Prognostic Value Of CRP Levels And CRP Gene Polymorphisms In Large-artery Atherosclerotic Stroke

Ischemic stroke(IS)is a heterogeneous multifactorial disease and multiple elements are correlated with its pathogenesis.Different inflammatory pathways may have different impacts on IS because of pathophysiological processes.Most of the previous studies did not consider the potential different etiological subtypes of IS.Relatively little data is available on the association of CRP levels and CRP gene with prognosis in different IS subtypes.Here,we conducted a prospective study in patients with large artery atherosclerotic(LAA)subtype to evaluate the relationship between CRP levels and 5 GWAS-supported CRP levels-related SNPs of CRP gene and the outcome after the stroke event.Part I Prognostic value of C-reactive protein in large-artery atherosclerotic strokeObjective:To investigate whether C-reactive protein(CRP)levels in the acute phase of large-artery atherosclerotic(LAA)stroke predict long-term functional disability and recurrent vascular events.Methods:Patients with first-ever LAA ischemic stroke were prospectively registered in Nanjing Stroke Registry Program(NSRP)between January 2012 and June 2014.Clinical data were collected for all patients and venous blood samples were also collected within 2 weeks after the index stroke.Patients were followed up for 1 year.The primary outcome was neurologic functional disability at 1 year.The modified Rankin scale(mRS)was performed for the assessment of neurologic functional disability.A score of 0 to 2 was considered as good outcome and 3 to 6 as poor outcome.The secondary outcome were major vascular events(TIA,recurrent IS,or acute myocardial infarction[MI]),whichever came first,during the 1-year follow-up.The Kaplan-Meier method was performed in survival analysis.Multiple logistic regression analysis and Cox proportional hazard model were applied to identify predictors of functional disability and recurrent vascular events,respectively.Results:A total of 625 eligible patients(458 males)were evaluated.During 1-year follow-up period,63 patients(45 males,18 females)had recurrent vascular events(including 9 TIA events,52 recurrent IS events and 2 MI events),53 lost to follow-up and 9 died.We tested CRP≤ median and>median mg/L as prespecified thresholds.We observed that CRP>2.40 mg/L was associated with poor functional prognosis(crude RR,2.59;95%CI,1.74-3.87).The positive result still existed after adjusting for potential confounders(adjusted RR,1.97;95%CI,1.21-3.21;P = 0.007).Furthermore,in sex-stratified analyses,CRP>2.40 mg/L increased the risk for poor functional prognosis both in male(adjusted RR,1.84;95%CI,1.02-3.31)and female(adjusted RR,2.68;95%CI,1.05-6.84).In multivariate logistic regression model,log-transformed CRP levels was associated with functional outcome in overall patients(adjusted RR,2.18;95%CI,1.32-3.60),both in male(adjusted RR,2.08;95%CI,1.14-3.81)and female(adjusted RR,2.70;95%CI,1.04-7.00).In univariate Cox regression model,CRP>2.40 mg/L was related with recurrent events(crude HR,1.73;95%CI,1.04-2.87).However,this association no longer existed after adjusting for potential risks(adjusted HR,1.53;95%CI,0.91-2.57).Stratified by sex,CRP>2.40 mg/L was not associated with recurrent events in female(adjusted HR,0.99;95%CI,0.38-2.54)or male(adjusted HR,1.86;95%CI,0.98-3.54).Also,no association was found between log-transformed CRP levels and recurrent events(adjusted HR,1.45;95%Cl,0.89-2.37).Conclusions:Elevated CRP levels are associated with poor functional disability in patients with LAA stroke at 1-year,both in male and female.No positive relationship was found between elevated CRP levels and recurrent vascular events.Part II CRP gene polymorphisms and functional outcome of large artery atherosclerotic strokeObjective:Elevated C-reactive protein(CRP)levels increase the risk of poor functional disability in patients with ischemic stroke(IS).This study aimed to investigate the association between CRP gene polymorphisms and 3-month functional disability of large artery atherosclerotic(LAA)stroke in Han Chinese.Methods:Patients with first-ever LAA IS were prospectively enrolled in Nanjing Stroke Registry Program(NSRP)between August 2013 and October 2015.Five single nucleotide polymorphisms(SNPs)(rs876537,rs2794520,rs3093059,rs7553007 and rs 11265260)in CRP gene related to CRP levels in Asian by genome-wide association study(GWAS)were genotyped.The functional outcome at 3 months after the index stroke was assessed by the modified Rankin scale(mRS).Associations between genotypes and functional outcome of LAA IS were analyzed with logistic regression model.Binary logistic regression models were applied to assess the association between SNPs and the risk of poor outcome after LAA IS.Linkage disequilibrium(LD)analysis and haplotypes were also analyzed.Results:A total of 690 eligible patients were evaluated.The mean age was 61.10 ±10.83 years,507(73.48%)were male.SNPs rs2794520(P = 0.014),rs3093059(P =0.012)and rs11265260(P = 0.006)were significantly associated with CRP levels in acute IS.Two SNPs,rs3093059(dominant model:adjusted OR 2.49;95%CI 1.55-4.00;recessive model:adjusted OR 3.67;95%Cl 1.22-11.03)and rs11265260(dominant model:adjusted OR 2.51;95%CI 1.56-4.02;recessive model:adjusted OR 4.70;95%CI 1.63-13.56),independently predicted 3-month poor outcome of first-ever LAA IS,after adjusting for age,sex,body mass index(BMI),hypertension,diabetes,dyslipidemia,smoking.The power of sample size for rs3093059 and rs11265260 were 0.802,0.851,respectively.The above significant results were still existed after Bonferroni correction(P<0.05/3).In addition,haplotype analysis indicated that after adjusted for age,sex,BMI,hypertension,diabetes,dyslipidemia,smoking,patients with TCCCC haplotype(OR = 2.54;95%CI,1.14-5.68;P = 0.023)and TACAC haplotype(OR = 2.40;95%CI,1.24-4.64;P = 0.009)had higher frequency of poor outcome when compared to those with CACAC haplotypeConclusions:SNPs rs3093059 and rs11265260 in CRP gene may influence the 3-month functional outcome of first-ever LAA IS in Han Chinese.