Genetics Markers of CHD Risk in Men and Women

描述(由申请人提供)：我们建议确定影响炎症和内皮功能障碍的几个基因的变异性是否与来自西部纽约健康研究的700名男性和229名绝经后女性的MI几率有关。我们将研究以下具体目标。1)我们假设急性心肌梗死患者C-反应蛋白基因座上的特定单倍型频率高于对照组(-732G/A)、1059G/C和+1444C/T水平相关的等位基因。与对照组相比，心肌梗塞患者的IL-6产生水平(-597G/A、-572G/C和-174G/C)水平的等位基因组成的单倍型频率更高，而IL1a/IL1 BILL1RN基因区的特异性单倍型频率更低；2)病例组E-选择素基因特定功能多态的等位基因和单倍型频率(128R和G98T)将高于对照组；3)利用DNA池策略快速筛选相关生物学途径中29个候选基因的大量单核苷酸多态(SNPs)，并测试选定的基因座与急性MI的风险；4)对于那些有关联证据的基因座，确定捕捉每个基因座变异的单倍型标签SNPs(HtSNPs)，并测试这些SNPs与单倍型和MI风险的关联性。次要目标将a)探索早产儿心肌梗死(55岁或以下)男性之间的上述联系，b)探索基因-基因和基因-环境的相互作用。在伊利县和尼亚加拉县(95%的合格病例，ICD9410-410.9)，心肌梗死患者在心肌梗死后平均4个月从医院记录审查中确定病例对象。他们在1996-2001年间接受了采访和检查。对照受试者随机从相同的县(应答率59.5%)选择，并进行同期临床检查。对照将按年龄、性别和种族与病例逐一配对。这种创新且具有成本效益的方法可能会对急性心肌梗死背后的遗传风险产生新的见解。

DESCRIPTION (provided by applicant): We propose to determine whether the variability in several genes that influence inflammation and endothelial dysfunction is related to the odds of MI among 700 men and 229 postmenopausal women from the Western New York Health Study. We will examine the following specific aims. 1) We hypothesize that cases of acute MI will have a higher frequency of specific haplotypes at the C-reactive protein locus composed of alleles associated with higher levels of CRP production (-732G/A), 1059G/C, and +1444C/T) than matched controls. MI cases will have a greater frequency of haplotypes composed of alleles associated with higher levels of IL-6 production (-597G/A, -572G/C, and -174G/C) than controls, and a lower frequency of specific !haplotypes in the IL1A/IL1 BILL1RN gene region; 2) cases will have a higher frequency of alleles and haplotypes for specific functional polymorphisms of the E-selectin gene ($128R and G98T) than controls; 3) to utilize DNA pooling strategy for rapid screening of large numbers of single nucleotide polymorphisms (SNPs) in 29 candidate genes in relevant biological pathways and test selected loci for association with risk of acute MI; 4) for those loci with evidence of association, to identify haplotype tagging SNPs (htSNPs) that capture the variation at each locus and test for association between these SNPs and haplotypes and risk of MI. Secondary aims will a) explore the above associations among men with premature MI (55 years of age or less) and b) explore gene- gene and gene- environment interactions. MI case subjects were identified from hospital record review in Erie and Niagara counties (95% of all eligible cases, ICD9 410-410.9) an average of 4 months post MI. They were interviewed and examined in 1996-2001. Control subjects were randomly selected from the same counties (59.5% response rate) and had a contemporaneous clinical exam. Controls will be individually matched to cases by age, sex, and ethnicity. This innovative and cost efficient method may yield new insights into the genetic risks underlying acute MI.