Abstract
Long noncoding RNAs (lncRNAs) serve as regulators or effectors of the p53 regulatory pathway. The lncRNA-p53 regulatory network plays an important role in ischemia-induced apoptosis and may be important for post-stroke recovery. Eight genetic variants of p53-related lncRNAs were genotyped in 982 patients to explore the association of single nucleotide polymorphisms (SNPs) in the genes related to the p53 regulatory pathway with ischemic stroke (IS) prognosis in a northern Chinese population. Long- and short-term outcomes were assessed by stroke recurrence and modified Rankin Scale score 3 months after stroke, respectively. We first identified that p53 rs1042522 and LINC-ROR rs2027701 could be associated with IS recurrence risk. On further cumulative effect analysis, we found that these two polymorphisms could jointly be associated with IS recurrence. Patients carrying 2-4 risk alleles showed a significantly higher IS recurrence risk than those harboring no or a single risk allele. In contrast to rs2027701 and rs1042522, the other SNPs were not associated with IS recurrence. Subsequently, we found that TUG1 rs2240183 CC genotype was associated with a favorable IS outcome after adjusting for confounding factors. However, the other seven genetic variants of p53-related lncRNAs were not associated with a functional outcome after stroke. p53 rs1042522 and LINC-ROR rs2027701 may exert combined effects on IS recurrence, and TUG1 rs2240183 may be a new biomarker to predict short-term IS outcomes as it modulates p53-mediated apoptosis.
Highlights
P53 Related Lncrnas Polymorphisms And Ischemic Stroke Recurrence p53 rs1042522 was associated with ischemic stroke recurrence risk under dominant model (95%CI = 1.099–2.527,p = 0.016,OR = 1.666) not under recessive model (95%CI = 0.727–1.643,p = 0.669, OR = 1.093 ).Subjects who carrying CG + GG have higher IS recurrence risk.We identified that LINC-ROR rs2027701 was related with IS recurrence risk.The GG genotype of LINC-ROR rs2027701 was increased the risk of ischemic stroke recurrence under recessive model (95%CI = 1.070–2.311,p = 0.021,OR = 1.573) .In contrast to rs2027701 and rs1042522, other SNP rs937283, rs4713998,rs3743773, rs1059698,rs2240183 and rs13281615 was not associated with IS recurrence risk. (Table 3–4,Fig. 2)
Based on the above findings, we explored the cumulative effect of lncRNA-p53 regulatory pathway SNPs on IS recurrence risk.The combined effects of the two polymorphisms was accessed according to the number of risk alleles.Patients were classified into two groups according to the number of risk alleles(rs2027701 G and rs1042522 G allele).Patients with 2–4 risk alleles had 1.732-fold (95%CI = 1.1882.500,p = 0.004) increased risk of IS recurrence relative to those with 0–1 risk alleles.Our results showed that subjects carrying more than 1 risk allele had higher recurrence risk of IS than patients with 0–1 risk allele(Table 5)
We first identified for that P53 rs1042522 and LINC-ROR rs2027701 may correlate with the risk of IS recurrence.In our further cumulative effect analysis, we found that these two polymorphisms may jointly be associated with IS recurrence.Patients carrying 2–4 risk alleles had significantly increased risk of IS recurrence compared with those carrying 0–1 risk alleles.Our study indicated that LINC-ROR-p53 interaction plays a role in the prognosis of IS
Summary
Ischemic stroke(IS) making up 2/3 stroke is main mortality and disability in China, bring heavy financial and mental burden to society and family[1].Thorough understanding about the pathophysiology of stroke is necessary.Functional recovery after stroke is decided by post-stroke neuronal damage,which are related by pathophysiological process.Currently, it is reported that the mechanisms of post-stroke injury include inflammation, apoptosis of penumbra, excitotoxicity and oxidative stress[2,3].Neuron apoptosis is main reason for penumbra damage[2,3].Identification the effect of different genetic background on apoptosis would provide a new path for IS prognosis.Long noncoding RNAs (lncRNAs) are a class of more than 200 nucleoties RNA that barely involved in protein coding but regulating gene expression at post-transcriptional and transcriptional levels, epigenetic regulation, chromatin modification[4].Our previous review have indicated that the lncRNAs expression profile was altered in MCAO animal models and blood of IS patients[5]. LncRNAs has found to be play vital roles in pathophysiological processes of IS and post-stroke recovery by regulating apoptosis[6,7]. The expression levels of lncRNAs pRlncRNA-1, LincRNA-P21, LINC-PINT, Taurine Upregulated Gene 1(TUG1) and Regulator of reprogramming(LINC-ROR) are regulated by p53 and are p53 effectors [12,13,14,15,16]. We highlight several lncRNAs related to the p53 pathway and determine whether lncRNA-p53 regulatory network SNP are associated with prognosis of IS
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