{"id":152210,"date":"2025-11-21T16:19:07","date_gmt":"2025-11-21T16:19:07","guid":{"rendered":"https:\/\/www.newsbeep.com\/ie\/152210\/"},"modified":"2025-11-21T16:19:07","modified_gmt":"2025-11-21T16:19:07","slug":"angiotensin-converting-enzyme-insertion-deletion-genotype-rs4646994-association-with-increased-risk-of-stroke-a-case-control-study-in-eastern-iran-bmc-neurology","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/ie\/152210\/","title":{"rendered":"Angiotensin-converting enzyme insertion\/deletion genotype (rs4646994) association with increased risk of stroke: a case-control study in Eastern Iran | BMC Neurology"},"content":{"rendered":"

The IS is a multifactorial disorder with established risk factors encompassing both modifiable environmental influences and inherent genetic susceptibility. Epidemiological investigations have consistently implicated genetic determinants in modulating the risk of IS. To explore this further, the present case-control study evaluated the ACE I\/D gene polymorphism in individuals with IS and healthy control subjects within a specific region of Iran. This analysis revealed that the heterozygous ID genotype was the most prevalent in both the case and control cohorts. This observation aligns with those of a prior study conducted by Nouryazdan et al., which reported a similar ACE I\/D genotype distribution in a Western Iranian population [18<\/a>]. Furthermore, a meta-analysis encompassing data from 14,000 subjects reported the following frequency ranges for ACE I\/D genotype: II (22\u201330%), ID (45\u201350%), and DD (28\u201335%) [19<\/a>]. In the present study, analysis of the data from these populations yielded the following genotype frequencies: DD (27.7%), ID (47.1%), and II (26.2%). These observed frequencies align closely with the ranges reported by Li et al. in their meta-analysis.<\/p>\n

This research investigated the association between the ACE I\/D polymorphism and IS in an Eastern Iranian population. The findings demonstrated a higher prevalence of the ID and DD genotypes among individuals with IS, compared to the control group. Furthermore, the D allele frequency exhibited a statistically significant difference between the case and control groups (p < 0.04). In a study performed on an Indonesian population, the DD genotype frequency was reported at 23% in IS cases, compared to 17% in the healthy population [20<\/a>]. Similarly, Goyal et al.. observed a significant association between the DD genotype and stroke in an Indian population (13.8% vs. 0.8%) [21<\/a>].<\/p>\n

A research conducted by Addisu Melake et al. demonstrated that the ACE-DD genotype and the D allele were significantly more common among the patients, compared to the control subjects, with odds ratios of 3.71 (95% CI: 1.02\u201313.5, p < 0.05) and 2.07 (95% CI: 1.06\u20134.03, p < 0.05), respectively [22<\/a>]. Conversely, Tuncer et al. found no statistically significant differences between IS patients and healthy control subjects in a Turkish population regarding genotype distribution or allele frequency [23<\/a>]. A meta-analysis of 50 studies (comprising 10,070 case and 22,103 control subjects) conducted by Zhang et al. concluded that the D allele is associated with a modestly increased risk of IS, albeit with low penetrance [24<\/a>].<\/p>\n

Previous research has demonstrated that individuals possessing the II genotype exhibit lower concentrations of the ACE enzyme, compared to those with the DD genotype [11<\/a>]. Individuals carrying the D allele of the ACE gene (DD and ID genotypes) exhibited a diminished release of nitric oxide following aerobic exercise, suggesting a potential association among this genetic variation, blood pressure regulation, and endothelial function [25<\/a>]. Mechanistically, the presence of the D allele is linked to higher ACE enzymatic activity and, consequently, increased production of angiotensin II relative to the I allele [25<\/a>].<\/p>\n

Angiotensin II exerts a direct effect on renal sodium homeostasis by augmenting the activity of specific molecules, including the Na+\/H + exchanger and Na+\/K + ATPase in the proximal tubule, and modulating several ion transporters within the distal nephron and collecting tubules. Furthermore, angiotensin II stimulates the release of aldosterone from the adrenal glands, leading to enhanced reabsorption of sodium and water in renal epithelial cells. This physiological cascade results in an expansion of blood volume and an elevation in blood pressure, potentially contributing to the development of hypertension [26<\/a>].<\/p>\n

Angiotensin II is a potent activator of multiple intracellular signaling pathways, including the mitogen-activated protein kinase cascade, the phosphoinositide 3-kinase\/AKT pathway, and cAMP-dependent protein kinase signaling. These pathways play critical roles in the regulation of cell growth, differentiation, cytoskeletal reorganization, and cell cycle progression [27<\/a>]. Furthermore, increased ACE expression in macrophages and smooth muscle cells within coronary artery plaques is recognized as a significant factor in the pathogenesis of ischemic heart disease [18<\/a>, 28<\/a>]. This pathophysiological mechanism may similarly elevate the risk of IS in cerebral blood vessels.<\/p>\n

Findings of this study indicated a potential association between the DD genotype of the ACE gene and elevated blood pressure, defined as SBP >140 mmHg or diastolic blood pressure >90 mmHg, with a prevalence of 38.2% in individuals with hypertension, compared to 33.4% in normotensive individuals. This trend has been reported across multiple populations [29<\/a>,30<\/a>,31<\/a>]; however, contrasting results have also been observed in some previous studies, which did not identify a similar association [32<\/a>, 33<\/a>]. These inconsistencies suggest that factors, such as geographic location, population heterogeneity, ethnicity, and other ecological variables, may influence genotype distribution. Furthermore, environmental factors, including nutrition and physical activity, are known to induce epigenetic modifications. The interplay between these epigenetic alterations and underlying genetic polymorphisms contributes to the complex genetic architecture of blood pressure regulation, potentially explaining the observed variability in association studies concerning the ACE I\/D gene polymorphism across diverse populations.<\/p>\n

This study had certain limitations that warrant consideration. The small sample size may have limited the statistical power to detect subtle associations between the ACE genotype and IS. Furthermore, the absence of serum ACE activity assays precluded a direct assessment of the functional consequences of the observed genotypes on circulating enzyme levels, potentially impacting the accuracy of the interpretation of the genotype-phenotype relationship. Additionally, the scope of this investigation was restricted by the analysis of a limited number of single-nucleotide polymorphisms. The genetic background and regional factors of the study participants from Eastern Iran may influence allele frequencies and disease associations. Unique ancestry, migration history, and environmental factors such as diet and lifestyle can affect genetic predispositions and disease risk, limiting the generalizability of our findings to other populations. Future studies with multi-regional, large cohorts, diverse genetics, and functional validation\u2014 including ACE enzyme activity and mRNA expression\u2014are needed to confirm our results and clarify their broader relevance.<\/p>\n","protected":false},"excerpt":{"rendered":"The IS is a multifactorial disorder with established risk factors encompassing both modifiable environmental influences and inherent genetic…\n","protected":false},"author":2,"featured_media":152211,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[85966,103,61,11829,60,21167,31111,6458,16282,56892],"class_list":{"0":"post-152210","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-angiotensin-converting-enzyme","9":"tag-health","10":"tag-ie","11":"tag-iran","12":"tag-ireland","13":"tag-ischemic-stroke","14":"tag-neurochemistry","15":"tag-neurology","16":"tag-neurosurgery","17":"tag-polymorphism"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/152210","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=152210"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/152210\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/152211"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=152210"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=152210"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=152210"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}