【作者】 侯丽平；

【导师】 顾东风；

【作者基本信息】 中国协和医科大学 ， 流行病与卫生统计学， 2009， 博士

【摘要】 第一部分:PLA2G7脂蛋白相关磷脂酶A2（lipoprotein-associated phospholipase A2,Lp-PLA₂）是心血管疾病中一种新的炎症标记物,由PLA2G7基因编码。本研究中,我们从中国汉族人群中选取827例冠心病病例（包括512例心肌梗死病例）和947例年龄和性别匹配的对照,对PLA2G7基因中的8个单核苷酸多态性（single nucleotidepolymorphism,SNP）位点进行了基因分型。我们随机挑选了416例对照和689例冠心病病例（包括423例心肌梗死病例）进行血浆Lp-PLA₂活性的测定。结果显示冠心病组和心肌梗死组Lp-PLA₂活性（233.42±57.66和234.27±59.51 nmol/ml/min）显著高于对照组（211.47±58.61 nmol/ml/min）。使用logistic回归校正传统危险因素后,Lp-PLA₂活性每增加一个标准差,冠心病和心肌梗死的比值比分别为1.27（95%CI,1.07～1.50）和1.27（95%CI,1.05～1.54）。单点分析和单体型分析提示V279F和I198T多态与Lp-PLA₂的活性下降有关,但这两个SNP位点与冠心病之间不存在显著的关联。单变量和多变量分析均提示rs13210554多态的T等位基因增加中国汉族人群心肌梗死的患病风险。总之,本研究提示血浆Lp-PLA₂活性与中国汉族人群冠心病和心肌梗死独立相关。V279F和I198T多态显著降低Lp-PLA₂的活性,位于启动子区的rs13210554多态与心肌梗死显著关联。Lp-PLA₂活性可能影响中国汉族人群冠心病和心肌梗死的患病风险。第二部分:TNF肿瘤坏死因子α（tumor necrosis factor alpha,TNF-α）是一个主要的促炎细胞因子,可能参与心血管疾病的发病过程。TNF基因多态位点与冠心病的关联研究已有报道,但研究结果很不一致。本研究拟在中国汉族人群中全面分析TNF基因遗传变异与冠心病的关系。为发现新的SNP多态位点,随机挑选了48例冠心病病例,对包含TNF基因编码区及上下游各约1kb的4739个碱基对的区域进行了重测序。从7个发现的SNP位点中选择4个（-806C＞T、-308G＞A、-238G＞A和+467G＞A）,在804例冠心病病例（包括504例心肌梗死病例）和905例年龄和性别匹配的对照中进行了基因分型,进一步分析这些SNP位点与冠心病易感性间的关系。在整个样本中进行的分析未发现单个位点及单体型与冠心病存在显著的关联。但是,我们发现基因与吸烟之间存在显著的交互作用。在不吸烟个体中,与G/G基因型纯合子个体相比,-238G＞A多态的A等位基因携带者具有较低的冠心病患病风险（比值比0.48,95%CI 0.24～0.94,P=0.033）,心肌梗死的患病风险更低（比值比0.36,95%CI 0.15～0.88,P=0.026）。单体型分析进一步证实了单点分析的结果。另外,我们还发现在吸烟个体当中-806C＞T多态与心肌梗死存在显著的关联（P=0.039）。总之,本研究发现TNF基因与吸烟之间存在显著的交互作用。单点分析和单体型分析均提示-238G＞A多态的A等位基因能降低中国汉族人群不吸烟个体冠心病的患病风险。更多还原

【Abstract】 Section one:PLA2G7The human PLA2G7 gene encodes lipoprotein-associated phospholipase A2（Lp-PLA₂）, an emerging risk factor for cardiovascular diseases.In the present study,eight single nucleotide polymorphisms（SNPs） in the PLA2G7 gene were genotyped in 827 patients with coronary heart disease（CHD）,of which 512 were patients with myocardial infarction（MI）,and 947 age- and gender-matched controls in a Chinese Han population. Plasma Lp-PLA₂ activity was measured in 416 randomly selected controls and 689 randomly selected CHD patients,including 423 MI patients.Lp-PLA₂ activity in CHD and MI cases was significantly higher（233.42±57.66 and 234.27±59.51 nmol/ml/min,respectively） than in controls（211.47±58.61 nmol/ml/min）.After adjusting for traditional risk factors by logistic regression,the odds ratios for CHD and MI per 1 standard deviation increment of Lp-PLA₂ activity were 1.27（95%CI,1.07-1.50） and 1.27（95%CI, 1.05-1.54）,respectively.Both single SNP analysis and haplotype analysis showed that the V279F and I198T polymorphisms were significantly associated with the reduced Lp-PLA₂ activity but neither was associated with increased CHD risk.Both univariate and multivariate analyses,adjusting effects of conventional factors,indicated that the rs13210554 T allele increased the risk of MI in this Chinese Hart population.In summary,an independent association of increased plasma Lp-PLA₂ activity with CHD and MI existed in this Chinese Han Population.Although V279F and I198T mutations significantly decreased the activity of Lp-PLA₂,only the promoter rs13210554 polymorphism was associated with MI. Lp-PLA₂ activity appears to influence the CHD and MI risk in Chinese Han population.Section two:TNFTumor necrosis factor alpha（TNF-α） is a primary pro-inflammatory cytokines and has been implicated in cardiovascular disease pathogenesis.Relationship between polymorphisms in TNF gene and CHD has been reported,but remains a controversial one.A single nucleotide polymorphism（SNP） discovery in a total of 4739 base pairs in the promoter region,exon region and exon/intron boarding region of TNF gene in randomly selected 48 patients by direct sequencing was conducted.Four SNPs（-806C＞T,-308G＞A, -238G＞A,and +467G＞A） out of seven polymorphisms identified were further investigated for associations in 804 CHD patients（of which 504 patients with MI） and 905 age-and gender-matched controls.No main effects of loci and haplotypes reached statistical significance in the total sample.However,a significant gene-smoking interaction was observed. In nonsmokers,compared with individuals of G/G genotype,individuals carrying the A allele of the -238G＞A polymorphism showed a lower risk of developing CHD（odds ratio 0.48,95%CI 0.24-0.94,P=0.033）,and an even lower risk of developing MI（odds ratio 0.36,95%CI 0.15-0.88,P=0.026）.Haplotype analysis confirmed the results of individual polymorphism analyses.In addition,the -806C＞T polymorphism was found to be associated with MI in smokers（P=0.039）.This study identified a significant interaction between TNF gene and smoking status.Both single locus and haplotype analyses indicated that A allele of the -238G＞A polymorphism decreased the risk of CHD among nonsmokers in Chinese Han population.更多还原