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PECAM-1 gene polymorphism (rs668) and subclinical markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

ABSTRACT: The platelet endothelial cell adhesion molecule 1 (PECAM-1) plays an important role in many inflammatory processes, including the development of atherosclerosis. Polymorphism rs668 of the PECAM-1 gene (373C/G) is functional, and it was reported to be associated with increased serum levels of PECAM-1. We investigated the association between the rs668 polymorphism of PECAM-1 and subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). Five hundred and ninety-five T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Geno-typing of the PECAM-1 gene polymorphism (rs668) was performed using KASPar assays. The control examinations were performed 3.8 ± 0.5 years after the initial examination. Higher CIMT was found in patients with T2DM in comparison with subjects without T2DM. Statistically sig-nificantly faster progression of the atherosclerotic markers was shown in subjects with T2DM in comparison with the control group. When adjusted to other risk factors, the rs668 GG genotype was associated with an increased risk of carotid plaques in subjects with T2DM. We concluded that our study demonstrated a minor effect of the rs668 PECAM-1 on markers of carotid atherosclerosis in subjects with T2DM.

SUBMITTER: Popovic D

PROVIDER: S-EPMC5026281 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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<i>PECAM-1</i> gene polymorphism (rs668) and subclinical markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

Popović D D Nikolajević Starčević J J Šantl Letonja M M Makuc J J Cokan Vujkovac A A Reschner H H Bregar D D Petrovič D D

Balkan journal of medical genetics : BJMG 20160701 1

The platelet endothelial cell adhesion molecule 1 (PECAM-1) plays an important role in many inflammatory processes, including the development of atherosclerosis. Polymorphism rs668 of the <i>PECAM-1</i> gene (373C/G) is functional, and it was reported to be associated with increased serum levels of PECAM-1. We investigated the association between the rs668 polymorphism of PECAM-1 and subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). Five hundred and ...[more]

PMID: 27785409

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Project description:Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA). We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10-16, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors. Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10-7) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10-5), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects. We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.MethodsThe MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.ResultsIn a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.ConclusionOur study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.Trial registrationThe MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Dataset Information

PECAM-1 gene polymorphism (rs668) and subclinical markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

Publications

<i>PECAM-1</i> gene polymorphism (rs668) and subclinical markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

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