, 6 Genome-wide association studies have found that single nucleotide polymorphisms in several genes, such as renin-angiotensin-aldosterone system (RAAS) and apolipoprotein (apo)E-CI-CII cluster gene, are closely implicated to be associated with AS risk or the marker of AS.7, 8
Belonging to the crucial component of the RAAS, angiotensin I-converting enzyme (ACE) plays a central role in the production of aldosterone-stimulating peptide angiotensin II (Ang II) in endothelial cells of normal vessels.9, 10 Circulating ACE levels are demonstrated to correlate with polymorphism of the ACE gene.11 As a most common functional polymorphism of this gene, the insertion/deletion (I/D) polymorphism would influence the level of ACE, subsequently resulting in the alteration of the Ang II plasma level.12 Overproduction of Ang II due to the mutation of D allele may lead to the remodeling of the vascular tissue and augmentation of the atherosclerotic process.13 Recently, several studies have shown the close linkage between ACE I/D polymorphism and AS; however, the results are inconsistent and inconclusive.14, 15, 16 Furthermore, most of those studies have also revealed that the copy number of the D allele varied among different populations; but to date, whether such ethnic or racial discrepancies alter this association between allelic ACE gene and AS is still unclear.16, 17
Therefore, we conducted a meta-analysis of the currently available studies to evaluate the association between ACE I/D polymorphism and AS risk. Moreover, subgroup analyses were performed to explore associations with discrepancies in different populations.
Section snippets
Search Strategy
We performed a systematic search of the MEDLINE, EMBASE, and ISI Web of Science databases up to March 2018 using the following keywords: (“angiotensin converting enzyme” or “ACE” or “peptidyl-dipeptidase A” or “genetic polymorphism” or genetic variation”) and (“atherosis” or atherosclerosis” or “arteriosclerosis” or “atherosclerotic plague” or “atheroma” or “intima-media thickness” or “AS” or “atherogenesis”or “atherosclerotic plague” or “artery disease” or “arterial lipoidosis”). Language
Study Selection and Characteristics
In total, we preliminarily identified 1444 citations from the initial database search based on our criteria, and 1307 remained after removal of duplicate references. Through screening of titles and abstracts, 98 articles were estimated as potentially relevant. Finally, 15 articles including 16 studies with a total of 2808 AS cases and 3316 controls were included in the present meta-analysis (Fig 1).14, 15, 16, 17,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34
The baseline characteristics of all
Discussion
We conducted a meta-analysis to evaluate the potential association between ACE I/D polymorphism and AS based on available data from original published studies. The pooled result from this study showed that the allele of the ACE gene was associated with the increased risk of AS, especially in Europeans. Additionally, frequencies of this mutation in Europeans were higher than those in Asians, and individuals with homozygotes would be more susceptible to AS than heterozygous subjects, indicating
Conflict of Interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
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Financial Support: This study was partially supported by grants from the New-star Plan of Science and Technology of Shaanxi Province (2015LJXX-07); the China Postdoctoral Science Special Foundation (2015T81036); the Fundamental Research Funds for the Central Universities (qngz2016004); and the China Postdoctoral Science Foundation Funded Project (2014M560790).
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These authors contributed equally to this work.