Epidemiology of Calcineurin Gene Polymorphisms, Serum Calcineurin, and LVH

描述（由申请人提供）：动物和人体研究的大量证据表明，钙调磷酸酶途径是左心室肥厚（LVH）发病机制的关键介质。先前的研究表明，参与这一途径的基因变异会增加LVH的风险。然而，因果变异尚未确定。此外，几乎所有与LVH相关的钙调磷酸酶途径原位激活的人类研究都是基于移植心脏的，目前还没有基于人群的研究报告来评估血清钙调磷酸酶蛋白水平和酶活性是否可以作为人类心脏中活化的钙调磷酸酶途径的生物标志物。本研究的目的是评估血清钙调磷酸酶蛋白和酶活性在人群水平上作为LVH生物标志物的效用，并确定与钙调磷酸酶通路相关的基因变异，这些基因会导致LVH的风险。利用家庭血压计划（FBPP）的高血压遗传流行病学网络-左心室肥厚遗传研究（HyperGEN- LVH）收集的基因型数据和标本，我们提出了四个目标：1)建立测定血清钙调磷酸酶蛋白水平和酶活性的方法，将该方法应用于1101名非裔美国高血压患者的血清样本，并测试蛋白质水平和酶活性与LVH之间的关系；2)对钙调神经磷酸酶通路4个候选基因（CnA1、CnA2、CnB1和MCIP1）的140个snp与血清钙调神经磷酸酶蛋白水平和酶活性的遗传关联进行研究；3)评估LVH与140个snp和另外9个NFATC4 snp的相关性，NFATC4是钙调磷酸酶的下游靶点，参与调节LVH； 4)在FBPP-GENOA网络中使用HyperGEN协议和阅读中心进行LVH表型分析的非裔美国人参与者中复制重要的遗传发现。我们期望本研究的结果将在人群水平上对LVH的遗传和分子机制有更深入的了解，并为高血压患者LVH的筛查试验和新的药物靶点提供新的机会。公共卫生相关性：本研究有望在人群水平上突破LVH的遗传和分子机制，并为LVH中钙调磷酸酶途径的流行病学研究提供新的机会。该项目也可能对临床试验的设计产生重大影响，以药物靶向钙调磷酸酶途径预防和治疗高血压受试者的LVH。

DESCRIPTION (provided by applicant): Abundant evidence from animal and human studies suggests that the calcineurin pathway is a key mediator in the pathogenesis of left ventricular hypertrophy (LVH). Previous studies suggest that variation in genes involved in this pathway contributes to the risk of LVH. However, causal variants have not been identified. In addition, almost all human studies of in-situ activation of the calcineurin pathway in relation to LVH were based on transplant hearts and there are no reports of population-based studies to evaluate whether serum calcineurin protein level and enzymatic activity can serve as biomarkers of activated calcineurin pathways in the human heart. The objective of the proposed study is to evaluate the utility of serum calcineurin protein and enzymatic activity as biomarkers for LVH at the population level and to identify variants in genes involved in the calcineurin pathway that contribute to the risk of LVH. Utilizing genotype data and specimens collected from the Hypertension Genetic Epidemiology Network - Genetics of Left Ventricular Hypertrophy Study (HyperGEN- LVH) of the Family Blood Pressure Program (FBPP), we propose four aims 1) to develop assays to measure serum calcineurin protein level and enzymatic activity, apply the assays to serum samples of 1101 hypertensive African Americans, and test associations between protein level and enzymatic activity with LVH; 2) to conduct a genetic association study of 140 SNPs in four candidate genes (CnA1, CnA2, CnB1, and MCIP1) involved in the calcineurin pathway with serum calcineurin protein level and enzymatic activity; 3) to evaluate associations of LVH with the 140 SNPs plus another 9 SNPs of NFATC4, which is a downstream target of calcineurin and participates in regulating LVH, and 4) to replicate significant genetic findings in the African-American participants from the FBPP-GENOA network who were phenotyped for LVH using the HyperGEN protocol and reading center. We anticipate that results from this study will provide greater understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for screening tests and novel pharmacological targets to prevent or treat LVH in hypertensive subjects. PUBLIC HEALTH RELEVANCE: The proposed study could lead to a breakthrough in the understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for epidemiological studies of the calcineurin pathway in LVH. This project could also have a major impact on the design of clinical trials to pharmacologically target the calcineurin pathway to prevent and treat LVH in hypertensive subjects.