A Genetic Variant of miR-34a Contributes to Susceptibility of Ischemic Stroke Among Chinese Population

Abstract

miRNAs are small non-coding RNAs modulating gene expression, and variants in miRNA genes are involved in the pathogenesis of ischemic stroke (IS). However, the effect of miR-34a polymorphisms on IS susceptibility has rarely been reported. In the present study, we investigated the association between rs12128240, rs2666433, and rs6577555 of the miR-34a gene and IS susceptibility. Snapshot assay was used to detect miR-34a polymorphisms in 548 IS patients and 560 controls. Relative expression of miR-34a was measured by quantitative real-time PCR. We found that rs2666433 was associated with a significantly increased risk of IS (AA vs. GG: OR = 1.61, 95% CI = 1.05–2.52, P = 0.031; AA vs. GG+GA: OR = 1.58, 95% CI = 1.05–2.45, P = 0.026). For the IS subtypes, rs2666433 was associated with large artery atherosclerosis (AA vs. GG: OR = 2.09, 95% CI = 1.16–3.51, P = 0.007; AA vs. GG+GA: OR = 2.02, 95% CI = 1.15–3.33, P = 0.007; A vs. G: OR = 1.36, 95% CI = 1.07–1.81, P = 0.021). Additionally, the level of miR-34a was significantly up-regulated in IS patients compared to the controls ( P < 0.001), and patients with rs2666433 AA genotype had a higher level of miR-34a than those with GG+GA genotypes ( P < 0.001). Furthermore, increased level of homocysteine was observed in IS patients compared to the controls ( P < 0.001), especially in patients carrying the rs2666433AA genotype compared to those carrying the rs2666433 GG+GA genotypes ( P < 0.001). However, no significant association between rs12128240 or rs6577555 and IS was found. Collectively, our study found the association between miR-34a polymorphisms and the risk of IS among the Chinese population. The results may provide an explanation for etiology of IS and a potential biomarker or therapeutic target for IS. HIGHLIGHTS MiR-34a rs2666433 polymorphism was associated with an increased risk of ischemic stroke. The level of miR-34a was significantly up-regulated in ischemic stroke patients compared with controls, and patients with rs2666433 AA genotype had a higher level miR-34a than those with GG+GA genotypes. Furthermore, increased level of homocysteine was showed in IS patients compared to controls, and in patients carrying the rs2666433AA compared to those carrying the rs2666433 GG+GA.

Association of LncRNA‐GAS5 gene polymorphisms and PBMC LncRNA‐GAS5 level with risk of systemic lupus erythematosus in Chinese population

“…miRNA is a type of non‐coding RNA with a length of about 22 nt, which is the core molecule in the ceRNA hypothesis. It can promote the degradation of mRNAs or inhibit translation by binding with the 3′‐untranslated region (3′‐UTR) of target mRNA and further regulate a variety of biological behaviours 41 . Yan et al 42 found that lncRNA HIX003209 did not directly bind to TLR2, TLR4 and NF‐κB; however, it promoted TLR4/NF‐κB expression in macrophages through the sponge miR‐6089, which was critical for the development of rheumatoid arthritis.…”

Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: a pilot study

“…The present results revealed that MIR34A rs2666433 AA and AG genotype carriers were 5.7 and 2.8 more likely to develop cancer than GG carriers. A part of one recent publication related to the study of the MIR34A rs2666433 association with ischemic stroke in Chinese population 48 , the impact of this variant on CRC risk (or other types of cancer) has not been reported previously. Interestingly, we also found that nearly 43% of the cancer tissues showed a tendency for G to A shift, and a higher frequency of somatic mutation (92%) was observed in the adenocarcinoma subtype of CRC.…”

“…Recently, Sun et al, suggested that the rs2666433 variant may affect the binding of transcription factors to MIR34A promoter sequences 49 . Furthermore, Wei et al reported that ischemic stroke patients with rs2666433 (AA) genotype had a higher level of miR-34a than those with (GG + GA) genotypes 48 , suggesting that rs2666433 may influence miR-34a expression level in their population. However, we could not find a significant association between the specified microRNA variant and its tissue expression levels in the present samples.…”

“…Overall comparison and subgroup analyses were performed. Adjusted odds ratios (OR) with a 95% confidence interval (CI) was calculated to identify the strength of the association between the SNP and cancer risk under various genetic association models 48 ; allelic model (G versus A), homozygote comparison (GG versus AA), heterozygote comparison (AG versus AA), dominant model (GG + AG versus AA), and recessive model (GG versus AG + AA). The Wilcoxon matched-pair signed-rank test was carried out to compare the expression level between cancer samples and their corresponding adjacent non-cancer tissues.…”

A Functional Polymorphism in HIF-3α Is Related to an Increased Risk of Ischemic Stroke

“…Compared with the controls, the Hcy and NEFA serum levels among IS patients were significantly upregulated. Serum NEFA and Hcy were associated with atherosclerosis and IS formation, and high levels of Hcy and NEFA were correlated to poor prognosis in IS patients (Jickling and Spence 2014 ; Wei et al 2019 ). Wei (Wei et al 2019 ) found that serum Hcy levels were upregulated in IS patients, especially those carrying rs2666433 AA genotype.…”