PPARδ基因多态性与大动脉粥样硬化型脑梗死关系
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摘要
目的探讨过氧化物酶体增殖物激活受体δ(PPARδ)基因多态性与大动脉粥样硬化(LAA)型脑梗死的关系。方法应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测270例山东汉族LAA型脑梗死病人及236例同期健康体检者(对照组)PPARδ基因rs9794和rs2267668位点的基因型,采用Logistic回归模型分析PPARδ基因多态性与LAA型脑梗死的关系。结果脑梗死组和对照组rs9794位点的GG/GC基因型频率分别为30.37%(82/270)和44.07%(104/236),G等位基因频率分别为17.59%(95/540)和24.15%(114/472),脑梗死组rs9794位点的GG/GC基因型及G等位基因频率明显低于对照组(OR=0.554,95%CI=0.384～0.798,P<0.05;OR=0.670,95%CI=0.494～0.910,P<0.05);两组rs2267668位点基因型及等位基因频率比较差异无统计学意义(P>0.05)。多因素Logistic回归分析显示,PPARδ基因rs9794位点的GG/GC基因型是LAA型脑梗死的保护因素(OR=0.616,95%CI=0.407～0.932,P<0.05);rs9794和rs2267668位点多态性与LAA型脑梗死病人血管狭窄部位无关(P>0.05);不吸烟(OR=0.538,95%CI=0.348～0.832,P<0.05)、无高血压史(OR=0.328,95%CI=0.181～0.595,P<0.05)、无糖尿病史(OR=0.528,95%CI=0.332～0.841,P<0.05)、无冠心病史(OR=0.418,95%CI=0.279～0.627,P<0.05)人群PPARδ基因rs9794位点GG/GC基因型者发生LAA型脑梗死的危险性明显降低。结论 PPARδ基因rs9794位点G等位基因降低了LAA型脑梗死的易感性,在脑梗死的发生发展中可能是保护因素;吸烟史、高血压史、糖尿病史和冠心病史等传统危险因素减弱了rs9794位点GG/GC基因型对脑梗死的保护作用。
Objective To investigate the association between peroxisome proliferator activated receptorδ(PPARδ)gene polymorphism and large-artery atherosclerotic(LAA)cerebral infarction. Methods A total of 270 Chinese Han patients in Shandong,China,who were diagnosed with LAA cerebral infarction(cerebral infarction group)and 236 healthy individuals who underwent physical examination during the same period(control group)were enrolled,and polymerase chain reaction-restriction fragment length polymorphism was used to determine the genotypes of rs9794 and rs2267668 of the PPARδgene.A logistic regression model analysis was used to investigate the association between PPARδgene polymorphisms and LAA cerebral infarction.Results Compared with the control group,the cerebral infarction group had significantly lower GG/GC genotype and G allele frequencies of rs9794 GG/GC genotype:30.37%(82/270)vs 44.07%(104/236),(OR=0.554,95%CI=0.384-0.798,P<0.05);G allele:17.59%(95/540)vs 24.15%(114/472),(OR=0.670,95%CI=0.494-0.910,P<0.05).There were no significant differences in the genotype and allele frequencies of rs2267668 between the two groups(P>0.05).The multivariate logistic regression analysis showed that GG/GC genotype of rs9794 of the PPARδgene was a protective factor against LAA cerebral infarction(OR=0.616,95%CI=0.407-0.932,P<0.05).Polymorphisms of rs9794 and rs2267668 were not asso-ciated with the site of vascular stenosis in patients with LAA cerebral infarction.Among the people with GG/GC genotype of rs9794 of the PPARδgene,the individuals who did not smoke(OR=0.538,95%CI=0.348-0.832,P<0.05)or had no history of hypertension(OR=0.328,95%CI=0.181-0.595,P<0.05),diabetes(OR=0.528,95%CI=0.332-0.841,P<0.05),or coronary heart disease(OR=0.418,95%CI=0.279-0.627,P<0.05)had a significant reduction in the risk of cerebral infarction. Conclusion The G allele of rs9794 of the PPARδgene reduces the susceptibility to LAA cerebral infarction and may be a protective factor in the development and progression of cerebral infarction.The risk factors including the histories of smoking,hypertension,diabetes,and coronary heart disease weaken the protective effect of GG/GC genotype of rs9794 against cerebral infarction.
Objective To investigate the association between peroxisome proliferator activated receptorδ(PPARδ)gene polymorphism and large-artery atherosclerotic(LAA)cerebral infarction. Methods A total of 270 Chinese Han patients in Shandong,China,who were diagnosed with LAA cerebral infarction(cerebral infarction group)and 236 healthy individuals who underwent physical examination during the same period(control group)were enrolled,and polymerase chain reaction-restriction fragment length polymorphism was used to determine the genotypes of rs9794 and rs2267668 of the PPARδgene.A logistic regression model analysis was used to investigate the association between PPARδgene polymorphisms and LAA cerebral infarction.Results Compared with the control group,the cerebral infarction group had significantly lower GG/GC genotype and G allele frequencies of rs9794 GG/GC genotype:30.37%(82/270)vs 44.07%(104/236),(OR=0.554,95%CI=0.384-0.798,P<0.05);G allele:17.59%(95/540)vs 24.15%(114/472),(OR=0.670,95%CI=0.494-0.910,P<0.05).There were no significant differences in the genotype and allele frequencies of rs2267668 between the two groups(P>0.05).The multivariate logistic regression analysis showed that GG/GC genotype of rs9794 of the PPARδgene was a protective factor against LAA cerebral infarction(OR=0.616,95%CI=0.407-0.932,P<0.05).Polymorphisms of rs9794 and rs2267668 were not asso-ciated with the site of vascular stenosis in patients with LAA cerebral infarction.Among the people with GG/GC genotype of rs9794 of the PPARδgene,the individuals who did not smoke(OR=0.538,95%CI=0.348-0.832,P<0.05)or had no history of hypertension(OR=0.328,95%CI=0.181-0.595,P<0.05),diabetes(OR=0.528,95%CI=0.332-0.841,P<0.05),or coronary heart disease(OR=0.418,95%CI=0.279-0.627,P<0.05)had a significant reduction in the risk of cerebral infarction. Conclusion The G allele of rs9794 of the PPARδgene reduces the susceptibility to LAA cerebral infarction and may be a protective factor in the development and progression of cerebral infarction.The risk factors including the histories of smoking,hypertension,diabetes,and coronary heart disease weaken the protective effect of GG/GC genotype of rs9794 against cerebral infarction.
引文
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[8]HOLZAPFEL J,HEUN R,LUTJOHANN D,et al.PPARDhaplotype influences cholesterol metabolism but is no risk factor of Alzheimer’s disease[J].Neuroscience Letters,2006,408(1):57-61.
[9]LU L,WU Y,QI Q B,et al.Associations of type 2diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese[J].PLoSOne,2012,7(4):e34895.
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[12]SKOGSBERG J,KANNISTO K,ROSHANI L,et al.Characterization of the human peroxisome proliferator activated receptor delta gene and its expression[J].International Journal of Molecular Medicine,2000,6(1):73-81.
[13]RISERUS U,SPRECHER D,JOHNSON T,et al.Activation of peroxisome proliferator-activated receptor(PPAR)delta promotes reversal of multiple metabolic abnormalities,reduces oxidative stress,and increases fatly acid oxidation in moderately obese men[J].Diabetes,2008,57(2):332-339.
[14]IWASHITA A,MURAMATSU Y,YAMAZAKI T,et al.Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo[J].Journal of Pharmacology and Experimental Therapeutics,2007,320(3):1087-1096.
[15]YIN K J,DENG Z,HAMBLIN M,et al.Peroxisome proliferator-activated receptor delta regulation of miR-15ain ischemia-induced cerebral vascular endothelial injury[J].The Journal of Neuroscience:the Official Journal of the Society for Neuroscience,2010,30(18):6398-6408.
[16]BENETTI E,PATEL N S,COLLINO M.The role of PPAR-beta/delta in the management of metabolic syndrome and its associated cardiovascular complications[J].Endocrine,Metabolic&Immune Disorders Drug Targets,2011,11(4):273-284.
[17]DING X,YUAN H,GU R,et al.The association of peroxisome proliferator-activated receptorδand additional gene-gene interaction with C-reactive protein in Chinese population[J].International Journal of Endocrinology,2016,2016(1):8597085.
[18]LI Y B,SUN G Q.Case-control study on association of peroxisome proliferator-activated receptor-delta and SNP-SNP interactions with essential hypertension in Chinese Han population[J].Functional&Integrative Genomics,2016,16(1):95-100.
[19]WANG Y J,ZHAO X Q,LIU L P,et al.Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China:the Chinese Intracranial Atherosclerosis(CICAS)Study[J].Stroke,2014,45(3):663-669.
[20]LIU C Y,CHEN C Q.Intra-and extracranial atherosclerotic stenosis in China:epidemiology,diagnosis,treatment and risk factors[J].European Review for Medical and Pharmacological Sciences,2014,18(22):3368-3379.
[21]GRUNDY S M.Inflammation,hypertension,and the metabolic syndrome[J].JAMA-Journal of the American Medical Association,2003,290(22):3000-3002.
[2]MUKHERJEE D,PATIL C G.Epidemiology and the global burden of stroke[J].World Neurosurgery,2011,76(6,S):S85-S90.
[3]WANG Y,ZHAO X,LIU L,et al.Prevalence and outcomes of symptomatic intracranial large artery stenosis and occlusions in China:the Chinese Intracranial Atherosclerosis(CICAS)Study[J].Stroke,2014,45(3):663-669.
[4]WINTHER M,KANTERS E,KRAAL G,et al.Nuclear factor kappaB signaling in atherogenesis[J].Arteriosclerosis,Thrombosis,and Vascular Biology,2005,25(5):904-914.
[5]FEIGE J N,GELMAN L,MICHALIK L,et al.From molecular action to physiological outputs:peroxisome proliferatoractivated receptors are nuclear receptors at the crossroads of key cellular functions[J].Progress in Lipid Research,2006,45(2):120-159.
[6]CHEANG W S,FANG X,TIAN X Y.Pleiotropic effects of peroxisome proliferator-activated receptor gamma and delta in vascular diseases[J].Circulation Journal:Official Journal of the Japanese Circulation Society,2013,77(11):2664-2671.
[7]BRUNELLI L,CIESLIK K A,ALCORN J L,et al.Peroxisome proliferator-activated receptor-delta upregulates 14-3-3epsilon in human endothelial cells via CCAAT/enhancer binding protein-beta[J].Circulation Research,2007,100(5):e59-e71.
[8]HOLZAPFEL J,HEUN R,LUTJOHANN D,et al.PPARDhaplotype influences cholesterol metabolism but is no risk factor of Alzheimer’s disease[J].Neuroscience Letters,2006,408(1):57-61.
[9]LU L,WU Y,QI Q B,et al.Associations of type 2diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese[J].PLoSOne,2012,7(4):e34895.
[10]中华医学会神经病学分会,中华医学会神经病学分会脑血管病学组.中国急性缺血性脑卒中诊治指南2014[J].中华神经科杂志,2015,48(4):246-257.
[11]ADAMS H P,BENDIXEN B H,KAPPELLE L J,et al.Classification of subtype of acute ischemic stroke.Definitions for use in a multicenter clinical trial.TOAST.Trial of Org 10172in acute stroke treatment[J].Stroke,1993,24(1):35-41.
[12]SKOGSBERG J,KANNISTO K,ROSHANI L,et al.Characterization of the human peroxisome proliferator activated receptor delta gene and its expression[J].International Journal of Molecular Medicine,2000,6(1):73-81.
[13]RISERUS U,SPRECHER D,JOHNSON T,et al.Activation of peroxisome proliferator-activated receptor(PPAR)delta promotes reversal of multiple metabolic abnormalities,reduces oxidative stress,and increases fatly acid oxidation in moderately obese men[J].Diabetes,2008,57(2):332-339.
[14]IWASHITA A,MURAMATSU Y,YAMAZAKI T,et al.Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo[J].Journal of Pharmacology and Experimental Therapeutics,2007,320(3):1087-1096.
[15]YIN K J,DENG Z,HAMBLIN M,et al.Peroxisome proliferator-activated receptor delta regulation of miR-15ain ischemia-induced cerebral vascular endothelial injury[J].The Journal of Neuroscience:the Official Journal of the Society for Neuroscience,2010,30(18):6398-6408.
[16]BENETTI E,PATEL N S,COLLINO M.The role of PPAR-beta/delta in the management of metabolic syndrome and its associated cardiovascular complications[J].Endocrine,Metabolic&Immune Disorders Drug Targets,2011,11(4):273-284.
[17]DING X,YUAN H,GU R,et al.The association of peroxisome proliferator-activated receptorδand additional gene-gene interaction with C-reactive protein in Chinese population[J].International Journal of Endocrinology,2016,2016(1):8597085.
[18]LI Y B,SUN G Q.Case-control study on association of peroxisome proliferator-activated receptor-delta and SNP-SNP interactions with essential hypertension in Chinese Han population[J].Functional&Integrative Genomics,2016,16(1):95-100.
[19]WANG Y J,ZHAO X Q,LIU L P,et al.Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China:the Chinese Intracranial Atherosclerosis(CICAS)Study[J].Stroke,2014,45(3):663-669.
[20]LIU C Y,CHEN C Q.Intra-and extracranial atherosclerotic stenosis in China:epidemiology,diagnosis,treatment and risk factors[J].European Review for Medical and Pharmacological Sciences,2014,18(22):3368-3379.
[21]GRUNDY S M.Inflammation,hypertension,and the metabolic syndrome[J].JAMA-Journal of the American Medical Association,2003,290(22):3000-3002.