Association between rs1761667 CD36 Polymorphism and Risk of Stroke in Korean Patients with Type 2 Diabetes
Stroke is a significant macrovascular complication that disproportionately affects patients with type 2 diabetes mellitus (T2DM). The prevalence of stroke in the general population is two to three times lower than among individuals with T2DM, where it accounts for 11.0% of all deaths. The pathophysiology of stroke involves complex processes, including oxidative stress, endothelial dysfunction, and pro-inflammatory responses. CD36, a scavenger receptor, plays a critical role in inflammation, innate immunity, and lipid metabolism, and has been implicated in the development of atherosclerosis. Despite its importance, the relationship between CD36 polymorphisms and stroke risk in patients with T2DM, particularly in relation to disease duration, remains underexplored. This study investigates the association between the rs1761667 single nucleotide polymorphism (SNP) in the CD36 gene and the risk of stroke in Korean patients with T2DM, stratified by disease duration.
The study included 759 patients with T2DM who visited Chungbuk National University Hospital between January 2015 and December 2018. The diagnosis of diabetes mellitus was based on the American Diabetes Association guidelines. Both microvascular complications (such as retinopathy, nephropathy, and peripheral neuropathy) and macrovascular complications (including cardiovascular disease, stroke, and peripheral artery disease) were evaluated. The rs1761667 CD36 polymorphism was genotyped using TaqMan probe-based real-time polymerase chain reaction (PCR). The genotyping process involved a mixture of PCR primers and fluorescent probes specific to rs1761667, with amplification conducted using a genotyping master mix. The PCR conditions included preheating at 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 60 seconds. Fluorescence was detected at the end of each cycle, and genotype data were automatically generated using a Bio-Rad CFX96 Real-Time PCR system. Genotypes were classified as GG, AG, or AA. The Hardy-Weinberg equilibrium was tested using the Chi-squared test, and data were expressed as means ± standard deviations for continuous variables or as percentages for categorical variables. Baseline characteristics were compared using Student’s t-test for continuous variables and the Chi-squared test for categorical parameters. Multiple logistic regression analyses were performed to evaluate risk factors associated with stroke, including age, body mass index (BMI), hypertension, hemoglobin A1c (HbA1c), and low-density lipoprotein (LDL)-cholesterol. All statistical analyses were conducted using SPSS for Windows, with significance set at P < 0.05. The study was approved by the Institutional Review Board of Chungbuk National University Hospital, and all participants provided written informed consent.
The genotypic distribution of CD36 rs1761667 met the Hardy-Weinberg equilibrium (P = 0.946). The frequency of the CD36 genotypes in the study population was as follows: GG, 51.5% (n = 391); AG, 40.4% (n = 307); and AA, 8.0% (n = 61). There were no significant differences in baseline characteristics between individuals with the GG genotype and those with the AG + AA genotypes. The mean age of the participants was 61.4 ± 12.4 years, and the mean BMI was 25.8 ± 3.8 kg/m². The mean duration of T2DM was 10.5 ± 7.9 years, and 55.2% of the study sample was male. Subgroup analyses were performed according to sex and duration of diabetes, revealing differences in clinical characteristics between men and women. However, no statistically significant differences were noted in the baseline characteristics of the female group based on the duration of diabetes.
The study found a higher prevalence of stroke among men with the AG + AA genotypes compared to those with the GG genotype (16.3% vs. 10.2%, respectively; P = 0.049). Further subgroup analysis based on the duration of diabetes revealed a significantly higher prevalence of stroke among patients with a T2DM duration of less than 10 years and the AG + AA genotypes compared to those with the GG genotype (18.0% vs. 4.8%, P = 0.001). Multiple logistic regression analysis for male patients with a diabetes duration of less than 10 years showed that the A allele was significantly associated with a higher risk of stroke (odds ratio 3.710, 95% confidence interval 1.148–9.709, P = 0.008) after adjusting for risk factors such as age, BMI, hypertension, HbA1c, and LDL-cholesterol. However, no significant differences in stroke prevalence were observed according to genotype among men with a diabetes duration of more than 10 years (15.7% vs. 16.0%, P = 0.946) or among women (AG + AA vs. GG, 8.1% vs. 5.9%, P = 0.435). Additionally, no association was found between the rs1761667 CD36 SNP and cardiovascular disease, peripheral artery disease, or microvascular complications in T2DM patients of either sex.
The findings of this study suggest that the rs1761667 CD36 polymorphism is associated with an increased risk of stroke in Korean men with T2DM, particularly in those with a relatively short duration of diabetes. Stroke is a major complication that worsens the prognosis of patients with T2DM and tends to occur at a younger age in this population compared to non-diabetic individuals. CD36 expression is upregulated in the presence of hyperglycemia, which may contribute to the increased risk of stroke. Previous studies have explored the association between CD36 polymorphisms and stroke in different populations. For example, Ikram et al. found that the CD36 rs3211928 polymorphism was significantly associated with stroke in Caucasian populations, while Zhang et al. reported that CD36 rs1761667 and rs3211928 polymorphisms may indicate a genetic susceptibility to ischemic stroke in Chinese Han populations. The present study extends these findings by being the first to investigate the relationship between the rs1761667 CD36 SNP and stroke in an Asian population with T2DM.
The role of CD36 in stroke pathology has been supported by several studies. CD36 is involved in the uptake of oxidized low-density lipoprotein (oxLDL), and polymorphisms in the CD36 gene may impair this process, leading to abnormal lipid metabolism and an increased risk of atherosclerosis and stroke. However, the exact mechanism by which the rs1761667 CD36 SNP influences CD36 expression and stroke risk remains unclear and warrants further investigation.
This study has several limitations. First, it did not evaluate direct CD36 expression according to genotype, which could provide more insight into the functional impact of the rs1761667 SNP. Second, the retrospective design of the study may have introduced recall bias or missing data, potentially leading to an underestimation of stroke prevalence. Additionally, the study did not assess the influence of the rs1761667 CD36 SNP on the clinical course of stroke. Despite these limitations, the study has notable strengths, including a relatively large sample size compared to previous studies and a comprehensive evaluation of both microvascular and macrovascular complications in T2DM patients.
In conclusion, this study demonstrates that the rs1761667 CD36 polymorphism is associated with an increased risk of stroke in Korean men with T2DM, particularly in those with a short duration of diabetes. These findings highlight the importance of genetic factors in the development of stroke in diabetic patients and suggest that further research is needed to validate these results in larger populations and to explore the underlying mechanisms. Future studies should also consider various parameters related to cerebrovascular disease to provide a more comprehensive understanding of the role of CD36 polymorphisms in stroke risk.
doi.org/10.1097/CM9.0000000000001501
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