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纽约健康研究的700名男性和229名绝经后女性的心肌梗死几率有关。我们将研究以下具体目标。1)我们假设急性心肌梗死病例在C反应蛋白位点上的特定单倍型频率高于匹配对照组，该位点由与高水平CRP产生（-732G/ a）、1059G/C和+1444C/T)相关的等位基因组成。与对照组相比，心肌梗死病例中由高水平IL-6产生相关的等位基因组成的单倍型（-597G/ a， -572G/C和-174G/C）的频率更高，特异性！IL1A/IL1 BILL1RN基因区域的单倍型；2) e -选择素基因（$128R和G98T）特异性功能多态性的等位基因和单倍型频率高于对照组；3)利用DNA池策略快速筛选相关生物学通路中29个候选基因的大量单核苷酸多态性（snp），并检测与急性心肌梗死风险相关的选定位点；4)对于那些有关联证据的位点，鉴定捕获每个位点变异的单倍型标记snp （htsnp)，并检测这些snp与单倍型和心肌梗死风险之间的关联。次要目标将是a)探索上述早发心肌梗死男性（55岁或以下）之间的关联，b）探索基因-基因和基因-环境的相互作用。从伊利和尼亚加拉县的医院记录审查中确定心肌梗死病例受试者（占所有合格病例的95%，ICD9 410-410.9），平均在心肌梗死后4个月。他们在1996-2001年接受了访谈和检查。对照受试者随机从同一县（有效率59.5%）中选取，并进行同期临床检查。对照将按年龄、性别和种族分别与病例匹配。这种创新和成本效益的方法可能会对急性心肌梗死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.